Interatrial shunt with physiological sensor

Abstract

An inter-atrial shunt with an integrated physiological sensor is provided for monitoring and treating cardiovascular syndromes including heart failure and pulmonary hypertension, where one or more sensors are attached to the shunt and measure physiological parameters within the inter-atrial shunt. The shunt may include an anchor having a first flared region, a second flared region, and a neck region disposed between the first flared region and the second flared region, and a biocompatible cover disposed on the anchor and forming a lumen. The one or more sensors may be pivotally coupled to the first flared region such that the one or more sensors may transition between a delivery configuration and a deployed configuration in which a sensing surface of the one or more sensors is in fluid communication with the lumen.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Patent Application No. 17 / 649,331, filed January 28, 2022, the entire contents of which are incorporated herein by reference. This application is also related to U.S. Patent Application No. 17 / 098,251, filed November 13, 2020, now U.S. Patent No. 11,234,702, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to devices and methods for regulating pressure within the circulatory system, and in particular to regulating blood pressure within the heart using an interatrial shunt having a physiological sensor. [Background technology]

[0003] There remain numerous cardiovascular and anxiety disorders with millions of patients with largely unmet clinical therapeutic needs. These disorders include, but are not limited to, syndromes known as heart failure (HF) and pulmonary arterial hypertension (PAH). Despite decades of advances in therapy, the majority of these patients have severely limited quality of life, including disabling symptoms, poor exercise tolerance, inability to perform work, recurrent hospitalizations for acute exacerbations, and unacceptably high mortality rates. This remains true even when patients are treated with the most beneficial optimal treatment regimens known as guideline directed medical therapy (GDMT). The present disclosure describes apparatus and methods for treating this broad group of disorders using an interatrial shunt device combined with an implantable physiological sensor. Heart failure and pulmonary arterial hypertension

[0004] Heart failure (HF) is defined as a pathophysiological condition in which the heart cannot pump enough blood to meet the body's demands, which in turn requires higher internal filling pressures. Most patients with HF suffer primarily from left ventricular (LV) failure, but right ventricular (RV) failure may be present as well, although usually to a lesser extent. The syndrome of HF results from the development of underlying heart disease, most commonly ischemic heart disease, systemic hypertension, diabetes, idiopathic cardiomyopathy, valvular heart disease, myocarditis, followed by a number of other less common causes.

[0005] HF affects 6 million Americans and over 26 million people worldwide. The prevalence of HF within the US population approximately doubles every decade of life. In the US, there are currently 870,000 newly diagnosed cases and 308,000 deaths per year. There are over 1 million hospitalizations per year, with acute decompensated heart failure (ADHF) being the leading cause of hospitalization. In addition, there are approximately 700,000 emergency department visits and at least 6 million doctor's office / clinic visits, which add social, logistical, and economic burdens to the system. In the coming decades, HF is expected to become an increasingly large health care problem as the population ages. HF is an incurable disorder in most cases.

[0006] Traditionally associated with reduced LV systolic function (a poorly contracting LV), it is now recognized that HF ​​also commonly occurs with normal or only mildly reduced contraction, where the problem is an overly stiff ventricle that has difficulty filling during diastole. LV systolic function is assessed by the ejection fraction (LVEF), which is the volume of blood ejected during systole divided by the end-diastolic volume. LVEF usually averages about 60%. HF is therefore divided into two clinical syndromes: heart failure with reduced ejection fraction (HFrEF), where LVEF is <40%, and heart failure with preserved ejection fraction (HFpEF), where LVEF is by some definition at least 40%. HFpEF patients tend to be older and more frequently female, hypertensive, and diabetic than patients with HFrEF. The prevalence of ADHF hospitalization is almost evenly split between HFpEF and HFrEF.

[0007] Regardless of LVEF and evidence-based treatment with guideline-directed medical therapy (GDMT), most patients have a progressive course characterized by worsening symptoms, ADHF hospitalization, and death. Patients hospitalized with ADHF have a 4% in-hospital mortality, a 10% 90-day mortality, and a 30% 1-year mortality rate according to a large registry study. Shah et al. analyzed 39,982 patients aged 65 years or older hospitalized with HF. Regardless of LVEF, 5-year mortality was 75% on average, and more than 96% either died or were re-hospitalized during follow-up. Hospitalization for ADHF is associated with high re-hospitalization rates and increased mortality. Re-hospitalization rates are 25% at 30 days and 50% by 6 months. With recurrent HF hospitalization, there is an increased risk of mortality. Median survival after the first, second, third, and fourth HF hospitalizations is 2.4, 1.4, 1.0, and 0.6 years, respectively. Overall, it will be appreciated that a therapy that successfully prevents ADHF-related hospitalization would likely increase life expectancy.

[0008] Outpatient GDMT for HFrEF focuses on giving the maximum tolerated dose of a medication category that reduces morbidity and mortality in large randomized clinical trials. These drugs include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, neprilysin inhibitors, beta-antagonists, mineralocorticoid inhibitors, ivabradine, and the soon to be sodium glucose cotransporter 2 inhibitors. However, in most cases, benefit is limited to patients with mild symptoms (New York Heart Association Class II). To achieve the best outcomes, drugs must be frequently titrated up or down to tolerance. These drugs are less effective at controlling symptoms, especially dyspnea (shortness of breath) on exertion or at rest. Chronic symptoms are best managed with oral diuretics, usually potent loop diuretics such as furosemide, and in some cases with the addition of a long-acting nitrate. ADHF may be treated with fluid removal with intravenous loop diuretics. Diuretic dosing, whether oral or parenteral, is highly empirical and often difficult to manage, and its excessive use is associated with dehydration, renal dysfunction, electrolyte imbalance, and death.

[0009] Several devices have evidence-based utility in HFrEF, including cardiac resynchronization therapy (CRT or biventricular pacing) with or without an implantable cardioverter-defibrillator (ICD), percutaneous mitral valve repair with the MitraClip device in patients with severe functional mitral regurgitation and moderate LV dysfunction, and ventricular assist devices for patients with end-stage disease.

[0010] HFpEF is different. Randomized trials of any of the medications or devices mentioned above have not met their primary endpoints. GDMT for HFpEF is limited to management of underlying predisposing conditions such as hypertension, atrial fibrillation, and treatment of symptoms and acute exacerbations with diuretics.

[0011] Precipitating factors associated with ADHF are dietary and medication non-compliance, reluctance to seek medical attention, inadequate therapy, and acute exacerbation of underlying cardiovascular disorders such as acute ischemic syndrome or hypertensive crisis. These factors either increase total body fluid volume by causing sodium and water retention by the kidneys, or they redistribute fluid from the splanchnic to the pulmonary venous volumetric bed, or both. Excess volume increases left-sided hydrostatic pressures, including left atrial pressure (LAP) and left ventricular end-diastolic pressure (LVEDP). Elevated hydrostatic pressure is the primary driving force for fluid transudation from pulmonary capillaries and veins into the pulmonary interstitium and ultimately into the alveolar airspaces, known as pulmonary edema. Approximately 90% of ADHF hospitalizations present with symptoms, signs, or laboratory values ​​of pulmonary congestion. Once ADHF develops, respiratory symptoms such as tachypnea and dyspnea become predominant. Ultimately, if this process is not reversed, severe pulmonary edema will ensue and there is an increased likelihood of death.

[0012] Normal LAP ranges from 6 to 12 mmHg. Since the early 1970s, Swan-Ganz catheter measurements of pulmonary capillary wedge pressure (PCWP) have served as an approximation of LAP. When PCWP elevation is sustained above 25 mmHg in patients with no history of HF, pulmonary edema develops within hours. Patients with chronic heart failure can tolerate higher filling pressures (30 to 35 mmHg) due to increased lymphatic drainage of the lungs. HF patients with elevated cardiac filling pressures are at increased risk for hospitalization and mortality, while other hemodynamic parameters such as right atrial pressure, pulmonary artery pressure, systemic arterial pressure, cardiac index, and systemic vascular resistance are less predictive.

[0013] Turning now to PAH, WHO clinical group I pulmonary hypertension, more commonly known as pulmonary arterial hypertension (PAH), is a rare but serious and complex set of clinical disorders. Prevalence in the United States ranges from 0.4 to 1.2 cases per 10,000 population, affecting approximately 13,000 to 40,000 patients. The average age at diagnosis is 50 to 65 years, with female patients predominating. One-half of patients have idiopathic (IPAH), including a minority with hereditary forms of PAH. The remainder have associated conditions (APAH), where the underlying etiology is most commonly a connective tissue disorder, primarily systemic sclerosis (scleroderma) among these. A small percentage of cases have other associated causes as their etiology, including drug-induced PAH, congenital heart disease (corrected and uncorrected), portal hypertension, and HIV. PAH is characterized by precapillary hypertension, with mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, PCWP or LAP ≤ 15 mmHg, and pulmonary vascular resistance (PVR) usually ≥ 3 Wood units. The early pathological basis of PAH is lesions of the distal pulmonary arteries (diameter < 500 μm), including medial hypertrophy, intimal proliferative fibrotic changes, and adventitial thickening with perivascular inflammatory infiltrates. Late findings are more complex lesions (plexiform, ectatic lesions) and thrombotic lesions.

[0014] Symptoms of PAH are nonspecific and initially associated with exertion, including shortness of breath, fatigue, weakness, chest pain, and fainting. As it progresses, symptoms of severe RV failure and low cardiac output predominate and often occur at rest. This includes abdominal and leg distension, profound fatigue, and significant intolerance to activity. PAH has profound psychosocial and economic impacts on patients and their caregivers. Risk factors for poor prognosis are evidence of RV failure, rapid progression of symptoms, recurrent fainting, deterioration of WHO functional class, reduced 6-minute walk distance (6MWD), reduced peak VO2 or VE / CO2 on cardiopulmonary exercise testing, elevated natriuretic hormone levels, imaging findings of right RV failure (reduced RV function, increased RA or RV size, RV eccentricity, pericardial effusion), and abnormal invasive hemodynamic measurements, including elevated right atrial pressure (RAP), low cardiac index (CI), and reduced mixed venous oxygen saturation (SvO2). Many of these parameters reflect the degree of RV failure, the most common cause of death.

[0015] Although palliative care has made significant advances in the past two decades, PAH remains a universally fatal disorder with a median survival of 5 years. There is one exception, which is potentially important when considering the use of interatrial shunts. A small number of patients with uncorrected congenital heart disease have preexisting left-to-right shunts, often due to atrial septal defects (ASDs), ventricular septal defects (VSDs), or patent ductus arteriosus. As PAH progresses, these shunts reverse direction and become predominantly right-to-left. This is known as Eisenmenger's physiology, and cyanosis of the extremities due to arterial oxygen desaturation becomes a frequent clinical finding. As a complement, Eisenmenger's patients with PAH are thought to have a survival advantage over patients with IPAH or APAH from other causes.

[0016] Currently, there are several approved drug classes, including prostanoids, prostaglandin receptor agonists, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, and calcium channel antagonists. Drug therapy results in significant symptomatic improvement and a slower rate of clinical deterioration. Sequential oral drug combination therapy is the most widely used strategy in clinical practice. Randomized trials adding newer agents to patients already receiving GDMT have shown improvements in combined endpoints of morbidity and mortality. When symptoms can no longer be controlled with oral medications, patients receive parenteral prostanoids and eventually require indwelling catheters and infusion pumps. Continuous intravenous epoprostenol is the only drug shown to increase survival. However, parenteral prostanoids are often associated with frequent and disabling adverse effects, such as vomiting, headache, hypotension, facial flushing, jaw and leg pain, and diarrhea. Serious adverse events associated with intravenous delivery systems include pump malfunction, local site infection, catheter obstruction, and sepsis. Abrupt interruption of therapy precipitates rebound worsening of pulmonary hypertension, acute RV decompensation, and death. Patients refuse parenteral therapy, or it must be discontinued in approximately 30% of cases. Lung transplantation is an essential treatment option for patients with PAH, but due to a shortage of donor lungs and lower survival rates than for other lung disorders, fewer than 200 US patients with PAH are transplanted each year.

[0017] It should be understood that, in addition to HF and PAH, there are other cardiovascular or cardiopulmonary disorders familiar to those skilled in the art, including, but not limited to, mitral annular calcification causing mitral stenosis associated with left or right ventricular dysfunction, refractory pulmonary edema with or without cardiogenic shock due to acute myocardial infarction, acute myocarditis, chronic thromboembolic pulmonary hypertension, weaning from extracorporeal membrane oxygenation (ECMO) therapy, etc. Like HF and PAH, there are resulting increases in cardiac filling pressures that may be the target of specifically indicated therapies, including the use of implantable sensors, the use of interatrial shunt devices, or both. There are also other interventions performed on patients with cardiovascular or cardiopulmonary disorders involving transseptal catheter placement, including mitral valve repair, left atrial appendage obstruction, pulmonary vein ablation for atrial fibrillation, etc., and upon completion of the intervention, the patient may also benefit from transseptal placement of an implantable sensor or an interatrial shunt, or both in combination. (Experiments with Implantable Pressure Sensors in HF and PAH)

[0018] Implantable pressure sensors include circuitry to measure absolute pressure, which is compared to an external reference pressure to calculate a gauge pressure. Alternatively, designs that measure differential pressure between two ventricles or blood vessels have also been described. Two main types of pressure sensors are used for implantable cardiovascular applications: piezoresistive and capacitive. Piezoresistive strain gauges can be bonded to a force collector, such as a diaphragm, to measure the strain or deflection (force) applied over an area (pressure). Strain gauge transducers are usually connected to form a Wheatstone bridge circuit to maximize output. Capacitive sensors use a diaphragm and a pressure cavity to create a variable capacitor. Both sensor types are currently fabricated using microelectromechanical (MEM) technology, resulting in very small packaging of approximately 1.0 x 1.0 x 0.1 mm. Piezoresistive devices are more suitable for periodic measurements than continuous measurements due to their higher power consumption.

[0019] In some applications, capacitive sensors are a better choice due to their higher sensitivity to pressure changes, lower noise, and lower temperature sensitivity. The main challenges to achieve accurate, durable, and practical implantable sensor performance are to have a hermetic biocompatible package that withstands the ingress of corrosive body fluids and their well-known effects on delicate electronic components, a package that minimizes residual internal stresses on the sensing element, robust offset drift compensation, low enough power requirements to allow a leadless design for remote powering / telemetry with sufficient range and bandwidth, defibrillation protection, and compatibility with magnetic resonance scanning. It will be understood by those skilled in the art that other sensor technologies that measure pressure, flow, velocity, temperature, pH, or concentration of a chemical species can be similarly applied to the implanted cardiovascular environment when they are shown to be capable of performing advantageously.

[0020] Implantable sensors measuring intracardiac or pulmonary artery pressures have been used successfully to inform clinicians of impending decompensation and guide medication adjustments. This approach shows benefit in comparison to standard GDMT to improve symptoms and prevent ADHF episodes in a broad population of HF patients, whether HFrEF or HFpEF. More recently, sensors have also been used in the management of patients with severe PAH.

[0021] Implantable hemodynamic monitoring systems are being developed for outpatient HF assessment and management with the goal of reducing episodes of clinical decompensation. As an example, investigational implantable pressure sensors placed in the left atrium via a transseptal catheter placement procedure include devices developed by Savacor-St Jude Medical, now Abbott Laboratories (Abbott Park IL), and by Vectorius Medical Technologies (Tel Aviv, Israel). As another example, devices placed in the pulmonary artery that measure pulmonary artery pressure (PAP), a surrogate / estimate for LAP, include products by CardioMEMs, now Abbott Laboratories (Abbott Park IL), and Endotronix, Inc. (Lisle, IL). There are other examples of implantable pressure sensors from multiple manufacturers familiar to those skilled in the art.

[0022] Example: Savacor HeartPOD TMThe system includes an implantable sensor lead that is connected to an antenna coil positioned subcutaneously or to a specially designed CRT / ICD system that is integrated into the generator header as described in Ritzema J, et al. "Direct left atrial pressure monitoring in ambulatory heart failure patients: Initial experience with a new permanent implantable device" Circulation 2007;116;2952-2959 and Maurer MS, et al. "Rationale and design of the left atrial pressure monitoring to optimize heart failure therapy study (LAPTOP-HF)" J Cardiac Failure 2015;21:479-488. Additional components include a handheld Patient Advisory Module (PAM) for communication with the implant and for uploading patient data to and downloading prescriptions from secure web-based software used by clinicians. The sensor lead had a cylindrical, hermetically sealed sensor module, 3 mm in diameter by 7 mm in length, with a titanium pressure-sensing diaphragm at its distal end, containing internal piezoresistive strain gauges and application-specific circuitry for measuring and communicating LAP, temperature, and intracardiac electrograms. A folded Nitinol anchor affixed the sensor module at the interatrial septum, accommodating any septal thickness.The anchor was designed to fold forward when constrained for deployment to facilitate later percutaneous extraction of the sensor lead, if required, using standard pacing lead removal techniques, as described in Pretorious V, et al. "An implantable left atrial pressure sensor lead designed for percutaneous extraction using standard techniques" Pacing Clin Electrophysiol 2013 May;36(5):570-7.

[0023] The implanted LAP sensor is powered and responsively measured through the skin by 125 kHz radio frequency wireless telemetry from the PAM. When held in the correct location over the subcutaneous antenna coil, the PAM vibrates momentarily to indicate to the patient that acquisition is taking place, and vibrates again (typically 15 seconds) when acquisition is complete. During the responsive measurement, high fidelity physiological pressure and ECG waveforms are collected and stored on the PAM. LAP is calculated by subtracting the absolute pressure acquired by the implant from an atmospheric reference measured by a second pressure sensor located within the PAM.

[0024] Patient sensor readings were uploaded daily via the Internet to a centralized, secure database. Waveform and trend data were reviewed by the patient's HF physician either periodically or based on alerts generated when parameters exceeded boundaries. The physician then downloaded updated prescriptions and instructions to the PAM for patient viewing. The PAM's reminder feature alerted patients to measure resting LAP within scheduled morning and evening time windows before they took their heart failure medication.

[0025] The PAM can be set up to display the LAP value, include the dosage, and inform the patient when medication is due. This is done in two ways. First, the prescription is adjusted according to the overall LAP trend. This type of dosing was called "Static Rx". When enabled, the PAM also provides a "Dynamic Rx" which allows therapy to be adjusted according to the current LAP value. TM DynamicRx displays physician-instructed patient self-management orders called "Low, Low, Optimal, High, and Very High LAP Ranges." Each range is associated with prescriptions for medication dosing, activity level, sodium and fluid intake, and physician contact orders. Local investigators adjust these ranges for each patient. DynamicRx prescriptions are at the discretion of the local investigator, but the general goal is to reduce or eliminate diuretic doses for low or very low LAP and increase diuretic or long-acting nitrate vasodilator doses for high or very high LAP.

[0026] Sensor drift compensation included internal autoregulation for changes in temperature and atmospheric pressure. Longer term changes in sensor offset may be due to intrinsic drift in the internal gauges and electronics, or extrinsic changes from neoendocardial tissue growth across the sensor membrane. As explained in "Noninvasive calibration of cardiac pressure transducers in patients with heart failure: An aid to implantable hemodynamic monitoring and therapeutic guidance" by McClean et al., J Card Fail 2006;12:568-576, the accuracy of the implanted sensor can be assessed by simultaneously measuring intracardiac and airway pressures during a Valsalva maneuver. Within 2-3 seconds of increasing intrathoracic pressure above 20 mmHg, intracardiac pressure during diastole equals airway pressure. In practice, implanted LAP sensors are checked periodically during clinic visits by having the patient perform a Valsalva maneuver while exhaling into a mouthpiece connected to the atmospheric reference pressure sensor of the PAM. This results in quantification and correction of offset drift, regardless of cause. In addition, it has been discovered that specific features within the LAP waveform can be used to detect and automatically compensate for offset drift between clinic visits.

[0027] Ritzema et al., in "Physician-directed patient self-management of left atrial pressure in advanced chronic heart failure," Circulation 2010;121:1086-1095, reported that the Savacor HeartPOD was a reliable, cost-effective, and cost-effective treatment for 40 consecutive patients with HFrEF or HFpEF and a history of NYHA class III or IV HF with prior ADHF hospitalization. TMWe report a prospective observational first-in-human study using the system. Patients were implanted with sensors and readings were obtained twice daily. Over the first 3 months, patients and clinicians were blinded to sensor readings and treatment was continued according to routine clinical assessment. A physician-directed patient self-management regimen (DynamicRx) was then applied. Freedom from HF events (ADHF hospitalization or all-cause death) was 61% at 3 years and significantly decreased in frequency after the first 3 months. LAP decreased from a mean of 17.6 mmHg in the first 3 months to 14.8 mmHg during pressure-guided therapy (P=0.003). The frequency of elevated readings (>25 mmHg) was reduced by 67% (P<0.001). LAP control was defined empirically when the frequency of pressures above 25 mmHg was below 10% for 6 consecutive months. LAP control was achieved in 77% of patients. HF events were 98% less frequent during LAP-controlled cycles than during cycles without LAP control (P<0.001). There was also a significant improvement in symptoms and LVEF. The doses of renin-angiotensin system inhibitors and beta-antagonists were titrated up by 37% (P<0.001) and 40% (P<0.001), respectively, while the dose of loop diuretics was reduced by 27% (P=0.15). The authors clearly demonstrated that LAP elevation always precedes clinical decompensation. Also, implantable LAP monitoring coupled with self-management therapeutic strategies may transform the management of advanced heart failure by promoting more optimal therapy and improved outcomes.

[0028] The original design of the HeartPOD LAP sensor had a sensing diaphragm that protruded approximately 1 mm into the left atrium beyond its three anchoring legs that rested on the left atrial side of the septum. In later improved versions, the anchor legs were placed more proximally on the sensor module body such that the sensing diaphragm protruded approximately 2.5 mm into the LA. In comparative cross-species pathology studies, Trainor and colleagues demonstrated in "Comparative pathology of an implantable left atrial pressure sensor" ASAIO journal 2013;59:486-492 and "Integrated microscopy techniques for comprehensive pathology evaluation of an implantable left atrial pressure sensor" J Histotechnology 2013;36:17-24 that in a comparative pathology study of three species, sheep, dogs, and humans, significant new endocardial tissue (pannus) formation was observed across the sensing diaphragm in 20 of 31 original sensors compared to only 3 of 40 specimens with improved geometry sensors. Of the 20 original sensors with tissue coverage, 7 had demonstrable artifacts in the LA pressure waveform. In each case with artifacts, pannus formation across the sensing diaphragm had a thickness >0.3 mm. These data indicate that when tissue coverage exceeds this thickness, the tissue interferes with fluid pressure measurements. None of the improved sensors had waveform artifacts or tissue thickness >0.3 mm. It can be concluded that the improved sensor geometry eliminated waveform artifacts and promoted long artifact-free sensor waveform fidelity by preventing overgrowth of thick neoendocardial tissue.

[0029] Troughton et al., in "Direct left atrial pressure monitoring in severe heart failure: long-term sensor performance," J Cardiovasc Trans Res 2011;4:3-13, showed that with the original design of the sensor, waveform artifacts were seen in approximately 15% of cases by 4 months and absent thereafter. This indicates that the waveform artifacts were likely a result of device healing and were caused by compression or retraction of the diaphragm from mechanical coupling to the atrial wall due to interconnecting tissue overgrowth. When sensors with improved geometry were used, the waveform artifacts were eliminated in the next 41 consecutive patients. Thus, a design change that advances the pressure-sensing diaphragm 2.5 mm from the septal wall into the left atrium minimizes tissue thickness over the sensor and decouples it from the contraction and extension movements of the atrial wall.

[0030] As reported in Maurer et al. "Rationale and design of the Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy Study (LAPTOP-HF)," J Card Fail 2015;21:479-88, a randomized controlled outcomes study was conducted in which the LAPTOP-HF trial examined the safety and efficacy of the HeartPOD system in NYHA functional class III patients who had either been hospitalized for HF in the past 12 months or had elevated B-type natriuretic peptide levels regardless of ejection fraction. Treated patients measured LAP twice daily and used physician-directed patient self-management to guide therapy, while the control group received optimal medical therapy only. Enrollment in the LAPTOP-HF trial was halted early due to a perceived excess of transseptal-related complications. The trial was conducted at a time before widespread use of new catheter placement techniques had significantly improved transseptal safety. Preliminary results were presented during the Late Breaking Clinical Trials Session at the 2016 Heart Failure Society of America meeting, as reported in Abraham WT, et al. "Hemodynamic monitoring in advanced heart failure: Results from the LAPTOP-HF trial," J Card Fail 2016;22:940. When results were analyzed using the CHAMPION trial endpoint of recurrent heart failure hospitalization (see below), the results of the LAPTOP-HF trial were similar to those of CHAMPION, showing a relative risk reduction of 41% (p=0.005).

[0031] Another example of intracardiac sensing is a next-generation implantable LAP monitoring system called V-LAP, developed by Vectorious Medical Technologies (Tel Aviv, Israel). The sensor is wireless and wire-free, with a cylindrical profile (14 mm in length and 2.5 mm in diameter). As described in PCT International Patent Publication No. WO 2014 / 170771 and Perl et al., "A Novel Wireless Left Atrial Pressure Monitoring System for Patients with Heart Failure, First Ex-Vivo and Animal Experience," J Cardiovascular Translational Research 2019, 12:290-298, the sensor employs a MEMS variable capacitor sensing surface located at the left atrial pole of the sensor module and application specific integrated circuit technology featuring on-board automatic drift compensation. The majority of the sensor length is comprised of an inductor antenna coil wrapped around a small ferrite core. The sensor is anchored in the fossa ovalis using two woven superelastic Nitinol disks such as the Amplatzer ASD closure device, which occupy an 18mm diameter area of ​​the fossa ovalis. The system also includes an external wearable belt that remotely powers the implant, displays pressure readings to the patient, and transmits LAP waveform information to a web-based database. Animal studies have shown that the device is safe and communicates with the external belt at depths of up to 30cm. The device is currently in early human clinical trials and appears to be functioning well in the first 21 patients implanted with short-term follow-up.

[0032] Another embodiment of an intracardiac pressure sensor is the CardioMEMS Champion TMA HF monitoring system that measures PAP using a wireless pressure sensor designed to be implanted in a branch of the pulmonary artery during a right heart catheterization procedure. The sensor is located in a hermetically sealed fused silica body that is 15 mm in length, 3.4 mm in width, and 2 mm in thickness and is encapsulated with medical grade silicone. The housing contains an inductor coil and a pressure sensitive MEMS variable capacitor with a high Q LC resonant circuit such that the resonant frequency changes as pressure changes. An external electronics unit transmits RF pulses to the sensor, where the energy is re-emitted after excitation ceases and pressure information is encoded in the frequency of the sensor transmitted signal. Pressure readings are uploaded to a database where the physician views the patient's PAP waveform including systolic, diastolic, and mean pressures, as well as trend plots of heart rate. The patient is then contacted and given instructions on how to adjust therapy.

[0033] Abraham et al. have reported extensively on the results of the CHAMPION trial of the CardioMEMS system in "Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomized controlled trial" The Lancet DOI:10.1016 / S0140-6736(11)60101-3, "Sustained efficacy of pulmonary artery pressure to guide adjustment of chronic heart failure therapy: complete follow-up results from the CHAMPION randomized trial" Lancet 2016;387:453-461. doi.org / 10.1016 / S0140-6736(15)00723-0, and "Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction" Circ Heart Fail 2014;7:935-944. This was a patient-blinded randomized controlled trial of 550 NYHA class III patients with a history of HF hospitalization in the prior 12 months, regardless of systolic function (22% of patients had LVEF ≥ 40%), who underwent GDMT. In the treatment group, PAP trends were used to adjust medications, which in most cases were loop diuretics and long-acting nitrates. During follow-up (mean 17.6 months), the treatment group had a 39% reduction in HF hospitalization compared to the control group (p<0.0001). HF hospitalization in HFpEF patients was 50% lower in treatment patients vs. control group (P<0.0001). The effect in patients with HFrEF was less pronounced but still highly statistically significant.In response to pulmonary artery pressure information, further modifications in diuretic and venous dilator therapy were made in the treatment groups regardless of EF. These data establish that volume management, whether with diuretics (salt and water removal) or long-acting nitrates (venous dilation), given in response to elevated left-sided pressure reduces episodes of ADHF in both HFrEF and HFpEF.

[0034] Benza et al. reported in "Monitoring pulmonary arterial hypertension using an implantable hemodynamic sensor" Chest 2019;156(6):1176-1186 on the safety and usefulness of the CardioMEMS device in 27 patients with RV failure with NYHA III (85%) or IV (15%). All patients used at least two medications, including 69% with parenteral prostacyclin. Patients were followed up for 2.5±1.4 years. Twenty-six patients were successfully implanted with sensors without major complications. Most patients (92%) were female and aged 51±18 years, 50% with IPAH and 31% with APAH, an associated connective tissue disease. There were eight hospitalizations related to RV failure, six of these in two patients. There were 5 deaths, 3 at 1 year, 1 death due to PA rupture during implantation, and 2 at 2 years. There was a significant reduction in mean PAP (42±13 to 34±14) and increase in CO (5.8±1.5 to 6.8±1.8) at 1 year. Improvements in RV stroke volume, vascular compliance, and RV efficiency, as well as reductions in RV1 conversion work and total pulmonary resistance, were also observed. NYHA functional class (P<0.001), natriuretic peptides (P<0.01), and Minnesota Heart Failure Quality of Life Questionnaire score (P<0.001) also improved from baseline, reflecting hemodynamic changes. The authors concluded that implantable monitoring in PAH patients appears safe, may reduce hospitalizations, and allows rapid optimization of hemodynamic and functional outcomes.

[0035] Compared to PAP, the LAP waveform contains more specific information about LA, LV filling, compliance, and function, as well as the role of functional mitral regurgitation in ADHF. As an example, consider the meaning and specificity of the rise in mean LAP vs. PAP, regardless of systolic, mean, or diastolic pressure. Both will be elevated due to intravascular volume overload, LV failure, or LA outflow obstruction. In addition, PA pressure is also elevated in precapillary (PAH) or postcapillary (secondary) pulmonary hypertension. Secondary pulmonary hypertension is a common condition associated with left-sided HF. First, there are reactive changes that cause pulmonary artery constriction that will respond to improving HF. Then, in response to the long rise in pulmonary venous pressure from HF, the pulmonary arterial vasculature develops fixed lesions that are the same as in PAH. In this setting, PA diastolic pressure, which is usually very similar to LAP, will be elevated substantially higher than LAP. If PAP is used to induce diuretic therapy for HF and substantial secondary PAH is present, PA diastolic pressure will substantially overestimate LAP, and hyperdiuresis resulting in very low LAP with associated dehydration, worsening renal function, and electrolyte imbalances requiring hospitalization will become more frequent. For example, in the CHAMPION trial, the incidence of dehydration leading to hospitalization in the PAP induction therapy group was twice that of the control group using standard clinically based diuretic dosing.

[0036] There are several other diagnostic features in the LAP waveform known to those familiar with cardiac hemodynamic physiology, including the composition of the waveform's components (a and v waves, x and y dips, etc.). Also, individual pressure measurements in an outpatient setting are not sufficient in themselves to predict the extent to which, or whether, a patient will respond to a given therapy. Many patients have highly variable pressures, subject to rapid physiological changes from acute myocardial ischemia or afterload changes resulting from severe functional mitral regurgitation. Their LAP out-of-control variations are unstable and can range from normal values ​​to mean pressures as high as 50 mmHg, with giant v waves as high as 80-100 mmHg. These changes can occur over only a few hours, and in some cases, over only a few minutes. Even so, these rapid variations rarely result in significant adverse HF events, such as ADHF hospitalization or death. In fact, when detected, these changes can be highly diagnostic and aid in individual patient management. It should also be understood that single observation hemodynamics are only a "snapshot" and not a complete physiological picture: pressure trends over time are more useful for predicting clinical outcomes.

[0037] To be successful, implantable hemodynamic monitoring may utilize frequent caregiver data review and automated alert responses, approximately every week, development of effective prescription changes to the data, transmission of prescription changes to the patient, diligent patient adherence to those prescriptions, and time for the patient to express response or non-response to the changes. It also takes time to recognize when filling pressures are worsening and to determine, often through trial and error, the medication and dosage to which the patient will respond. Although better than standard medical therapy, pressure-guided therapy has similar inherent delays and multiple points of failure. Physician-directed patient self-management overcomes many of these limitations. Despite these shortcomings, clinical evidence is accumulating that implantable hemodynamic monitoring has revolutionized the treatment of HF patients and is, so far, the only intervention to demonstrate significant outcome benefits for HFpEF patients in randomized controlled clinical trials. For the first time, there is also evidence that pressure-guided therapy may have a role in the management of PAH.

[0038] Finally, with regard to implantable sensors, the types described thus far have been limited to devices that directly measure pressure. This is only because they have been the most studied and have proven their durability as chronic implants. In addition, our understanding of physiology allows physicians to glean meaning from pressure values ​​as they have been established over many years from experience with cardiac catheter placement. In short, pressure data are actionable and they have been successfully proven to guide therapeutic decision-making.

[0039] The limitations of standard and hemodynamically guided therapies establish a clear need for a means to automatically regulate left and right atrial pressures in HF and PAH, respectively. Such a means should be effective without delay, prevent overtreatment of the patient or causing other cardiac, vascular, or end-organ dysfunction, be compatible with or complementary to other therapies, not require "hands-on" management by the caregiver, and be recognized as a medical breakthrough. (Experiments with interatrial shunts in HF and PAH)

[0040] In the context of the potential benefits of interatrial shunts, it is important to understand the implications of having a naturally occurring congenital atrial septal defect (ASD) involving the middle portion of the interatrial septum, known as ostium secundum ASD. ASD is one of the most common types of congenital heart defects. When large enough, ASDs present with bilateral atrial and RV hypertrophy due to left-to-right atrial shunting with volume overload of the right heart during childhood or early adulthood. Flow in the pulmonary artery to aorta (Qp:Qs) is often >2:1. These defects must be closed to prevent the development of PAH, which causes RV failure and death.

[0041] However, often ASDs are well tolerated and are present only in adulthood, often as incidental findings on echocardiograms. Patients with small ASDs, <10 mm in diameter or with Qp:Qs <1.5, generally do not develop volume overload, pulmonary hypertension, and subsequent RV failure. Guideline recommendations are not to close these defects unless there is evidence of progressive RV dilatation or systemic thromboembolism originating from the venous system (paradoxical embolism), as discussed, for example, in Webb G and Gatzoulis MA, "Atrial septal defects in the adult: recent progress and overview," Circulation 2006;114:1645:1653 and Baumgartner H,et al., "ESC guidelines for the management of grown-up congenital heart disease (new version 2010)," Eur Heart J 2010;31:2915-2957. It is recommended that these patients be followed up every few years by echocardiography. Nevertheless, their risk of developing right ventricular volume overload is very small.

[0042] As discussed in Wiedemann HR "Earliest description by Johann Friedrich Meckel, Senior (1750) of what is known today as Lutembacher syndrome (1916)" Am J Med Genet. 1994 Oct 15. 53(1):59-64 and Aminde LN, et al. "Current diagnostic and treatment strategies for Lutembacher syndrome: the pivotal role of echocardiography" Cardiovasc Diagn Ther 2015;5:122-132, Lutembacher syndrome is usually defined as the coexistence of mitral stenosis (MS) of rheumatic origin and a left-to-right shunt at the atrial level, most often an ostium secundum type ASD. ASD can also be iatrogenic or secondary to complications of transseptal crossing. The classical teaching is that these two lesions each modify the hemodynamic and clinical manifestations of the other, and that the frequent pulmonary edema and hemoptysis characteristic of MS are reduced by the decompressive effect of the ASD. Specifically, the elevated LAP caused by MS drives the unloading of blood into the right atrium through the ASD, relieving the accumulation of backpressure in the pulmonary veins, thus avoiding pulmonary congestion. Pulmonary vascular resistance, RV compliance, severity of MS, and size of the ASD are important factors that determine the hemodynamic and clinical outcomes in these patients.

[0043] Thus, it has been observed that HF ​​patients with coexisting congenital ASD may have a better outcome and closure of the ASD may reveal subclinical LV dysfunction by inducing immediate ADHF with resultant pulmonary edema. This fact has been prominently noted as a caveat in ESC, AHA / ACC, and Canadian guidelines for treating adults with congenital heart disease, as discussed, for example, in Viaene D, et.al. "Pulmonary oedema after percutaneous ASD-closure" Acta Cardiol. 2010 Apr;65(2):257-60, Schubert S, et al. "Left ventricular conditioning in the elderly patient to prevent congestive heart failure after transcatheter closure of atrial septal defect" Catheter Cardiovasc Interv 2005;64:333-337, and Davies H, et al. "Abnormal left heart function after operation for atrial septal defect. Br Heart J 1970;32:747-753." When ASD closure is being considered in adults with suspected left ventricular dysfunction, it is recommended to first occlude the defect with a balloon and measure the rise in LAP to clarify the potential to develop overt clinical HF. This is because the ASD acts as a "pop-off" valve for the systemic (left) ventricle and prevents pulmonary venous hypertension if LV dysfunction is present. As previously explained, patients with ASD and Eisenmenger physiology have improved survival rates in PAH. Thus, there is now a large body of evidence showing that ASD prevents ADHF in the presence of LV dysfunction and acute RV failure in PAH.

[0044] Further support for the utility of having a right-to-left atrial shunt in PAH comes from experiments with balloon atrial septostomy (BAS), in which progressively larger balloons are inflated until systemic oxygen saturation just begins to drop. Balloon sizes typically range from 4 to 12 mm in diameter, averaging about 8 mm.

[0045] Whether the shunt is accomplished by implantation of a BAS or a permanent shunt device, left atrial access must first be accomplished by transseptal catheterization, a procedure well known to those skilled in the art of cardiac catheterization. Briefly, a transseptal catheterization system is placed across the interatrial septum in the region of the fossa ovalis (FO), the central and thinnest area of ​​the interatrial septum, usually from an entry site in the right femoral vein. This is the same general location where congenital ostium secundum ASDs will be located. The FO in adults is typically 15-20 mm in its long axis dimension and ≦3 mm in thickness, but in some circumstances may be up to 10 mm thick. LA ventricular access may be achieved using a variety of different techniques, including needle puncture, stylet puncture, screw needle puncture, and radiofrequency ablation. In a BAS, the passage between the two atria is dilated to create an iatrogenic ASD. The passage is similarly dilated to facilitate passage of a shunt device of the desired orifice size. Dilation is accomplished by advancing a tapered sheath / dilator catheter system or by inflation of an angioplasty balloon across the FO.

[0046] In PAH, successful BAS decompresses the RV, increases LV preload, systemic cardiac output, and oxygen transport, and causes only moderate arterial O2 desaturation. Studies such as Sandoval J,et al. "Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment" J Am Coll Cardiol 1998;32:297-304, Kurzyna M,et al. "Atrial septostomy in treatment of end-stage right heart failure in Patients with pulmonary hypertension" Chest 2007;131:977-983, and Ciarka A,et al. "Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension" Chest 2007;131:1831-1837 have shown improvements in WHO / NYHA symptom class, exercise capacity, RAP, reduction in sympathetic activation, and B-type natriuretic peptide levels. Factors associated with procedure-related mortality have been evaluated in 320 literature septal dehiscence cases as reported in Sandoval J,et al. eds,Right Ventricle in Health and Disease,New York: Humana Press,Springer Science Business Media; 2015. These are RAP>20mmHg, CI<1.5 L / min / 2, pre-existing LV dysfunction. One-month perioperative mortality as low as 2% has been reported in Maluli H,et al.Atrial Septostomy: A contemporary reviewClinical Cardiology. 2015;38:393. Despite these benefits, BAS has important limitations.It is difficult to predict the size of the balloon to be used. In some cases, the FO is more elastic and bounces back after balloon deflation, in others it is more fibrous and can tear. Increased mortality has been associated when septal dehiscence creates too large a shunt, resulting in significant systemic oxygen desaturation (<80%). See, for example, Rich S, et al. "Atrial septostomy as palliative therapy for refractory primary pulmonary hypertension" Am J Cardiol 1983; 51:1560-1561. Maintenance of shunt patency is another limitation affecting about one-third of patients, often requiring multiple procedures over a period of several months, as discussed in Sandoval J, et al. "Effect of atrial septostomy on the survival of patients with severe pulmonary arterial hypertension" Eur Respir J 2011:1343-1348. BAS is currently used rarely and is considered as palliative therapy or a bridge to lung transplantation in some experienced centers.

[0047] The aforementioned observations have led to the development of percutaneously implanted interatrial shunt prostheses, which are currently being tested in human clinical trials in HF and PAH. In HF, by shunting blood from the left atrium to the right atrium, pressure in the LA is reduced or prevented from rising as high as it would otherwise (LA decompression). Such implementation prevents, alleviates, or limits symptoms, signs, and syndromes associated with pulmonary congestion. These include severe shortness of breath, pulmonary edema, hypoxia, the need for emergency hospitalization, mechanical ventilation, and in some cases, death. In PAH, the shunt device would divert flow from the right atrium to the left atrium due to a reversal of the normal interatrial pressure gradient. The goal is to reduce RV preload and increase left-sided cardiac output and tissue oxygen delivery without causing significant arterial oxygen desaturation. The expected outcomes are reduction in symptoms, increased exercise capacity, prevention of acute RV decompensation, and improved life expectancy.

[0048] Specifically, in HF, the primary physiological mechanism of interatrial shunting is to relieve the LV of excess volume and pressure by shunting blood from the left atrium to the right atrium as regulated by the interatrial pressure gradient. In so doing, the amplitude and duration of the extraregular fluctuations of LAP and LVEDP are limited. In the vast majority of HF patients, LAP exceeds RAP. In the absence of severe RV dysfunction, the amount of LAP-RAP increases as left ventricular failure worsens and LAP rises. Thus, the amount of blood shunted to the right heart increases with worsening left-sided heart failure. When LAP and LVEDP are elevated, the LV is operating on a steeper portion of its diastolic compliance curve, regardless of whether the patient has HFrEF or HFpEF. The reduction in LV end-diastolic volume leads to a consequent and substantial reduction in LV end-diastolic pressure. There will be an identical baseline reduction in upstream filling pressures, including LAP, pulmonary venous pressure, and pulmonary arterial pressure. This change in LV volume and pressure is similar to the action of a diuretic to remove excess volume, except that the shunt functions automatically, instantaneously, and continuously. Also, the effect is automatically appropriate to the level of LAP or LVEDP. The higher the left filling pressure, the more shunting and therefore the more unloading. At smaller interatrial gradients, there is less shunting, and therefore the effect on LV volume and filling pressure becomes progressively smaller until it becomes negligible. Thus, unlike diuretic therapy, overtreatment that would cause volume depletion and a significant drop in cardiac output is prevented. Finally, the interatrial shunt does not require any adjustments by the physician or the patient, and the therapy is complementary to all known medication and device therapies, including implantable hemodynamic monitoring with pressure-induced drug dosing. The expected clinical outcome would be a reduction in, or even prevention of, pulmonary congestion symptoms.

[0049] Shunt flow is generally governed by the pressure gradient between the atria and the hydrodynamic properties of the shunt device. The latter is typically influenced by the shunt geometry and biomaterial composition. For example, it has been shown that the general flow quality of similar shunt designs is related to the mean interatrial pressure gradient and the effective orifice diameter. One concern with interatrial shunt devices for HF, such as those seen in uncorrected congenital ASD, is that if the shunt is too large, RV volume overload will develop, eventually causing precapillary PAH with RV failure. The patient may then develop Eisenmenger's physiology, which involves a reversal of the direction of shunt flow from the right atrium to the left atrium. As already mentioned, with small shunts, the extra volume is well tolerated due to the large vascular compliance of the right heart and systemic veins. Thus, a critical dimensional consideration for interatrial shunt devices is that the shunt is large enough to unload the left heart, but small enough not to overload the right heart.

[0050] Two types of percutaneously implantable shunts have been described in the medical and patent literature. Small clinical trials have shown that both types are associated with improvements in symptoms, quality of life measures, and exercise capacity. The first type of shunt is hereafter referred to as an orifice-plate mesh shunt. The orifice-plate mesh shunt comprises a metal mesh with a central hole that wraps around both sides of the septum, anatomically mimicking the location and geometric characteristics of small congenital ostium secundum ASD. The shunt geometry generally resembles a thin plate with a hole therein. In most embodiments, the "plate" consists of both the mesh material and the atrial septal tissue surrounded by the mesh.

[0051] A modified Amplatzer septal occluder with custom fenestration was the first device approach attempted, as discussed in a study conducted by Schubert et al., "Left ventricular conditioning in the elderly patient to prevent congestive heart failure after transcatheter closure of atrial septal defect," Catheter Cardiovasc Interv 2005;64:333-337. In that study, patients with ASDs who suffered elevated LAPs when the defect was occluded were implanted with fenestrated Amplatzer occluders. As reported in "Fenestrated occluders for treatment of ASD in elderly patients with pulmonary hypertension and / or right heart failure", 2008;21:44-49, DOI: 10.1111 / j.1540-8183.2007.00324.x, Bruch and colleagues implanted 5-8 mm diameter fenestrated Amplatzer septal occluders in 15 elderly ASD patients with large left-to-right shunts, pulmonary hypertension, and / or right heart failure who were at high risk for LV failure. Symptomatic patients showed improvement in NYHA class and no HF decompensation occurred. RV end-diastolic dimension and pulmonary artery pressure were significantly reduced.However, long-term follow-up as reported in Lammers AE, et al. "Efficacy and long-term patency of fenestrated Amplatzer devices in children" Catheter Cardiovasc Interv 2007; 70:578-584 and Sandoval J, et al. "Effect of atrial septostomy on the survival of patients with severe pulmonary arterial hypertension" European Respiratory Journal. 2011; 38:1343-1348, shows that this device is associated with a high rate of closure, possibly related to the lack of controlled endothelialization in the passage between the atria. Fenestrated Amplatzer devices have been largely abandoned because they require the creation of a rather large passage through the septum, leaving a lot of foreign material in the septum with the risk of thrombus formation.

[0052] The placement of in situ expanded stents in a diabolo or hourglass shape has shown improved patency over modified fenestrated Amplatzer devices. Diabolo stents are mostly used in PAH, as described in Troost E, et al. "Modified technique of stent fenestration of the interatrial septum improves patients with pulmonary hypertension" Catheter Cardiovasc Interv 2009; 73:173-179, but the initial design carried the risk of acute stent embolization. Both fenestrated Amplatzer and Diabolo stents achieved outcomes similar to BAS, but the long-term risk of occlusion / stenosis may result in an ineffective shunt.

[0053] A second example of an orifice-plate mesh shunt currently in clinical trials is the interatrial shunt device IASD II, developed by Corvia Medical, Inc. (Tewksbury Massachusetts). The IASD II consists of a self-expanding superelastic nitinol mesh that forms a pair of disk-like flanges with a central open orifice structure. The maximum diameter of the disk is 19.4 mm and the orifice diameter is 8 mm. Each disk flange has multiple bundle-like legs that unfold into a pre-set configuration that wraps around the LA and RA sides of the interatrial septum. The device is anchored by applying its bite force, which compresses the septal tissue between the flanges. The exposed metal frame is not encapsulated.

[0054] In the REDUCE LAP-HF feasibility study, described in Hasenfuss G,et al, "Rationale and design of the reduce elevated left atrial pressure in patients with heart failure (Reduce LAP-HF) trial," J Cardiac Fail 2015;21:594-600, on behalf of the REDUCE LAP-HF trial investigators, and Hasenfuss,G.,et al, "A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre,open-label,single-arm,phase 1 trial," Lancet 2016;387:1298-304, on behalf of the REDUCE LAP-HF study investigators, shunt placement was successful in 64 of 68 patients. The study population was exclusively HFpEF, including a mix of NYHA class II and III patients with baseline elevated LAP, borderline pulmonary hypertension, and normal RV function. No patient had a need for cardiac surgical intervention for perioperative or major adverse cardiac or cerebrovascular events or device-related complications during the first 6 months. There was sustained improvement in NYHA class, quality of life scores, and 6-minute walk distance ("6MWD") continuing to 1 year later. Transthoracic echocardiography confirmed the presence of a left-to-right shunt at 12 months in 48 of 64 (75%) patients, but did not assess shunt narrowing. There was a gradual but stable reduction in LV end-diastolic volume index with a concomitant increase in RV end-diastolic index. Tricuspid annular plane systolic excursion (TAPSE) improved significantly at 12 months with an increase in RVEF, suggesting that the RV tolerates the additional volume generated by the shunt. The Qp:Qs ratio at 12 months averaged 1.25. Shunted patients benefited from an improvement in exercise capacity accompanied by a reduction in LAP during exercise.Symptoms and quality of life measures also improved in >40% of patients by 1 year.

[0055] Feldman et. al., followed by Shah et. al., reported on the REDUCE LAP-HF I trial in Feldman T, et al. "A transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction (REDUCE LAP-HF I): A phase 2, randomized, sham-controlled trial" 10.1161 / CIRCULATIONAHA.117.032094 and Shah SJ, et al. "One-year safety and clinical outcomes of a transcatheter interatrial shunt device for the treatment of heart failure with preserved ejection fraction in the Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF I) Trial. A Randomized Clinical Trial" JAMA Cardiol. doi:10.1001 / jamacardio.2018.2936. This was a phase 2 randomized, parallel-group, blinded, multicenter trial in patients with NYHA class III or ambulatory class IV HF, LVEF ≥ 40%, exercise PCWP ≥ 25 mmHg, and PCWP-RAP gradient ≥ 5 mmHg. Participants were randomized to the IASD II device versus a sham control procedure. Patients and investigators assessing patients during follow-up were blinded to treatment assignment. The primary efficacy endpoint was exercise PCWP at 1 month. The primary safety endpoint was major adverse cardiac, cerebrovascular, and renal events (MACCRE) at 1 month. A total of 44 patients were randomized to the IASD (n = 22) and control (n = 22) groups. The mean age was 70 ± 9 years, and 50% were female.At 1 month, shunt therapy had a greater reduction in PCWP compared to the sham control group (P=0.028 considering all phases of exercise). In addition, PCWP during passive leg elevation and during 20W exercise decreased to a greater extent in shunted patients. At 1 year, there was a trend for a reduction in MACCRE and HF events requiring intravenous therapy. The IASD II device is currently being evaluated in a larger pivotal randomized blinded controlled trial called REDUCE-LAP HF II (NCT030880330).

[0056] Another example of such a mesh-type shunt is the Atrial Flow Regulator (AFR) device, developed by Occlutech International AB (Helsingborg, Sweden). The AFR is similar to the Amplatzer-type double-disk occluder used to close congenital ostium secundum ASDs, which additionally contains a short open barrel orifice at the center that connects the two disks. The shunt is available with orifice sizes from 4 to 10 mm in 2 mm increments and with different barrel lengths to accommodate FOs of different thicknesses. The disk diameter ranges from 22 to 26 mm, depending on the orifice size.

[0057] In the AFR-PRELIEVE trial (NCT03030274), reported in Paitazoglou C, et al. "The AFR-PRELIEVE TRIAL: A prospective, non-randomized, pilot study to assess the Atrial Flow Regulator (AFR) in Heart Failure Patients with either preserved or reduced ejection fraction," EuroIntervention 2019; Jaa-588 2019, doi: 10.4244 / EIJ-D-19-00342, a feasibility study on the Occlutech device, 36 patients with NYHA class II or IV HF and PCWP ≥ 15mmHg at rest or ≥ 25mmHg during exercise were enrolled regardless of LVEF (44.5% HFrEF, 55.5% HFpEF). Successful implantation and patency at 3 months were 100%. Qp:Qs was on average 1.2. There were significant improvements over baseline in NYHA class, exercise capacity, and quality of life scores. Long-term data have not yet been published.

[0058] Rajeshkumar R,et al. "Atrial septostomy with a predefined diameter using a novel Occlutech atrial flow regulator improves symptoms and cardiac index in patients with severe pulmonary arterial hypertension", Cathet Cardiovasc Inerv 2017;1-9, a single-center open-label study using the AFR device, reported a good intermediate term in patients with severe PAH presenting with fainting and RV failure. Twelve (12) patients aged 28±8 years with NYHA III (n=9) or IV (n=4) symptoms were successfully implanted without major complications. Patients received 8 or 10 mm devices. RAP immediately decreased by 4.1±3.2 mmHg after shunt implantation. All patients had elimination of fainting and NYHA improved to class II (n=7) and class III (n=5) at the duration of follow-up. 6MWD improved from 377±33 to 423±31 m. Cardiac index and systemic oxygen transport also improved significantly. The shunt remained patent in all patients at a median follow-up of 6 months. SaO2 decreased from 98±0.2 to 92±3 at rest and to 85±3% after exercise. The AFR device is currently being evaluated in the PROPHET trial (NCT03022851), a prospective randomized study, to assess the safety and efficacy of AFR in 30 patients with PAH.

[0059] The primary advantage of the orifice-plate mesh shunts described above over other shunt designs is the simplicity of manufacture. Although relatively simple in theory and construction, orifice-plate mesh type shunts have several significant shortcomings that are expected to reduce their overall potential for clinical safety and effectiveness.

[0060] The first disadvantage of orifice-plate devices is that they are prone to narrowing or closure during the post-implantation healing cycle. For example, neoendocardial tissue ingrowth, referred to as pannus, grows from the underlying tissue, covering the mesh and narrowing or partially occluding the shunt orifice. During the post-implantation cycle, the local trauma caused by crossing and expanding the FO plus the chronic effect of the constant pressure applied by the mesh material on the septal tissue induces a local healing response. This response involves the activation of an inflammatory process, attracting lymphocytes and phagocytes to the area of ​​tissue injury. These inflammatory cells release various cytokines that in turn signal fibroblasts and smooth muscle cells from the wound edge to dedifferentiate, migrate, proliferate, and encapsulate the affected portion of the implanted device. The fibroblasts and smooth muscle cells then secrete extracellular matrix material, consisting of collagen and proteoglycans. The extracellular matrix forms a mass of pannus. The duration of this healing phase in humans is typically up to 6-9 months, but may be longer if there is a chronic source of tissue injury, such as device compression or erosion of adjacent tissue. Eventually, the pannus becomes covered with neoendothelial cells, halting or stabilizing the pannus growth. Over the long term, the collagen of the pannus regenerates but generally retains its space-occupying properties. Such tissue ingrowth typically spreads across the surfaces of the implant struts, mesh, or discs, and may substantially narrow the orifice lumen or even completely occlude the shunt. Shunt narrowing or occlusion inhibits or prevents LA decompression, limiting any positive effects for the patient.

[0061] The degree of luminal narrowing can be highly variable between patients due to differences in the severity of local injury; i.e., the more injury, the worse the pannus formation. In addition, variability also results from differences in host wound healing responses. For example, the amount and properties of extracellular matrix can affect the duration of healing and the amount of material deposited. Thus, for orifice-plate mesh shunts, the final orifice lumen size will be highly variable. These processes will be known to those skilled in the art, as they are generally similar to the type of late luminal loss that occurs in arteries when bare metal stents are used to treat atherosclerotic stenosis.

[0062] A second disadvantage of orifice-plate mesh shunts is the potential for paradoxical embolism. Paradoxical embolism refers to a thromboembolism occurring within the venous vasculature as an embolus traverses from right to left through the cardiac shunt into the systemic arterial circulation (venous thromboembolism or VTE). The most severe complication of paradoxical embolism occurs when an embolus lodges within the cerebral circulation, resulting in cerebral infarction (stroke). Most frequently, VTE is the result of in situ thrombosis (deep vein thrombosis or DVT) within the deep veins of the lower extremities or pelvis.

[0063] HF is a well-recognized risk factor for DVT and VTE, especially in patients with reduced left ventricular systolic function, as reported in Howell MD, et al. "Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study" J Clin Epidemiol. 2001;54:810-816. Approximately 3% of deaths in patients with heart failure are due to VTE, which is usually associated with pulmonary embolism, as reported in Beemath A, et al. "Pulmonary embolism as a cause of death in adults who died with heart failure" Am J Cardiol. 2006;98:1073-1075. There is evidence that the risk of paradoxical embolism is directly related to the orifice size of naturally occurring atrial level shunts, such as ASD. In patients with clinically significant ASD (typically 20 mm or greater in diameter) referred for occlusion, the incidence of paradoxical embolism has been reported to be up to 14%. See, e.g., Chiche O, et al. "Prevalence of patent foramen ovale and stroke in pulmonary embolism patients" Eur Heart J. 2013;34:1142 and Bannan A, et al. "Characteristics of adult patients with atrial septal defects presenting with paradoxical embolism" Catheter Cardiovasc Interv 2009;74:1066-9.

[0064] Clinically relevant venous emboli tend to form more proximally in the popliteal vein or in the larger veins of the upper thigh or pelvis. The diameter of the popliteal vein ranges from 6.2 to 20.1 mm. Often, emboli are described as having the morphology of a cylinder of the venous lumen, with a width equal to the diameter of the originating vein. These thrombotic tendencies also tend to be elongated and correspond to the length of the occluded venous segment. Since ischemic damage from embolic blockages is limited to the draining organ territories supplied by the occluded vessel, larger emboli tend to cause more damage and have more dangerous consequences associated with them, especially when the occluded vessel perfuses the brain.

[0065] From these observations, it seems reasonable to expect that orifice-plate mesh shunts would theoretically have a similar risk of paradoxical embolism due to their anatomical similarity to congenital ostium secundum ASD. It is easily understandable that thin plate-orifice mesh type artificial shunts may be more susceptible to paradoxical embolism than other types of shunts with longer orifice geometries, e.g., nozzles. For any given amount of RA volume (blood or thrombus), the statistical likelihood of retrograde crossing the shunt into the LA would be expected to be a complex function of the duration of pressure gradient reversal, the flow pattern within the RA, the shunt tunnel distance, which affects the length of the flow velocity streamline, the flow velocity, and the orifice size.

[0066] A third disadvantage of orifice-plate mesh shunts is that percutaneous removal from the body is only possible at the time of implantation. If the shunt develops fatigue or corrosion cracks in its metal framework that become a nidus for infection, or erodes or otherwise impinges on other vital cardiac structures, it cannot be removed by percutaneous retrieval / removal techniques. This is because the shunt, with its large "footprint" on the interatrial septum, is enclosed within pannus tissue. The shunt can only be safely removed by open-heart surgery. This involves the heart being bypassed using an extracorporeal membrane pump oxygenator (cardiopulmonary bypass), thus opening the heart, the shunt being removed by extensive surgical dissection of the pannus, and the septum being repaired. Performing such a surgical procedure in patients with already established severe HF or PAH would likely be contraindicated due to unacceptable morbidity and mortality risks.

[0067] A fourth disadvantage of orifice-plate mesh type shunts is that their geometry makes them relatively inefficient in supporting high flows. For any given pressure gradient across the shunt, the orifice plate geometry requires a larger orifice because it has a reduced effective orifice size compared to other geometries such as a venturi-shaped lumen or a cone-shaped nozzle. This is because with an orifice-plate, there is more energy loss associated with vortex flow at the edge of the orifice. Orifice-plate geometries can be categorized as having a relatively low discharge coefficient, which is a dimensionless fluid-mechanical parameter that relates the flow to the actual orifice size. For practical purposes, the discharge coefficient is the ratio of the area of ​​the exiting jet vena contracta, the narrowest part of the jet, compared to the shunt orifice. For example, the discharge coefficient for an orifice plate installed in a pipe tends to be around 0.6, but rarely exceeds 0.65. The outflow coefficient is affected by the orifice and chamber dimensions, the pressure gradient, and the viscosity and / or Reynolds number of the blood for the specific flow conditions. This differs from the more efficient passage of flow through a constricted nozzle or classical Venturi-type constriction, where the outflow coefficient is usually greater than 0.9 and typically in the range of 0.94-0.98. As a result, compared to more efficient shunt lumen geometries, orifice-plate mesh shunts require a larger orifice diameter to accommodate the same amount of flow for any given pressure difference across the shunt.

[0068] Sizing decisions for orifice-plate mesh type shunts come from the study of Kaye et al. "Effects of an interatrial shunt on test and exercise hemodynamics: results of a computer simulation in heart failure" J Cardiac Fail 2014;20:212-221, who simulated the hemodynamic effects of an ASD using a validated computer model based on hemodynamic data from HFpEF patients. They inferred that the optimal size for a plate orifice type of shunt resembling an ASD was 8 mm in diameter by showing that LAP would be reduced from 28 mmHg to 17 mmHg during exercise. The tradeoff was a 12% reduction in peak cardiac output and a pulmonary to systemic blood flow ratio (Qp:Qs) of 1.3 to 1.4, as well as a slight increase in RA pressure. With a smaller shunt orifice size, e.g., 6.4 mm, the exercise LAP was still reduced to about 20 mmHg with a smaller reduction in systemic cardiac output, with smaller Qp:Qs, and without any apparent increase in right atrial pressure. After healing, it can be expected that an orifice-plate mesh type shunt may have a reduction in the mean orifice diameter in the 6 mm range. However, a nozzle or venturi configuration with an orifice diameter ranging from 5 to 6 mm would be equivalent to an orifice plate ASD diameter of about 6.3 to 7.4 mm.

[0069] A fifth disadvantage of orifice-plate mesh shunts is that they tend to occupy a large area or footprint on the interatrial septum. The flanges of the device that anchor the shunt typically occupy the entire area of ​​the fossa ovalis and may overlap the adjacent muscular portion of the interatrial septum. These flanges exert a constant pressure on the septum, causing injury and stimulating an exacerbated healing response as described above. Also, the stiffness of the mesh may interfere with the normal motion of the muscular septum. The flanges may additionally impinge on adjacent cardiac structures such as the roof of the left atrium, the right pulmonary vein ostium, and the aortic root and sinuses of Valsalva, and due to chronic abrasive contact or constrictive compressive forces, they may erode into these critical structures. Such erosion has been associated with severe complications, including cardiac tamponade and death. For example, the similarly sized Amplazer ASD disk occlusion device described above has been associated with erosion into adjacent tissues, occasionally with a fatal outcome.

[0070] A sixth disadvantage of orifice-plate mesh shunts is the potential difficulties associated with placing a relatively large device with a complex three-dimensional geometry, i.e., accurately positioning the shunt within the FO, obtaining sufficient tissue anchoring, preventing migration, and having the device conform to irregularities in the cardiac anatomy. For example, in a report of orifice-plate mesh shunt implantation attempts in 66 patients in the above-cited Lancet publication by Hasenfuss, et al., device placement of the IASD II was not possible in two patients. Also, of the 64 implanted patients, the device had to be removed or reimplanted in another three patients due to misplacement, migration, or embolism on the first implantation attempt.

[0071] The last and seventh disadvantage of orifice-plate mesh shunts is that their large footprint on the atrial septum may prevent or make it impossible to perform other interventional procedures that require transseptal access. The large flange diameter and small mesh pore size generally allow catheter crossing of the atrial septum only through the central shunt orifice itself. Transseptal procedures using small diameter catheters, such as atrial fibrillation RF ablation, can be performed through the orifice-plate lumen only if it is not blocked by pannus and the orifice location allows access into all four pulmonary veins. Other structural heart disease procedures that have large diameter delivery systems and / or require crossing the FO at a specific location may encounter difficulties or simply be impossible. These procedures include left atrial appendage occlusion, mitral valve marginal ("MitraClip") repair, and transvascular mitral valve replacement. For example, optimal placement of the MitraClip requires subsequent crossing of the FO in the superior quadrant. The guiding catheter has a tip outer diameter of 7.3 mm (22 Fr). Similar transseptal access may be required to perform a revision mitral valvuloplasty with the Cardioband device sold by Valtech. In these cases, the only alternative may be a higher-risk therapeutic approach involving trans-left ventricular apical access or open-heart surgery.

[0072] The second type of shunt is called a valved unidirectional shunt. These shunts attempt to overcome some of the shortcomings of the orifice-plate device. For example, valved unidirectional shunts have embodiments that contain one-way or check valves to limit reverse shunting and paradoxical embolism. Some of the valve configurations are designed to open when the LA-RA pressure gradient exceeds a certain threshold. Other valve configurations close only when the RA pressure exceeds the LA pressure (reverse gradient).

[0073] U.S. Patent No. 9,034,034 to Nitzan, the entire contents of which are incorporated herein by reference, addresses many of the shortcomings of plate-like orifice mesh shunts described above. One embodiment of a Nitzan-type shunt includes an hourglass or diabolo outer shape and has a small FO footprint that minimizes septal injury, which is expected to minimize pannus growth and obliteration of the shunt lumen. The one-way valve is also designed to reduce the potential for reverse shunting and paradoxical embolism. The relatively small footprint of the shunt in contact with the septum and the encapsulated collapsible nitinol frame are designed to facilitate percutaneous extraction from the septum and retrieval from the body using a standard S-tube snare and large bore sheath, thus making the device easier to retrieve. The venturi-like inner lumen of the diabolo shape provides better bulk flow characteristics and allows for a smaller orifice for the same amount of flow compared to orifice plate shunts. And finally, the small footprint on the FO and hourglass shape are designed to facilitate accurate placement and retention during implantation. This geometry also minimizes interference with the normal motion of the interatrial septum, and the small footprint provides space to surround the shunt for other potential interventional procedures requiring transseptal catheter placement.

[0074] One embodiment of the Nitzan design was implemented as a first generation "valved" shunt manufactured by V-Wave, Ltd (Caesarea, Israel). Designed to support unidirectional left / right flow, the shunt has a self-expanding frame constructed from laser cut Nitinol tubing. The frame includes five sinusoidal circumferential struts interconnected by six longitudinal bars. The frame is heat set so that it has an asymmetric hourglass or diabolo shape. The shunt is deployed such that the neck (5.3 mm outer diameter) is placed across the FO and secured in place by its outer geometry. The widest part of the shunt has a conical shape with an outer diameter of approximately 14.3 mm at the LA end of the shunt, which serves as the "entry" port on the distal end of the inlet funnel in the HF. The inlet funnel is deployed in the left atrium to align the neck of the shunt with the region of the FO. A second, slightly narrower, bell-shaped section forms the exit portion of the shunt, which expands to a maximum outer diameter of 11.4 mm at the RA end of the shunt. The shunt does not require flanges, discs, or tissue anchors to secure it in place. Septal retention is achieved without the application of constant pressure, tension, or abrasive contact on the tissue adjacent to the device neck.

[0075] The aforementioned valved shunt has a single inner lumen, where flow is entrained in an inlet funnel in the LA, passes through a constricted neck with a 5.1 mm inner diameter, similar to a Venturi-type orifice, and then exits through a bioprosthetic valve positioned near the RA end of the shunt. The inlet funnel and central neck region are encapsulated with expanded polytetrafluoroethylene (ePTFE) to form a skirt or cover over the frame. The skirt is designed to promote laminar flow and limit pannus ingrowth during device healing. The outlet bell-shaped portion contains three glutaraldehyde-fixed porcine pericardial leaflets that are sutured to a series of holes in the Nitinol frame in the right atrial region of the ePTFE encapsulation. The leaflets are designed to create a smooth outlet channel, remain in an open position, and close only when RA pressure exceeds LA pressure by 1-2 mmHg, thus preventing reverse right-to-left shunting.

[0076] For deployment, the V-Wave shunt is compressed within a loading tube, which is attached to a triple-latch cable delivery catheter. The loading tube is inserted into the 14F delivery introducer sheath previously placed after transseptal catheter placement from the right femoral vein across the FO. The shunt is then advanced through the sheath until the inlet funnel is deployed into the LA. The entire system is withdrawn as a unit until the LA funnel contacts the left side of the FO. The delivery catheter latch is unlatched from the shunt and the delivery catheter is withdrawn, thus holding the right atrial side of the shunt against the delivery sheath by its radial force alone. The delivery sheath is then withdrawn, thereby deploying the outlet bell-shaped portion of the shunt on the RA side of the FO. Device placement can be guided and confirmed by fluoroscopy and echocardiography, e.g., intracardiac or transesophageal echo.

[0077] Preclinical studies on the V-Wave shunt were conducted in an established young sheep model that produced an ischemic cardiomyopathy form of heart failure as established in the peer-reviewed publication by Eigler et al. "Cardiac Unloading with an Implantable Interatrial Shunt in Heart Failure: Serial Observations in an Ovine Model of Ischemic Cardiomyopathy" Structural Heart 2017;1:40-48. Sheep were pretreated with sequential coronary microembolization as described in the publications by Huang et al. "A stable ovine congestive heart failure model" and "Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular response" Am J Physiol Heart Circ Physiol. 2004;286:H2141- H2150. After several weeks, sheep developed severe LV systolic dysfunction and elevated LV, LA, and pulmonary artery pressures. Once HF was established, sheep were enrolled in a 12-week survival study. V-Wave valved shunts were associated with significant improvements in LA pressures and LVEF. All episodes of worsening heart failure were ameliorated and, in some cases, reversed with an interatrial shunt. However, concurrent control animals with established heart failure were not implanted with V-Wave shunts and demonstrated progressive deterioration in LVEF and intracardiac / pulmonary pressures during follow-up. Physiologic improvements in shunted animals were substantial, even when shunt volumes were assessed to be insignificant. Pulmonary / systemic blood flow ratios (Qp:Qs), as measured by oximetry, were 1.1-1.2, which is consistent with a very small shunt and was well tolerated.The 5 mm diameter shunt selectively unloaded the left heart, leading to a sustained reduction in LAP, improving LV performance, preserving inotropic and lusitropic function, and inhibiting remodeling. Secondary pulmonary hypertension was prevented, and right-sided heart pressures and function were preserved.

[0078] [ka] In another peer-reviewed published manuscript by, n=38 patients were implanted with a V-Wave valved shunt in a human feasibility study. Patients were 66±9 years old with NYHA class III or ambulatory class IV HF and had either HFrEF (n=30) or HFpEF (n=8). Comorbidities known to be associated with poorer prognosis were frequently present, including coronary artery disease, diabetes, atrial fibrillation, and chronic renal dysfunction. Other risk factors included elevated levels of natriuretic peptides, reduced exercise capacity, elevated intracardiac and pulmonary artery pressures, increased pulmonary vascular resistance, and reduced cardiac output. All patients underwent GDMT prior to study enrollment. Shunt implantation was successful in all 38 patients with no perioperative mortality, and no device exchanges were performed. The time to completion of all study-related procedures, including shunt placement, averaged just over 1 hour.

[0079] The rate of major device- or procedure-related complications during the first 12 months was 2.6% (perioperative cardiac tamponade resulting from transseptal catheter placement was observed in one patient). There were no device-related deaths, strokes, or thromboembolic events during a median follow-up of 28 months. There were no cases of device dislodgement, migration, embolism, thrombosis, or erosion on follow-up echocardiograms. No shunts required removal or replacement for infection or strut cracking. Follow-up imaging studies indicate that there remained adjacent locations on the FO potentially available to perform transseptal procedures and treat other cardiac conditions, including, for example, atrial fibrillation ablation, left atrial appendage occlusion, or mitral valve repair.

[0080] Pulmonary-to-systemic flow ratio (Qp:Qs) as measured by echocardiography increased from 1.0±0.1 at baseline to 1.2±0.1 at 3 months post-implant (p<0.01). At 3 and 12 month follow-up, there was improvement in NYHA class (classes I and II in 78% and 60% of patients, respectively), quality of life (>5 point improvement in 74% and 73% of patients, respectively), and 6MWD (mean increase of 41±63 and 28±83 m, respectively, p<0.02 for all), without changes in objective measures of systolic, diastolic, or global RV function. Rates of HF hospitalization and all-cause mortality were substantially and significantly below expected compared to the specifically matched CHAMPION control and treatment groups described above.

[0081] Shunt patency was defined as LA to RA flow through the shunt on a transesophageal echo / Doppler study. All shunts were patent at 3 months, but by 12 months, 5 of 36 (14%) had become obstructed and another 13 of 36 (36%) had stenosis (narrowing) at the valve. The underlying cause of the valve stenosis was definitively determined. Excised V-Wave shunts from three patients were retrieved and underwent histopathological analysis at 30, 34, and 27 months after implantation. Two of the patients required cardiac transplantation and the third patient died due to progressive progression of HF. The implant site was completely healed as evidenced by coverage of the implant surface by fully mature, endothelialized (CD31 positive) fibrocellular neoendocardium. Complete endothelial coverage was demonstrated microscopically and via SEM. Local biocompatibility was optimal in all explants, as demonstrated by the complete lack of inflammatory response to the collagenous apical bioprosthetic leaflets, the polytetrafluoroethylene (ePTFE) encapsulation, or the metal frame. No thrombosis was recorded. The bioprosthetic leaflets lost motility due to adhesion of their commissural edges by fibrous cellular pannus. The interatrial channel remained patent, and there was no pathological or functionally significant calcification in the conduit or tip. Thus, the bioprosthetic leaflets were thickened and narrowed with neoendocardial hyperplasia (pannus).

[0082] At a median follow-up of 28 months, patients with widely patent shunts had lower long-term rates of death, left ventricular assist device placement or heart transplant (p<0.001), and HF hospitalization (p<0.008), along with a reduction in pulmonary capillary wedge pressure (23.3±5.4 mmHg at baseline to 18.0±4.0 mmHg at 12 months, p<0.011). Patients who maintained widely patent shunts tended to be older and had more severe underlying cardiac disease and comorbidities, particularly reduced renal function, lower exercise capacity, worse resting hemodynamics, and lower LVEF in HFrEF patients. Patients with widely patent shunts also had significantly higher shunt flows during the early months after implantation. These "sicker" patients maintained their bioprosthetic leaflets in a more open configuration due to the higher shunt flow. Patients with stenosed shunts behaved as crossover controls and returned to a natural rate of disease progression after 1 year. Subjects with patent shunts had improvements in PCWP, PAP, pulmonary vascular resistance, LVEF, and exercise capacity. Subjects also had fewer long-term heart failure events, including death, HF hospitalization, combined death and HF hospitalization, or hospitalization for any cause. Patients with patent shunts did not have a deterioration in right heart function. It was therefore concluded that having a long-term patent shunt is of great clinical advantage. These observations established the proof of concept that interatrial shunts have the intended device effect.

[0083] V-Wave went on to develop a second generation Nitzan type shunt, called the Ventura® interatrial shunt, in which the bioprosthetic tissue valve was removed and an ePTFE encapsulated skirt extended from the left atrial inlet port to the right atrial outlet port. Data from GLP and non-GLP chronic preclinical studies of normal physiology animal models showed that 31 consecutive 5.1 mm valveless shunts were successfully implanted. All shunts were widely patent at follow-up ranging from 45 to 180 days. Valveless shunts heal with neointimal hyperplasia (pannus) forming over the external seal where the neck crosses the fossa ovalis. Even if one of the atrial cones of the shunt contacts an atrial structure, the pannus tends to leave the lumen in the neck region widely patent and preserve shunt function intact. Endothelialization developed progressively over the luminal surface of the ePTFE encapsulation. The normal physiology model had a transatrial left-right gradient of 2-3 mmHg, much smaller than that expected in HF. Nevertheless, the shunts remained widely patent without evidence of device thrombosis, whether treated with anticoagulation or dual antiplatelet therapy. There was no thromboembolism or infarction of any downstream organs.

[0084] Second-generation Ventura® shunts are currently being implanted in a small (n=14) patient feasibility study and in 82 of 100 scheduled patients in the open-label roll-in enrollment arm of the RELIEVE-HF pivotal trial (NCT NCT03499236). All patients were successfully implanted with a shunt. According to transesophageal echocardiographic follow-up at 6 months, 47 of 47 shunts that reached 6-month follow-up in the RELIEVE-HF roll-in enrollment are widely patent.

[0085] In summary, these implantable shunt devices, regardless of the specific design features, have consistently demonstrated beneficial therapeutic effects in patients with HF, with left-to-right interatrial shunts decompressing left cardiac preload, resulting in improved symptoms, exercise capacity, quality of life, and a reduction in episodes of HF exacerbation requiring emergency hospitalization. Similar outcome results have been reported for all shunt devices in different patient populations encompassing nearly all etiologies of HF, regardless of LV ejection fraction. Thus, there is a strong class effect associated with improved physiology from having and maintaining a patent left-to-right interatrial shunt over a range of optimal shunt orifice sizes. Similarly, interatrial shunt results in PAH indicate that right-to-left shunts reduce RV preload, with associated improvements in symptoms, exercise capacity, quality of life, and potentially a reduction in episodes of acute exacerbation of right-sided HF requiring hospitalization. Whether by BAS or shunt, the class effect has been demonstrated in that the beneficial mechanism is improved physiology to have and maintain a patent right-to-left interatrial shunt over a range of optimal shunt orifice sizes. Nevertheless, as discussed, orifice-plate mesh type shunts are believed to have several significant shortcomings that may limit their adoption by practitioners. The second generation Ventura® shunt device and other similar designs overcome all of the shortcomings of the orifice-plate mesh shunt design.

[0086] Specifically, the dimensions and materials of the Ventura® shunt make it highly resistant to narrowing due to pannus or thrombus formation. Pannus formation is arrested some distance before its migratory growth along the shunt surface can reach the orifice lumen. The length of the shunt, its orifice size, and the protrusion of the protective hood into the right atrial chamber reduce the likelihood and severity of paradoxical embolism. These shunts are successfully percutaneously removed after up to 6 months in animal models, leaving a residual 5 mm round defect in the septum, another differentiating feature. The nozzle or Venturi effect with high outflow coefficient makes these shunts highly efficient relative to orifice-plate mesh shunts, allowing for a smaller size, and in conjunction with their external hourglass shape, they occupy the smallest available footprint on the fossa ovalis. The external shape, by itself, anchors the shunt in place without pinching septal tissue. The external hourglass shape also reduces contact with adjacent areas, greatly limiting the chance of device erosion into critical cardiac structures. This geometry makes shunt delivery in complex 3-dimensional anatomical structures relatively simple, with a near 100% success rate. Finally, the small footprint leaves ample space to access the LA from other locations on the fossa ovalis adjacent to the shunt, allowing a wide range of structural heart disease and electrophysiologic ablation procedures to be performed following shunt placement and healing. (Known efforts to incorporate sensors with shunts)

[0087] Shunts incorporating sensors are described, for example, in U.S. Patent No. 8,091,556 B2 to Keren et al., U.S. Patent No. 8,070,708 B2 to Rottenberg et al., U.S. Patent No. 9,681,948 B2 to Levi et al., and U.S. Patent Nos. 8,696,611 B2 and 9,707,382 B2 to Nitzan et al., all of which are assigned to the assignee of the present disclosure and the entire contents of each are incorporated herein by reference. U.S. Patent No. 10,413,284 B2 to McNamara, the entire contents of which are incorporated herein by reference, also describes shunts having sensors, as described below. These patents generally describe that sensors can be incorporated into interatrial shunts to adjust the orifice area of ​​a valve or gate via mechanical means, for example, with a motor, and that sensor information can be useful for other purposes, such as making diagnoses and guiding drug therapy.

[0088] As an example, U.S. Patent No. 8,091,556 to Keren et al. describes a method of reducing LAP using a shunt equipped with a flow regulator, such as a valve controlled by a sensor, a programmable signal processor, and a power source. The processor collects data and can communicate externally, even to the patient, who can then notify a physician when the device is activated due to a worsening HF condition. The physician then establishes medical therapy to reduce the severity of the patient's condition.

[0089] U.S. Patent No. 8,070,708 B2 to Rottenberg et al. describes an interatrial shunt with a flow regulation mechanism that responds to changes in differential pressure between the atria. The flow regulation mechanism may include a valve that changes in a controlled manner by a differential pressure threshold. In some embodiments, the differential pressure regulation device may be actively controlled, for example, by the patient or a healthcare provider. In another embodiment, a pressure-dependent closed loop is described that employs one or more pressure transducers. The pressure transducers may measure one or more ventricles, the LAP, absolute pressure at the RAP, or the differential pressure between two of these or any two ventricles. The implant may be wirelessly controlled from an external transmission unit. Blood flow changes in response to valve positioning may be monitored remotely.

[0090] U.S. Patent No. 9,681,948 B2 to Levi, et al. describes a medical implant with an opening for blood flow through the interatrial septum that may have a sensor mounted on the anchor portion of the interatrial shunt device. The anchoring device may include a flap or other unit adapted to close the orifice, and the opening and closing of the flap may be controlled in response to the sensor output. The sensor may be located adjacent to the device or remote from the device. Operating energy may be provided to the controller by an embedded battery and / or by an external source. In some embodiments, the anchor device is coupled to a pacemaker or ICD and shares its power source. For example, the opening of the flap may depend on the absolute pressure in one or more of the ventricles, on the temperature in one or more of the ventricles, on the patient's blood pressure, and / or on the patient's blood oxygen content. The control may also depend on any of the parameters used by the pacemaker, for example, in synchronous pacing. A sensor may be mounted on a petal or petals of the anchor portion of the shunt located on one side of the atrial septal wall, while a second sensor is mounted on a petal located on the other side of the wall. Thus, readings from both of the sensors may be read and compared to determine the relative condition on the other side of the atrial septum. The patent explains that any type of sensor may be used, and that more or fewer sensors may be mounted on the anchor portion of the shunt device. For example, the sensors may include one or more pressure sensors, oxygen sensors, B natriuretic peptide (BNP) sensors, sensors of toxic components, flow sensors, and / or pH sensors.

[0091] U.S. Patent Nos. 8,696,611 B2 and 9,707,382 B2, both to Nitzan et al., describe embodiments of a diabolo-shaped shunt for adjusting blood pressure between two atrial chambers. The patents include experimental evidence that interatrial pressure difference can be measured by leaflet opening angle, and postulate that the angle can be determined by imaging modalities such as ultrasound. By quantifying the pressure, a physician can then adjust medication to help stabilize the patient and prevent (pulmonary) edema.

[0092] U.S. Patent No. 10,413,284 B2 to McNamara et al. describes a system for treating a cardiac condition in a patient, the system comprising a cylindrical core section defining a passageway, a first annular flange adapted to engage a first surface of the atrial septum, a second annular flange adapted to engage a second surface of the atrial septum, and a motor mounted to a body element coupled to the movable flap to form an opening in the atrial septum and allow blood to flow between the left and right atria. The patent describes the system further including a sensor for detecting data related to at least one of blood chemistry, blood pressure, temperature, electrical characteristics of the patient's heart, chemical characteristics of the blood, and biomarkers in the blood. The patent further describes the system may include a microprocessor in communication with the sensor. A sensor for detecting a plurality of physiological parameters associated with the heart is described. The system may communicate with a remote monitoring facility, which may include the capability to display the sensor data, control devices to deliver therapy to the patient, present the data to a clinician, and recommend appropriate treatment, such as administration of medication, based on the physiological data acquired by the sensors.

[0093] In view of the foregoing, it would be advantageous to provide an inter-atrial shunt that overcomes the shortcomings of known systems and devices, provides long-term patency, and additionally can provide actionable data regarding intracardiac physiological parameters that can be used to enable patients and their physicians to modify the course of a patient's treatment and / or medication.

[0094] Thus, a need exists for an inter-atrial shunt system and method that provides an inter-atrial shunt with demonstrated beneficial flow characteristics and long-term patency, includes one or more sensors that provide actionable data regarding intracardiac physiological parameters, and enables patients and their physicians to modify the course of the patient's treatment and / or medication. [Prior art documents] [Non-patent literature]

[0095] [Non-Patent Document 1] Pretorious V, et al. “An implantable left atrial pressure sensor lead designed for percutaneous extraction using standard techniques” Pacing Clin Electrophysiol 2013 May;36(5):570-7 Summary of the Invention [Means for solving the problem]

[0096] The present invention describes devices and methods for making and using improved interatrial shunts incorporating sensors to improve treatment and outcomes for patients with cardiovascular and cardiopulmonary disorders, specifically HF and PAH. More specifically, an interatrial shunt with an integrated physiological sensor is provided for monitoring and treating cardiovascular syndromes, including heart failure and pulmonary hypertension. In accordance with the principles of the present invention, one or more sensors are attached to the shunt to measure physiological parameters within the interatrial shunt, either directly affixed to or within the luminal surface of the shunt or mounted on a support structure disposed in spaced relation to the shunt lumen, with the one or more sensors positioned in a location that is subject to little or no pannus formation or cardiac wall motion artifacts.

[0097] As discussed in this disclosure, suitable sensors for use with implantable interatrial shunts illustratively measure pressure, blood flow, or blood velocity. In the embodiments presented, it should be understood by those skilled in the art that the term sensor is used in its most general sense as a device for measuring any suitable type of environmental phenomenon, including detecting an event or change in that environment. More specifically, implantable sensors suitable for use in the shunts of the present invention are those that indicate physiological parameters of interest and / or allow for the determination of specific therapeutic effects, including, but not limited to, flow, velocity, acceleration, pH, oxygen content or saturation, or concentrations of chemical species such as B-type natriuretic peptide.

[0098] In particular, interatrial shunts well suited for use in constructing devices according to the invention are described in U.S. Patent Nos. 9,707,382 B2, 9,980,815 B2, and 10,639,459 B2 to Nitzan et al., U.S. Patent Nos. 10,076,403 B1 and 10,251,740 B2 to Eigler et al., and U.S. Patent Application Publication Nos. US 2019 / 008628 A1 and US 2019 / 0262118 A1, and U.S. Patent Application Publication No. US 2019 / 0110911 A1 to Nae et al., each of which is incorporated herein by reference in its entirety. These shunts overcome many of the shortcomings of known shunts by having a suitable combination of design geometries and biomaterial properties, including having an encapsulating surface. Specifically, they: 1. reduce the susceptibility of the shunt to narrowing or closure due to neoendocardial tissue ingrowth, referred to as pannus, during the post-implant healing cycle; 2. reduce the potential and consequences of paradoxical thromboembolism from the right atrium to the left atrium; 3. facilitate the ability to non-surgically remove an implanted shunt that has embolized or completely healed from the body; 4. improve shunt effective orifice size relative to true orifice size; and 5. reduce shunt septal footprint, reduce interference with septal wall motion, minimize shunt impingement against the septum and adjacent cardiac structures, simplifying and improving shunt deployment success and allowing adjacent septal access for procedures requiring entry into the left atrium via a transseptal route.

[0099] In view of the aforementioned shortcomings of known interatrial shunts, a shunt with a sensor constructed according to the principles of the present invention provides a more durable configuration that maintains luminal patency over extended periods of time. The shunt of the present invention allows monitoring of atrial pressure and flow rate, thereby allowing a physician to adjust the patient's medication regimen, or in some embodiments, the flow characteristics of the shunt to redistribute interatrial blood volume and adjust pressure imbalances while reducing the risk of paradoxical embolism. Implantable sensors are provided to monitor, detect, and diagnose cardiovascular and cardiopulmonary conditions. Sensor data can be communicated to an external patient display device via RF telemetry or inductive coupling on a continuous or episodic basis and used as a guide to change or adjust medication therapy, add a proven device therapy, or perform a procedure to modify the physiological characteristics of the shunt. Data communicated from the implantable sensor can also be relayed in an encrypted format to the patient's physician via a suitable wide area network, such as telephone or the Internet.

[0100] With respect to utility in treating HF and PAH, anticipated outcomes of use of the shunts of the present invention include improved safety, improved implantation procedural success, long-term device performance and clinical efficacy, with resulting improvements in symptoms, exercise capacity, quality of life, and reduced episodes of clinical decompensation resulting in hospitalization and mortality. Additionally, the shunts of the present invention will reduce the adverse effects associated with the use of separately implanted shunts and sensors in close proximity to the interatrial septum, which may impede access to the left atrium for other therapeutic procedures, such as mitral valve repair, left atrial appendage occlusion, and treatment of atrial fibrillation with pulmonary vein ablation.

[0101] In accordance with the principles of the present invention, the shunt of the present invention provides HF patients with a reduction in left atrial pressure, relieving pulmonary congestion and lowering pulmonary artery pressure, among other benefits. The device of the present invention is configured for implantation across the interatrial septum, preferably through the fossa ovalis, as a unit or as part of a single procedure. Alternatively, the shunt portion of the device may be implanted first, with the option to add or activate a sensor component immediately thereafter, or at some unspecified later time when clinical utility is demonstrated.

[0102] In particular, the shunt constructed according to the principles of the present invention is designed to control the LAP by transferring a portion of the blood that normally flows from the left atrium to the left ventricle and diverting it instead to the right atrium, thereby gently reducing the LV end-diastolic filling volume. When the LAP is elevated, the LV operates on a steeper portion of its diastolic compliance curve. Thus, even a moderate reduction in LV end-diastolic volume can lead to a substantial drop in LV end-diastolic pressure. The reduction causes a consistent reduction in upstream filling pressures, including LAP, pulmonary venous pressure, and pulmonary artery pressure. The expected clinical outcome of these pressure reductions is expected to alleviate or even prevent pulmonary congestive symptoms. With smaller interatrial gradients with fewer shunts, the effect on LV volume and filling pressure becomes progressively smaller until it becomes negligible. Because interatrial shunts primarily affect LV filling and not afterload, a beneficial effect on lowering end-diastolic pressure would be expected for patients with heart failure associated with reduced ejection fraction (HFrEF) and for patients with heart failure with preserved ejection fraction (HFpEF), regardless of LV systolic function.

[0103] According to one aspect of the present invention, the shunt portion characteristics are optimized to overcome the shortcomings and limitations of known orifice-plate mesh type shunts. Thus, the shunt portion of the device of the present invention employs the shunts described in the above-incorporated patents and published applications of Nitzan et al., Eigler et al., and Nae et al. Furthermore, according to the present invention, one or more sensors are attached to the shunt, either directly or via a support structure, such that the sensors do not substantially detract from the shunt operation, do not interfere with the deliverability of the shunt, and do not impede access via the shunt to the left ventricle for subsequent interventional procedures.

[0104] The present invention provides a shunt incorporating a sensor to measure one or more of LAP, RAP, blood flow or blood flow velocity through the shunt orifice, or other intracardiac parameters. A sensor anchoring, storage, deployment procedure, and method of use are provided that minimizes interruption of shunt flow, maintains the smallest achievable size and septal footprint, is consistent with current best shunt deployment techniques, utilizes a reliable anchoring system, uses shunt design geometries and biomaterials to reduce waveform artifacts and extraneous sensor drift, and works seamlessly with the associated shunt to best utilize sensor data to manipulate medication in the setting of the shunt. Unlike current stand-alone intracardiac sensors, preferred embodiments of the present invention also allow measurement of shunt flow characteristics, a key physiological parameter that can guide therapy.

[0105] Subjects with various cardiac pathologies may be treated with and benefit from the shunt of the present invention. For example, in subjects with HF, improved control of LAP and LVEDP may provide various benefits, including, but not limited to, reduced pulmonary congestion, reduced pulmonary artery pressure, increased LVEF, increased fractional shortening, and reduced LV internal diameter in systole. Other cardiac pathologies that may be beneficially treated include large myocardial infarction with or without concomitant acute HF, which may be treated by deploying the device during or immediately after the myocardial infarction to reduce adverse myocardial remodeling and the development of refractory HF. Patients with acute viral myocarditis may be helped as well. The shunt of the present invention may also reduce the need for or aid weaning from extracorporeal membrane oxygenation (ECMO) devices, or reduce the need for emergency ventricular assist devices for heart transplantation. Patients with mitral valve repair using MitraClip or other similar therapies may benefit from the placement of the shunt of the present invention at the site of transseptal crossing to help further manage residual HF. Similar benefits may exist for patients undergoing pulmonary vein ablation for atrial fibrillation. A shunt constructed according to the principles of the present invention may also be used to manage residual HF resulting from left-sided heart dysfunction, which may similarly help maintain sinus rhythm. Patients with PAH, whether idiopathic or from associated causes, may benefit from the dual effects of a right-to-left shunt that unloads the RV and sensor-guided adjustment of medications that affect RV preload and afterload.

[0106] According to another aspect of the present invention, an alternative inter-atrial shunt for treating heart failure (HF) or pulmonary arterial hypertension (PAH) by shunting blood to relieve high pressure and monitoring at least one atrial physiological parameter is provided. The inter-atrial shunt may include an anchor having a first flared region, a second flared region, and a neck region disposed between the first and second flared regions, and a biocompatible cover disposed on the anchor and forming a lumen extending from the first flared region to the second flared region. In addition, the inter-atrial shunt may include a sensor having a housing, a sensing surface, and circuitry disposed within the housing for generating data indicative of the at least one atrial physiological parameter and communicating the data. The sensor may be pivotally coupled to the first flared region, for example, via a torsion spring, such that the sensor may transition between a delivery configuration and a deployed configuration in which the sensing surface is in fluid communication with the lumen. The biocompatible covering may include an opening sized and shaped to expose a sensing surface of the sensor when the sensor is in the deployed configuration such that the sensing surface is in fluid communication with the lumen.

[0107] The anchor may include a plurality of longitudinal struts interconnected by a plurality of circumferential struts and may transition between a folded delivery state and an expanded deployed state. In the deployed configuration, the sensor may be positioned between adjacent pairs of longitudinal struts of the plurality of longitudinal struts and between adjacent pairs of circumferential struts of the plurality of circumferential struts such that a sensing surface of the sensor is not obstructed by the plurality of longitudinal and circumferential struts when the sensor is in the deployed configuration. The torsion spring may be coupled to an outermost circumferential strut of the first flare region such that the torsion spring may pivot the sensor around the outermost circumferential strut. For example, a first end of the torsion spring may be coupled to the housing of the sensor and a second end of the torsion spring may be coupled to a longitudinal strut of the first flare region such that a portion of the torsion spring between the first and second ends wraps around the outermost circumferential strut. Additionally, the torsion spring can be constructed to bias the sensor toward the deployed configuration such that during delivery of the inter-atrial shunt within the delivery sheath, the sensor is held in the delivery configuration by the inner wall of the delivery sheath such that upon exiting the delivery sheath, the sensor transitions to the deployed configuration, in which the sensor can extend axially away from the anchor.

[0108] The sensing surface of the sensor may include a flexible sensing diaphragm. Additionally, the sensor may include a ferrite core wound over a telemetry coil disposed within the housing. The sensor may further include a MEMS sensor disposed within the housing. For example, the MEMS sensor may be selected from a list consisting of Wurth, TDK, or Fraunhoffer sensors. Alternatively or additionally, the sensor may include a strain gauge disposed within the housing. The data generated by the sensor may indicate left atrial pressure, right atrial pressure, or a rate of blood flow through the lumen. In some embodiments, the inlet of the first flared end region may be in a first plane and the outlet of the second flared end region may be in a second plane such that the first plane intersects with the second plane in the expanded deployed state.

[0109] According to yet another aspect of the present invention, a system is provided for treating heart failure (HF) or pulmonary arterial hypertension (PAH) by monitoring at least one atrial physiological parameter and displaying information indicative of the at least one atrial physiological parameter on a patient display device. The system may include an alternative interatrial shunt as described above having a sensor pivotally coupled to a first flared region of an anchor of the shunt, e.g., via a torsion spring, and a computer-readable medium having instructions that, when executed by a processor of the patient display device, cause the processor to receive data from the sensor and process the data for viewing on the patient display device. The system may further include a delivery sheath sized and shaped to receive the anchor in a collapsed delivery state and the sensor in a delivery configuration. The sensor may be biased toward a deployed configuration such that upon exiting the delivery sheath, the sensor transitions to the deployed configuration. [Brief description of the drawings]

[0110] Additional features of the present invention will be apparent from the detailed description, claims, and drawings, which are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure.

[0111] [Figure 1A] 1A-1C are perspective, end, and side views, respectively, of a preferred embodiment of a shunt structure suitable for use in a device constructed in accordance with the principles of the present invention. [Figure 1B] 1A-1C are perspective, end, and side views, respectively, of a preferred embodiment of a shunt structure suitable for use in a device constructed in accordance with the principles of the present invention. [Figure 1C] 1A-1C are perspective, end, and side views, respectively, of a preferred embodiment of a shunt structure suitable for use in a device constructed in accordance with the principles of the present invention.

[0112] [Diagram 2]FIG. 2 is a side view of an alternative embodiment of a shunt suitable for use in the present invention having cutouts in its polymer encapsulation to facilitate engagement with a delivery system.

[0113] [Diagram 3] FIG. 3 is a schematic diagram of a system of the present invention for monitoring and treating patients suffering from cardiovascular disease, such as HF and PAH, including a shunt having a wireless sensor that communicates with a patient display device and / or the patient's physician.

[0114] [Figure 4A] 4A and 5B are side and end views, respectively, of a shunt constructed in accordance with the principles of the present invention having a coaxial wireless LAP sensor. [Figure 4B] 4A and 5B are side and end views, respectively, of a shunt constructed in accordance with the principles of the present invention having a coaxial wireless LAP sensor.

[0115] [Figure 5A] 5A and 5B are side and end views, respectively, of an alternative embodiment of a shunt of the present invention having a non-coaxial wireless LAP sensor. [Figure 5B] 5A and 5B are side and end views, respectively, of an alternative embodiment of a shunt of the present invention having a non-coaxial wireless LAP sensor.

[0116] [Figure 6A] 6A and 6B are side and end views, respectively, of a further alternative embodiment of a shunt having a coaxial LAP sensor with an electronic coaxial lead. [Figure 6B] 6A and 6B are side and end views, respectively, of a further alternative embodiment of a shunt having a coaxial LAP sensor with an electronic coaxial lead.

[0117] [Figure 7A]7A-7F are side and end views, respectively, of another embodiment of a shunt of the present invention having a replaceable sensor. [Figure 7B] 7A-7F are side and end views, respectively, of another embodiment of a shunt of the present invention having a replaceable sensor. [Figure 7C] 7A-7F are side and end views, respectively, of another embodiment of a shunt of the present invention having a replaceable sensor. [Figure 7D] 7A-7F are side and end views, respectively, of another embodiment of a shunt of the present invention having a replaceable sensor. [Figure 7E] 7A-7F are side and end views, respectively, of another embodiment of a shunt of the present invention having a replaceable sensor. [Figure 7F] 7A-7F are side and end views, respectively, of another embodiment of a shunt of the present invention having a replaceable sensor.

[0118] [Figure 8A] 8A-8B, 9A-9B, and 10A-10B are side and end views, respectively, of three embodiments of shunts of the present invention depicting alternative configurations for incorporating sensors between multiple layers of the shunt cover. [Figure 8B] 8A-8B, 9A-9B, and 10A-10B are side and end views, respectively, of three embodiments of shunts of the present invention depicting alternative configurations for incorporating sensors between multiple layers of the shunt cover. [Figure 9A] 8A-8B, 9A-9B, and 10A-10B are side and end views, respectively, of three embodiments of shunts of the present invention depicting alternative configurations for incorporating sensors between multiple layers of the shunt cover. [Figure 9B] 8A-8B, 9A-9B, and 10A-10B are side and end views, respectively, of three embodiments of shunts of the present invention depicting alternative configurations for incorporating sensors between multiple layers of the shunt cover. [Figure 10A]8A-8B, 9A-9B, and 10A-10B are side and end views, respectively, of three embodiments of shunts of the present invention depicting alternative configurations for incorporating sensors between multiple layers of the shunt cover. [Figure 10B] 8A-8B, 9A-9B, and 10A-10B are side and end views, respectively, of three embodiments of shunts of the present invention depicting alternative configurations for incorporating sensors between multiple layers of the shunt cover.

[0119] [Figure 11] FIG. 11 illustrates an asymmetric shunt constructed in accordance with the principles of the present invention with a LAP sensor.

[0120] [Figure 12A] 12A-12B, 13A-13B, and 14A-14B are side and end views, respectively, of three shunts of the present invention having coaxial wireless RAP sensors. [Figure 12B] 12A-12B, 13A-13B, and 14A-14B are side and end views, respectively, of three shunts of the present invention having coaxial wireless RAP sensors. [Figure 13A] 12A-12B, 13A-13B, and 14A-14B are side and end views, respectively, of three shunts of the present invention having coaxial wireless RAP sensors. [Figure 13B] 12A-12B, 13A-13B, and 14A-14B are side and end views, respectively, of three shunts of the present invention having coaxial wireless RAP sensors. [Figure 14A] 12A-12B, 13A-13B, and 14A-14B are side and end views, respectively, of three shunts of the present invention having coaxial wireless RAP sensors. [Figure 14B] 12A-12B, 13A-13B, and 14A-14B are side and end views, respectively, of three shunts of the present invention having coaxial wireless RAP sensors.

[0121] [Figure 15A] 15A-15D are, respectively, a side view of a shunt of the present invention with sensors measuring two physiological parameters, a graph of the calculated flow dynamic profile of velocity through the shunt, a graph of continuous wave Doppler flow velocity through the shunt with calculated velocity and pressure gradient, and a tracing of the RA pressure waveform. [Figure 15B] 15A-15D are, respectively, a side view of a shunt of the present invention with sensors measuring two physiological parameters, a graph of the calculated flow dynamic profile of velocity through the shunt, a graph of continuous wave Doppler flow velocity through the shunt with calculated velocity and pressure gradient, and a tracing of the RA pressure waveform. [Figure 15C] 15A-15D are, respectively, a side view of a shunt of the present invention with sensors measuring two physiological parameters, a graph of the calculated flow dynamic profile of velocity through the shunt, a graph of continuous wave Doppler flow velocity through the shunt with calculated velocity and pressure gradient, and a tracing of the RA pressure waveform. [Figure 15D] 15A-15D are, respectively, a side view of a shunt of the present invention with sensors measuring two physiological parameters, a graph of the calculated flow dynamic profile of velocity through the shunt, a graph of continuous wave Doppler flow velocity through the shunt with calculated velocity and pressure gradient, and a tracing of the RA pressure waveform.

[0122] [Figure 16A] 16A-16C are, respectively, a side view of an alternative embodiment of a shunt of the present invention arranged to measure two physiological parameters, a schematic representation of a color flow Doppler 2D echocardiographic image of the flow from LA to RA through the shunt, and a graph of continuous wave Doppler flow velocity through the shunt with calculated velocities and pressure gradients. [Figure 16B]16A-16C are, respectively, a side view of an alternative embodiment of a shunt of the present invention arranged to measure two physiological parameters, a schematic representation of a color flow Doppler 2D echocardiographic image of the flow from LA to RA through the shunt, and a graph of continuous wave Doppler flow velocity through the shunt with calculated velocities and pressure gradients. [Figure 16C] 16A-16C are, respectively, a side view of an alternative embodiment of a shunt of the present invention arranged to measure two physiological parameters, a schematic representation of a color flow Doppler 2D echocardiographic image of the flow from LA to RA through the shunt, and a graph of continuous wave Doppler flow velocity through the shunt with calculated velocities and pressure gradients.

[0123] [Figure 17A] 17A-17C are schematic diagrams illustrating the geometric features of the shunt portion of a shunt of the present invention, the location and mode of operation of sensors for measuring flow, and the inclusion of pacing leads, respectively. [Figure 17B] 17A-17C are schematic diagrams illustrating the geometric features of the shunt portion of a shunt of the present invention, the location and mode of operation of sensors for measuring flow, and the inclusion of pacing leads, respectively. [Figure 17C] 17A-17C are schematic diagrams illustrating the geometric features of the shunt portion of a shunt of the present invention, the location and mode of operation of sensors for measuring flow, and the inclusion of pacing leads, respectively.

[0124] [Figure 18] 18A-18C are graphs showing calculated flow dynamic pressure fields of a shunt constructed in accordance with the principles of the present invention, and FIG. 18C shows a shunt of the present invention including a strain gauge sensor.

[0125] [Figure 19A]19A and 19B are, respectively, a top view of a shunt of the present invention cut longitudinally and laid out in a flat configuration, and an end view of a shunt having a plurality of circumferentially spaced sensors. [Figure 19B] 19A and 19B are, respectively, a top view of a shunt of the present invention cut longitudinally and laid out in a flat configuration, and an end view of a shunt having a plurality of circumferentially spaced sensors.

[0126] [Figure 20A] 20A-20C are exemplary IEGM and pressure waveforms generated by an implanted LAP sensor illustrating LAP trends and response to changes in medical therapy, respectively, in a patient with heart failure. [Figure 20B] 20A-20C are exemplary IEGM and pressure waveforms generated by an implanted LAP sensor illustrating LAP trends and response to changes in medical therapy, respectively, in a patient with heart failure. [Figure 20C] 20A-20C are exemplary IEGM and pressure waveforms generated by an implanted LAP sensor illustrating LAP trends and response to changes in medical therapy, respectively, in a patient with heart failure.

[0127] [Figure 21A] 21A-21C are exemplary IEGM and pressure waveforms generated by an implanted LAP sensor showing LAP trends and response to structural heart disease interventions and changes in medical therapy, respectively, in patients with heart failure. [Figure 21B] 21A-21C are exemplary IEGM and pressure waveforms generated by an implanted LAP sensor showing LAP trends and response to structural heart disease interventions and changes in medical therapy, respectively, in patients with heart failure. [Figure 21C]21A-21C are exemplary IEGM and pressure waveforms generated by an implanted LAP sensor showing LAP trends and response to structural heart disease interventions and changes in medical therapy, respectively, in patients with heart failure.

[0128] [Figure 22] FIG. 22 is an exemplary graph of physiological parameter trends in a heart failure patient with an implanted pulmonary artery pressure sensor and response to implantation of an interatrial shunt and changes in medical therapy.

[0129] [Figure 23] FIG. 23 is an embodiment of a shunt of the present invention in which the electrical components of the sensor are located on the retention member of the shunt anchor.

[0130] [Figure 24A] Figures 24A-24C are end and side views, respectively, of an intra-atrial shunt formed from a wire braid covered with a biocompatible covering having a sensor affixed within the flow lumen of the shunt, while Figure 24C depicts the deployment of the shunt of Figures 24A-24B in the atrial septum. [Figure 24B] Figures 24A-24C are end and side views, respectively, of an intra-atrial shunt formed from a wire braid covered with a biocompatible covering having a sensor affixed within the flow lumen of the shunt, while Figure 24C depicts the deployment of the shunt of Figures 24A-24B in the atrial septum. [Figure 24C] Figures 24A-24C are end and side views, respectively, of an intra-atrial shunt formed from a wire braid covered with a biocompatible covering having a sensor affixed within the flow lumen of the shunt, while Figure 24C depicts the deployment of the shunt of Figures 24A-24B in the atrial septum.

[0131] [Figure 25A]25A and 25B illustrate a further alternative embodiment of a shunt of the present invention in which the intermediate region of the shunt anchor has a coil structure that serves as a circuit element of the sensor. [Figure 25B] 25A and 25B illustrate a further alternative embodiment of a shunt of the present invention in which the intermediate region of the shunt anchor has a coil structure that serves as a circuit element of the sensor.

[0132] [Figure 26A] 26A-26B illustrate an alternative embodiment of the shunt of FIGS. 19A and 19B in which sensors are positioned in laser cut frame elements formed in the shunt anchors. [Figure 26B] 26A-26B illustrate an alternative embodiment of the shunt of FIGS. 19A and 19B in which sensors are positioned in laser cut frame elements formed in the shunt anchors.

[0133] [Figure 27] FIG. 27 illustrates a further alternative embodiment of a shunt of the present invention in which the intermediate region of the shunt anchor has a coil structure that serves as a circuit element of the sensor.

[0134] [Figure 28] 28-30 illustrate alternative embodiments of the shunt of the present invention in which sensors are located at various regions on the shunt anchor. [Figure 29] 28-30 illustrate alternative embodiments of the shunt of the present invention in which sensors are located at various regions on the shunt anchor. [Diagram 30] 28-30 illustrate alternative embodiments of the shunt of the present invention in which sensors are located at various regions on the shunt anchor.

[0135] [Figure 31A] 31A-31E illustrate alternative embodiments of shunts of the present invention in which the cross-sectional profile of the sensor is varied. [Figure 31B]31A-31E illustrate alternative embodiments of shunts of the present invention in which the cross-sectional profile of the sensor is varied. [Figure 31C] 31A-31E illustrate alternative embodiments of shunts of the present invention in which the cross-sectional profile of the sensor is varied. [Figure 31D] 31A-31E illustrate alternative embodiments of shunts of the present invention in which the cross-sectional profile of the sensor is varied. [Figure 31E] 31A-31E illustrate alternative embodiments of shunts of the present invention in which the cross-sectional profile of the sensor is varied.

[0136] [Figure 32A] 32A-32D illustrate another alternative embodiment of a shunt of the present invention in which the cross-sectional profile of the sensor varies and includes a telemetry coil. [Figure 32B] 32A-32D illustrate another alternative embodiment of a shunt of the present invention in which the cross-sectional profile of the sensor varies and includes a telemetry coil. [Figure 32C] 32A-32D illustrate another alternative embodiment of a shunt of the present invention in which the cross-sectional profile of the sensor varies and includes a telemetry coil. [Fig. 32D] 32A-32D illustrate another alternative embodiment of a shunt of the present invention in which the cross-sectional profile of the sensor varies and includes a telemetry coil.

[0137] [Figure 33A] 33A-33C illustrate an alternative embodiment of a shunt of the present invention having a deployable sensor within a hermetically sealed housing, and FIG. 33D is a close-up view of the sensor of FIG. 33C. [Figure 33B] 33A-33C illustrate an alternative embodiment of a shunt of the present invention having a deployable sensor within a hermetically sealed housing, and FIG. 33D is a close-up view of the sensor of FIG. 33C. [Figure 33C]33A-33C illustrate an alternative embodiment of a shunt of the present invention having a deployable sensor within a hermetically sealed housing, and FIG. 33D is a close-up view of the sensor of FIG. 33C. [Figure 33D] 33A-33C illustrate an alternative embodiment of a shunt of the present invention having a deployable sensor within a hermetically sealed housing, and FIG. 33D is a close-up view of the sensor of FIG. 33C.

[0138] [Figure 34A] 34A-34E illustrate various views of the sensor of FIGS. 33A-33D, FIG. 34F illustrates a cross-sectional view of the sensor of FIG. 34E, and FIG. 34G is an exploded view of the sensor of FIGS. 34A-34F. [Figure 34B] 34A-34E illustrate various views of the sensor of FIGS. 33A-33D, FIG. 34F illustrates a cross-sectional view of the sensor of FIG. 34E, and FIG. 34G is an exploded view of the sensor of FIGS. 34A-34F. [Figure 34C] 34A-34E illustrate various views of the sensor of FIGS. 33A-33D, FIG. 34F illustrates a cross-sectional view of the sensor of FIG. 34E, and FIG. 34G is an exploded view of the sensor of FIGS. 34A-34F. [Fig. 34D] 34A-34E illustrate various views of the sensor of FIGS. 33A-33D, FIG. 34F illustrates a cross-sectional view of the sensor of FIG. 34E, and FIG. 34G is an exploded view of the sensor of FIGS. 34A-34F. [Figure 34E] 34A-34E illustrate various views of the sensor of FIGS. 33A-33D, FIG. 34F illustrates a cross-sectional view of the sensor of FIG. 34E, and FIG. 34G is an exploded view of the sensor of FIGS. 34A-34F. [Fig. 34F] 34A-34E illustrate various views of the sensor of FIGS. 33A-33D, FIG. 34F illustrates a cross-sectional view of the sensor of FIG. 34E, and FIG. 34G is an exploded view of the sensor of FIGS. 34A-34F. [Figure 34G] 34A-34E illustrate various views of the sensor of FIGS. 33A-33D, FIG. 34F illustrates a cross-sectional view of the sensor of FIG. 34E, and FIG. 34G is an exploded view of the sensor of FIGS. 34A-34F.

[0139] [Figure 35A] Figures 35A-35C illustrate the shunt of the present invention of Figures 33A-33C in a collapsed delivery state. [Figure 35B] Figures 35A-35C illustrate the shunt of the present invention of Figures 33A-33C in a collapsed delivery state. [Figure 35C] Figures 35A-35C illustrate the shunt of the present invention of Figures 33A-33C in a collapsed delivery state.

[0140] [Diagram 36] FIG. 36 illustrates an alternative embodiment of a shunt of the present invention in which the sensor is encapsulated within a biocompatible covering. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0141] An interatrial shunt for redistributing interatrial blood volume and reducing left atrial pressure is provided, which incorporates one or more physiological sensors and may be advantageous in treating subjects suffering from HF or other disorders associated with elevated left atrial pressure. A preferred embodiment of the shunt of the present invention includes an anchor, which may have an hourglass or "diabolo" shaped stent or frame, and a conduit formed by encapsulating the frame in a synthetic biocompatible material. The shunt is configured to be anchored into a passageway formed in the interatrial septum, preferably the fossa ovalis, and provides unidirectional blood flow from the left atrium to the right atrium when blood pressure in the left atrium exceeds that on the right side, and provides reversal of blood flow from the right atrium to the left atrium when blood pressure in the right atrium exceeds that on the left side. According to the present invention, one or more physiological sensors are coupled to the anchor, disposed on one or more support struts, or affixed to the biocompatible material.

[0142] 1A-1C, an illustrative embodiment of a shunt 10 is illustrated, which may be configured as described in any of the commonly assigned patents and applications herein incorporated by reference. The shunt 10 generally comprises an anchor 12 having three regions, namely, a flared or funnel-shaped end region 14, a flared or funnel-shaped end region 18, and a neck region 16 disposed between the end regions 14 and 18. The neck region 16 is configured to fit within an opening, such as a puncture, formed in the interatrial septum, preferably the fossa ovalis. The flared end regions 14 and 18 are configured to partially engage and protrude beyond the right and left sides of the interatrial septum, respectively, when implanted. The shunt 10 further comprises a conduit illustratively formed by encapsulating the anchor 12 with a biocompatible material 20, which covers all or substantially all of the anchor 12 and forms a conduit defining a lumen or internal passageway 22.

[0143] Flare region 14 is configured to be positioned within the right atrium, while flare region 18 is configured to be positioned within the left atrium. In one embodiment, anchor 12 includes longitudinal struts 24 interconnected by circumferential struts 26a-26e. The longitudinal struts 24 may inhibit or prevent shortening of anchor 12 during expansion, while sinusoidal or serpentine bending in circumferential struts 26a-26e allows the anchor to transition between a radially collapsed, generally cylindrical delivery state and an expanded, flared deployment state, as illustrated in FIGS. 1A-1C. As depicted in the figures, a conduit is formed by biocompatible material 20 that encapsulates the entirety of neck 16, flared end region 18, and flared end region 14. Biocompatible material 20 is preferably affixed to anchor 12 using a suitable biocompatible adhesive or by sandwiching the anchor between inner and outer layers of biocompatible material using sintering techniques.

[0144] In a preferred embodiment, anchor 12 is comprised of a self-expanding material, such as a superelastic alloy, and circumferential struts 26a-26e are treated to expand a predetermined amount upon deployment such that lumen 22, along with encapsulation 20, has a contour that allows for generally laminar flow between flared end section 18 (in the left atrium) and flared end section 14 (in the right atrium). The sinusoidal or serpentine bends 28 are such that all of the circumferential struts are in phase with circumferential struts 26a. This arrangement provides a shunt that requires less force to be applied to flared end region 18 to crimp it into a radially collapsed shape, such as for retracting it into a constraining tube, e.g., an introducer sheath, used for shunt delivery. Alternatively, the sinusoidal or serpentine bending 28 of the circumferential struts on the flared end region 14 is preferably 180 degrees out of phase with the sinusoidal or serpentine bending 28 in the neck region 16 and flared end region 18 such that the sinusoidal or serpentine bending does not extend beyond the ends of the longitudinal struts 24 in either the folded delivery state or the deployed state.

[0145] As described in the above-incorporated patents and published applications, anchor 12 may comprise a biocompatible metal framework or laser-cut solid metal tube made from Nitinol, titanium alloy, cobalt chrome alloy, MP35N, 316 stainless steel, L605, Phynox / Elgiloy, platinum chrome, or other biocompatible metals as known to those skilled in the art. While a preferred embodiment employs a superelastic self-expanding alloy, alternatively, another preferred embodiment of anchor 12 may comprise a plastically deformable material, such as a balloon-expandable material, or may be a shape memory alloy that transitions between a contracted delivery state and an expanded deployed state in response to a change in temperature. As will be recognized by those skilled in the art, certain alloys, such as nickel-titanium alloys, may exhibit superelastic or shape memory properties depending on the manufacturing processing techniques, and either set of properties may be advantageously employed in anchors for use in shunts constructed according to the principles of the present invention.

[0146] In one preferred embodiment, the anchor is heated to an austenite finish temperature A, ideally well below body temperature, in the range of 5-20° C., so that the Nitinol is in the superelastic austenite phase at body temperature. f The anchor is made of Nitinol with a diameter of 100 mm or less. Additionally, the anchor may have an adjustable diameter at the neck region 16 as described in co-pending, commonly assigned U.S. patent application Ser. No. 16 / 875,652, entitled "Devices with dimensions that can be reduced and increased in vivo, and methods of making and using the same," which is incorporated herein by reference in its entirety. The region of the anchor centered on the neck region 16, which may also be extended a distance into adjacent portions of the flared regions 14 and 18 by differential heat treatment, may be heated to an austenitic finish temperature A above body temperature, for example, within the range of 45-60°C. f At body temperature, the intermediate portion of the anchor is primarily or essentially in the martensite phase, which has shape memory, i.e., it is mechanically deformable to a larger diameter, such as by balloon expansion, but can be deformed to a larger diameter by either flushing with a warmed liquid, such as saline, or by heating by other means, such as RF induction. f The flared end regions 14 and 18 may be able to return to their original shape by application of transient heating to a temperature above 5° C. f and thus is primarily, or essentially, in the austenitic phase and remains superelastic at body temperature.

[0147] The surface finish applied to the anchor material may be selected to control the distance, thickness, composition, and / or growth pattern of pannus formation and thrombus formation, for example, the exterior surface of anchor 12 may be electropolished. The anchor may be coated with a biocompatible polymer or biological molecule such as heparin or pannus tissue or other suitable coating that inhibits or prevents thrombus formation.

[0148] In accordance with the principles of the present invention, the radial dimensions, axial lengths, and contours of the neck region 16 and flared end regions 14 and 18 are preferably selected to provide laminar flow through the interior of the shunt when implanted, reduce the formation of vortex currents, thus preventing thrombus formation, preventing pannus formation that may obstruct the neck region, encouraging surrounding tissue ingrowth around the exterior of the neck region, adequately anchoring the shunt against migration, providing a desired rate of blood flow between the left and right atria at physiological pressure differentials, and preventing or preventing retrograde paradoxical embolism.

[0149] When applied to the anchor, the biocompatible material 20 forms a conduit and preferably prevents transmural and transitional ingrowth of pannus material with a tissue thickness greater than 0.6 mm, except around the exterior of the neck region where the shunt contacts the interatrial septum, where the shunt is used to cross the septum following transseptal delivery. On the exterior surface of the neck region and extending into the continuous flaring region, the pannus tissue thickness may be greater than 0.6 mm.

[0150] As explained in Clowes et al. "Mechanisms of arterial graft healing: Rapid transmural capillary ingrowth provides a source of intimal endothelium and smooth muscle in porous PTFE prostheses" Am. J. Pathology 1986;123;220-230, the entire contents of which are incorporated herein by reference, experimental ePTFE vascular grafts having 60 micron internodal spacing were observed to develop rapid transmural infiltration with proliferating smooth muscle cells and granulation tissue, while ePTFE grafts with 30 micron internodal spacing were observed to develop a thin layer of only slowly growing endothelium that advanced only a few millimeters from the adjacent artery into the graft lumen. The porous polyester fabric covering employed on some atrial septal defect ("ASD") occlusion devices would be a poor choice for use in the shunts of the present invention, as such materials become completely meshed with perforating fibrous tissue. When the shunt 10 comprises an anchor 12 made of or including, for example, electropolished Nitinol, and the biocompatible material 20 is or includes an inert polymer, for example, ePTFE, or (unexpanded) PTFE, with an internodal distance of 30 microns or less, it is expected, and has been demonstrated in a normal sheep animal model, that the pannus may grow to a thickness of about 0.6 mm or less after transitionally extending a distance of 3 mm from the site of contact with the fossa ovalis ("FO") tissue. In such cases, it is expected that the internal lumen of the conduit will not narrow by more than a total of 1.2 mm from its original diameter at the neck. For purposes of this disclosure, the term "luminal narrowing" shall be defined as a minimum loss of shunt lumen diameter of more than 25%, and the term "luminal occlusion" is defined as total blockage of the lumen to blood flow (100% loss of lumen diameter). As used in this application, terms such as "about," "approximately," and "substantially," when used in conjunction with dimensions, are intended to mean within ±20% of the stated value, unless otherwise stated.

[0151] In yet another preferred embodiment, it has been demonstrated in a normal sheep animal model that when the shunt 10 includes an anchor 12 made of, for example, electropolished Nitinol, and the biocompatible material 20 includes, for example, an inert polymer, e.g., ePTFE, the proliferating smooth muscle cells and granulation tissue in the neck region infiltrate into the internodular spaces of the polymer, but do not chemically bond to the polymer. The shunt can thus be held in place by the mechanical interference of the proliferating tissue, thus making it resistant to embolization. Nevertheless, the attachment of tissue to the biocompatible material 20 can be overcome with the right retraction force, as provided by a vascular amplatz single loop snare placed around the neck region of the shunt device, which can be used to retract the shunt into a suitably sized introducer sheath. In this way, shunts such as those illustrated in Figures 1A-1C and 2 can remain removable even after they have been implanted for periods of up to six months or more. When so removed, the remaining proliferative tissue may form a ring that inhibits or prevents tearing of the septum, leaving a residual roughly circular hole in the interatrial septum that closely approximates the outer diameter of the shunt device in the neck region.

[0152] 1A-1C, anchor 12 has an hourglass shape formed from or including a superelastic metal, such as Nitinol, or any other suitable material known in the art. Circumferential struts 26a-26e and longitudinal struts 24 preferably have a unitary construction, i.e., the entire anchor 12 is laser cut from a tube of superelastic metal.

[0153] The biocompatible material 20 may comprise, for example, a sheet of polymer such as expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), silicone, polycarbonate, urethane, DACRON (polyethylene terephthalate), ultra-high molecular weight polyethylene (UHMWPE), or polyurethane. The biocompatible material may also or alternatively be or include a metal, ceramic, carbon nanotube array, or any other suitable biocompatible material. For example, the biocompatible material 20 may comprise ePTFE with an internodal distance of up to 30 microns and may be applied as inner and outer layers that are sintered together to form an integral conduit. Alternatively, the biocompatible material 20 may be applied to the inner lumen and the outside of the anchor using electrospinning techniques. Other methods of encapsulation and other suitable polymers that inhibit or prevent transmural ingrowth of pannus tissue may also be used, as would be understood by one of skill in the art. The exposed metal areas of anchor 12, and any other areas of the anchor, may optionally be electropolished or otherwise treated to inhibit thrombus formation using known methods.

[0154] The neck region 16 of the shunt 10 is preferably configured for implantation through the fossa ovalis of the interatrial septum, and in some embodiments, more preferably near or at the central portion of the fossa ovalis. As known to those skilled in the art, the fossa ovalis is a thinned portion of the interatrial septum that forms during fetal development of the heart, which appears as an indentation in the right side of the interatrial septum and is surrounded by a thicker portion of the interatrial septum. While the interatrial septum itself may be several millimeters thick and muscular, the fossa ovalis may be only about 1 mm thick and is formed primarily from fibrous tissue. In rare cases, the fossa ovalis may be up to 10 mm thick.

[0155] In some embodiments of the present invention, the shunt 10 may be asymmetrically shaped to take advantage of the natural features of the interatrial septum near the fossa ovalis and provide suitable flow characteristics, as described in co-pending, commonly assigned U.S. Patent Application Serial No. 16 / 408,419, entitled "Asymmetric shunt for redistributing atrial blood volume," which is incorporated herein by reference in its entirety. For example, in a preferred embodiment, the anchor comprises an hourglass or diabolo shape, the LA inlet funnel resembles a cone-shaped nozzle, and the RA outlet funnel is "bell" shaped, with the wide-mouthed lumen of the bell at the RA outlet port in the RA. The narrow entrance to the bell-shaped outlet funnel, which connects to an orifice in the neck region, may be configured to approximate a parabolic curved surface. This type of converging-diverging nozzle is similar in shape to the classical de Laval nozzle used in rocket engines. Flow from left to right is governed primarily by the smooth convergence of streamlines at the inlet cone and the divergence of streamlines exiting the bell. Such a nozzle configuration is highly efficient in the forward flow direction, having a discharge coefficient similar to that of a classical Venturi tube, e.g., about 0.94-0.98.

[0156] Referring now to FIG. 1C, points B and C are located on the leftmost circumferential strut 26e, which defines the LA inlet port. Points A and D are located on circumferential strut 26d, along the LA inlet funnel, from strut 26e toward the neck. Points H and E are located on circumferential strut 26b, along the RA outlet funnel, and points G and F are located on circumferential strut 26a, which defines the RA outlet port. In a preferred embodiment, the diameter of the lumen 22 in the neck region of the shunt orifice ranges from 5 to 6.5 mm. The portion of the shunt that crosses the FO, bounded by point ADEH, may be 3 mm in axial length, but may extend up to 10 mm in patients with thicker FOs. The diagonal length between points AB, CD, EF, and / or GH is preferably ≧3 mm, so that pannus cannot transitionally grow inward from the end of the shunt and thus obstruct the neck region 16. In addition, the horizontal component length between points AB, CD, EF, and / or GH, i.e., the distance the shunt protrudes into the left or right atrium, is preferably ≦15 mm to avoid interference with existing cardiac structures when implanted.

[0157] 1C as described above, and in accordance with another aspect of the present invention, it has been determined that providing lengths of compartments EF and GH greater than 3 mm would generally ensure that the end regions extending into the right atrium are generally located outside the flow path of blood returning from the inferior vena cava and are expected to be the most likely source of entrained emboli that may cause paradoxical embolism. The truncated infundibulum, bounded by ABCD and / or EFGH, may have a volume ≦2 ml.

[0158] Other embodiments of the shunt of the present invention may include anchors with different combinations and configurations of circumferential rings and axial strut elements. Specifically, such embodiments may have more or less longitudinal struts 24 and more or less circumferential struts 26a-26e, as depicted in Figures 1A-1C. These configurations may result in other shunt lumen geometries. In another embodiment, the anchor 12 may be made from a self-expanding polymer. Alternatively, the anchor need not be self-expanding and may be made from a plastically deformable biocompatible metal, such as 316L stainless steel, cobalt chromium alloy, or any other such suitable biocompatible material known to those skilled in the art. Such deformable shunt anchors may be delivered by an expansion member, such as a balloon, configured to achieve the desired lumen geometry. The deformable anchors can be designed to expand prismatically or at certain localized sites, with ductile hinges configured for more selective expansion, as taught by U.S. Patent No. 6,242,762 to Shanley, the entire contents of which are incorporated herein by reference.

[0159] 2, an alternative embodiment of a shunt suitable for use in constructing a device of the present invention is described. Shunt 200 includes anchor 221 and is similar in structure to that described with respect to the embodiment of FIGS. 1A-1C, having flared end regions 222 and 223 and neck region 224. When implanted within a patient's interatrial septum, flared end region 222 is disposed within the patient's right atrium, while flared end region 223 is disposed within the patient's left atrium, and neck region 224 is seated within a passageway formed within the interatrial septum. Anchor 221 includes longitudinal struts 225 and circumferential struts 226a-226e and is encapsulated by biocompatible material 227. Anchor 221 may be comprised of a self-expanding or plastically deformable material as described herein above. 1A-1C in that the biocompatible material 227, e.g., ePTFE, includes cutouts 228 adjacent to the circumferential struts 226a. The cutouts 228 extend proximally from the circumferential struts 226a a distance of 0.5 mm to 2 mm, preferably about 1 mm, and may allow the circumferential struts 226e to be releasably engaged with a delivery system, e.g., hooks, during deployment, as described in U.S. Patent Application Publication No. 2014 / 0350565 to Yacoby et al., the entire contents of which are incorporated herein by reference.

[0160] 2, the biocompatible material 227 may be trimmed manually or mechanically, or by laser cutting, from the circumferential struts 226a to create cutouts 228. In this manner, the shunt 220 may be positioned and repositioned within the passageway formed in the interatrial septum until the clinician is satisfied with the device placement before being released. In a preferred embodiment, the conduit formed by the biocompatible material 227 extends beyond the neck region 224 into the flared end region 222 a distance of at least 3 mm to ensure that pannus cannot grow transitionally along the lumen wall far enough to partially occlude the flow area of ​​the neck region 224. Additionally, the flared end region 222, when implanted within the interatrial septum, extends into the right atrium a distance of at least 3 mm, ensuring that the entrance of the flared end region 224 is generally not aligned with the flow path created by blood entering the right atrium from the inferior vena cava, thereby reducing the risk that emboli carried from the lower extremities into the right atrium would cause paradoxical embolism by passing through the shunt 220.

[0161] In accordance with the principles of the present invention, all of the shunt designs described in the commonly assigned patents and applications incorporated herein may be designed to be deployed across the fossa ovalis and modified to receive a sensor located on or coupled to the shunt. The shunts of the present invention may be delivered as described in U.S. Patent No. 9,713,696 B2, US 10,478,594 B2, and U.S. Patent Application Publication No. US2020 / 0078558A1, all to Yacoby et al., the entire contents of each of which are incorporated herein by reference.

[0162] Suitable sensors for use in the shunts of the present invention include, for example, the HeartPOD with leads, the V-LAP without leads, and the CardioMEMs pressure sensors without leads, which have established a track record of satisfactory performance in chronically implanted cardiovascular applications. As a class, these sensors are characterized as having a rigid encapsulated hermetic housing with an elongated multi-millimeter size form factor. In this disclosure, this group of devices is referred to as large format pressure sensors (LFPS). These devices may include circuitry such as a sensor gauge formed from or including a piezoresistor or variable capacitor with or without an on-board application specific integrated circuit processor, and circuitry (such as an antenna) for transmitting measurements outside the body in a manner as exemplified elsewhere herein. The hermetic housing may include or be fabricated from titanium, titanium alloys, or other suitable biocompatible metals, or alternatively, when appropriate, the non-electromagnetically shielded housing may be or include a ceramic such as zirconia, a glass such as fused silica, or other material known to those skilled in the art of implantable sensor materials.

[0163] The advantage of the wired LFPS design is that the RF antenna for external power and data readout can be relatively large (approximately 20 mm in diameter in the case of the HeartPOD) and surgically placed close to the skin (typically <5 cm deep). This allows for the use of a low-power communication device (e.g., PAM), which can be a battery-powered handheld computer. In another embodiment, a mobile smartphone can be RF-coupled with the wired implant for powering, data transmission, storage, and local processing for dose-by-dose physician-directed patient self-management (e.g., DynamicRx). The wired implant can also be easily coupled to cardiac rhythm management devices such as pacemakers or implantable defibrillators. Potentially, electrodes on the sensor housing or tethering system could be used to sense intracardiac electrograms (IEGMs) and pace the interatrial septum, obviating the need for a separate right atrial lead. One exemplary wired pressure sensor that may be used in the present shunt is the IntraSense Calibrated sensor, commercially available from Silicon Microstructures, Inc. (Milpitas, Calif.).

[0164] The leads of the wired implant may include an indifferent electrode sufficiently distant from the sensing electrode for bipolar pacing. The timing of electrical events in the cardiac cycle can be used in conjunction with the LAP waveform, particularly for diagnostic purposes. For example, one skilled in the art, such as a cardiologist, will appreciate that the P-wave of the IEGM slightly precedes the a-wave of the LAP tracing. The presence of the P-wave and absence of the a-wave is diagnostic of a rare disorder seen in heart failure patients known as atrial electromechanical dissociation. A number of conditions can be diagnosed by a combination of intracardiac pressure and IEGM, as described by U.S. Pat. No. 6,970,742 B2 to Mann et al., the entire contents of which are incorporated herein by reference. Another advantage of a wired sensor is that if the sensor should embolize from its optimal location on the interatrial septum, either at the time of implantation or at some later time, the sensor is tethered by the wire, making it relatively simple to reposition or retrieve and remove from the body.

[0165] Some disadvantages of the lead-equipped LFPS are that the proximal lead and communication antenna coil are best placed in a subcutaneous or submuscular surgical pocket located near the shoulder, like a pacemaker. This may be accomplished by performing a transseptal catheter placement from a subclavian or axillary vein, which is more difficult than from the standard location for venous access in the right femoral vein, for example. Alternatively, the lead can be placed from a transfemoral access site and then transported to a superior venous access site, as described in U.S. Patent Application Publication No. US2011 / 0022057 A1 to Eigler et al., the entire contents of which are incorporated herein by reference. Both approaches have proven clinically acceptable with the lead-equipped HeartPOD system. Another disadvantage of the lead-equipped LFPS is the increased possibility of device infection associated with the larger amount of placed hardware and the creation of a subcutaneous surgical pocket. Typically, the infection rate for pacemakers requiring device removal is about 1% per year.

[0166] The advantages and disadvantages of the leadless LFPS design are generally the opposite of the leaded LFPS as described above. Leadless sensors are less susceptible to device infections precisely because there are no subcutaneous pockets to infect or leads to introduce infection into the circulation. Leadless LFPSs can be more easily placed from transfemoral transseptal access without the need to reposition the leads to the superior venous access site. To minimize the risk of embolism, the leadless sensor must be tethered on its proximal side and released from the tether only after secure transseptal placement is confirmed. Even so, embolism during or after the insertion procedure is a possibility and the sensor may become lodged on the mitral or aortic valves or embolize into the systemic circulation, requiring surgical removal. Leadless LFPS modules are generally longer and more rigid due to the extra volume that may be required to house the RF coupling antenna. In addition, because the antenna is relatively small, perpendicular to the long axis of the sensor module, and placed substantially deeper below the skin (typically at least 9-13 cm when placed within the left atrium), the RF power supply may require a larger external coil and a larger electromagnetic flux for the same sensor and embedded processor power requirements. Additionally, the V-LAP leadless sensor includes an internal inductor coil that is wrapped around a small diameter ferrite, making demonstration of MRI compatibility more difficult.

[0167] Several important recent developments in implantable sensor technology may reduce form factor size and power requirements. Improved sensors implementing these features are referred to in this disclosure as small format pressure sensors (SFPS). In addition to the piezoresistive and capacitive type pressure sensors described above, recent advances in technology and novel material-based have enabled the development of micro- and potentially nano-scale pressure sensors for implantable medical applications, as described, for example, in Chang Y, et al. "State-of-the-art and recent developments in micro / nanoscale pressure sensors for smart wearable devices and health monitoring systems," Nanotechnology and Precision Engineering 2020;3:43-52, https: / / doi.org / 10.1016 / j.npe.2019.12.006. One class of examples are resonant devices, where pressure-induced stress changes their natural frequency. Compared to conventional sensors, resonant devices may provide higher accuracy and sensitivity because they are less susceptible to environmental noise.Surface acoustic wave resonators (SAW), Lamb wave resonators (LWR), and film bulk acoustic wave resonators (FBAR) are also known to those skilled in the art and are described, for example, in the following references, the entire contents of each of which are incorporated herein by reference: Wang WN, et al., "Tire pressure monitoring system and wireless passive surface acoustic wave sensor," Appl Mech Mater 2014, 536-537:333-7; Mu X, et al., "Dual mode acoustic wave sensor for precise pressure reading," Appl Phys Lett 2014, 105(11), 113507; Della Lucia F, et al., "Design, fabrication and characterization of SAW pressure sensors for offshore oil and gas exploration," Sensors and Actuators A: Phys 2015, 222:322-8; Kropelnicki P, et al., "CMOS-compatible ruggedized high temperature Lamb wave pressure sensor," J. Appl. Phys. 2015, 222:322-8; Micromech Microeng 2013,23(8),085018. [ka] , as described in Nagaraju M, et al. "A 400μW differential FBAR sensor interface IC with digital readout", 2015 joint conference of the IEEE international frequency control symposium and the European frequency and time forum, FCS 2015 - proceedings, Denver, Colorado, 2015, p. 218 - 21, Zhang M, et al. "A film bulk acoustic resonator-based high-performance pressure sensor integrated with temperature control system", J Micromech Microeng 2017, 27(4), 045004, Galipeau DW, et al. "Surface acoustic wave microsensors and applications", Smart Mater Struct 1997, 6(6): 658 - 67, Scholl G, et al. "Surface acoustic wave devices for sensor applications", Phys Status Solidi Appl Res 2001, 185(1): 47 - 58, and Yantchev V, et al. "Thin film lamb wave resonators in frequency control and sensing applications: a review", J Micromech Microeng 2013, 23(4), 043001.

[0168] In another example described in Chen LY, et al. "Continuous wireless pressure monitoring and mapping with ultra-small passive sensors for health monitoring and critical care," Nature Communication 2014, 5:5028, the entire contents of which are incorporated herein by reference, the authors developed a proof of concept for a 1×1×0.1 mm implantable pressure sensor that includes an LC oscillator fabricated using standard lithography techniques on a polyimide-coated silicon wafer with an embedded PDMS flexible substrate, and a copper-printed antenna. The paper describes that the sensor can be implanted in the skull of a rodent to chronically measure intracranial pressure. Other advances in 2D nanomaterials, including graphene, MXene, carbon nanotubes, and metal nanowires, can create flexible piezoresistive and capacitive pressure sensors that are stable and ultrasensitive. Breakthroughs in material science are also enabling self-powered pressure sensors that harvest mechanical energy directly from the environment, such as from a beating heart. SFPS devices have yet to demonstrate the long-term accuracy and durability in ambient environments required for chronically implantable sensors that can aid in the diagnosis of and guide therapy for cardiovascular and cardiopulmonary conditions. Nevertheless, the development of sufficiently robust, hermetic, biocompatible packaging with practical wireless transmission of data and external power schemes should enable reliable, small-format, flexible, implantable sensors that can be incorporated into and made consistent with the inventive shunts of the present disclosure to become available, either for pressure or other physiological parameter measurements.

[0169] 3, an exemplary embodiment of a system constructed in accordance with the principles of the present invention including a shunt of the present invention for measuring physiological parameters in the left atrium in patients with HF is described. The shunt 30 illustratively includes a Nitzan-type hourglass or diabolo-shaped nitinol anchor such as those described in Figures 1A-1C and 2, which may be fully or partially encapsulated with a biomaterial such as those described with respect to Figures 1A-1C and 2. It should be understood that other sensors with other sensor configurations such as those illustrated herein may also be suitably used in place of the shunt 30 depicted in Figure 3.

[0170] In FIG. 3, the shunt 30 includes a leadless sensor 34 having dimensions and characteristics consistent with the LFPS described herein above, coupled to the shunt frame via a support structure 35 including support struts 36 and a collar 38. Alternatively, the sensor or sensors may be of the SFPS type described above. The sensor 34 may include circuitry for measuring mechanical parameters including pressure, force, flow, velocity, acceleration, wall shear stress, temperature, etc., or electrical properties exemplified as IEGMs, resistance, impedance, current, inductance, capacitance, or chemical properties including pH, osmolality, chemical speciation, molecular concentration, reaction rates, or any other desired physiological parameter for which an acceptable sensor has been developed. By way of example, the circuitry may generate data indicative of left atrial pressure (e.g., in embodiments such as those illustrated in FIG. 3 or described with reference to FIGS. 4A-10 or 16A), right atrial pressure (e.g., in embodiments described with reference to FIGS. 12A-15A), or the velocity of blood flow through the lumen. Also, the sensor may include circuitry for measuring multiple properties, or may include multiple sensors, each including circuitry for measuring a respective property, contained within an integral package with other sensors. Alternatively, multiple independent sensors may be mounted on the biocompatible material that encapsulates the anchors of the shunt 30.

[0171] The leadless sensor module 34 preferably includes a suitably shaped (e.g., generally cylindrical), hermetically sealed housing with a sensing diaphragm or surface located therein facing toward the LA chamber. In an alternative embodiment, the sensing surface of the sensor 32 may be positioned facing toward the orifice of the shunt. In yet another embodiment, the sensor 34 may have a generally rectangular solid shape and may be positioned on any one or more of the longitudinal and / or circumferential struts of the shunt 30 in a manner as described with reference to Figures 26A-26B, 28, 29, 30, 31A-31E, and 32A-32D. It is understood that the three-dimensional geometry of the sensor is not limited in overall size and dimensions, so long as it does not sufficiently impede shunt flow or substantially reduce the clinical effectiveness of the shunt.

[0172] The leadless sensor module 34 may include circuitry for communicating data directly from the leadless sensor module 34 to a patient display device 370, illustratively a conventional smart phone programmed with a suitable application program and a touch screen display 372. Alternatively, the leadless sensor module 34 may include circuitry for communicating indirectly with the patient display device 370 via the optional patient module 360. Whether the optional patient module 360 ​​is used may depend on the communication mode employed by the leadless sensor module 34.

[0173] In one embodiment, the leadless sensor module 34 includes an RF transceiver circuit configured to exchange physiological data and programming instructions directly with the patient display device 370. In this manner, the patient may directly view a graph of a selected physiological parameter, such as RAP or LAP, provided in real time by the sensor module 34 for display in a window 372 of the patient display device 370. The patient display device 370 may also include programming to detect abnormal situations, such as an elevated LAP (illustratively above 30 mmHg), and take immediate action, such as alerting "take two Lasix now" and contacting a physician if the pressure is not sufficiently reduced within a specified time frame (illustratively below 20 mmHg within two hours).

[0174] The alert displayed by the patient display device 370 may also instruct the patient to seek medical assistance if the abnormal situation is not resolved within a prescribed time period. As depicted in FIG. 3, the patient display device 370 may also upload data received from the sensor module 34 to a physician's computer system 390 using either a telephone network or a wide area wireless network, for example, using a WiFi network and access points to transmit data over the Internet 380. It should be understood that any such communication of patient data over a WAN should preferably first be encrypted to maintain patient privacy. The patient display device 370 may also be programmed to transmit the alert directly to the patient's physician or a suitable monitoring service, prompting the physician to provide additional guidance regarding subsequent treatment steps. In this case, communication between the physician and the patient may also be bidirectional, using either text messaging from the physician to the patient or a telephone or VOIP call.

[0175] Optionally, the system for communicating data from the leadless sensor module 34 to the patient display module 370 and / or the physician's computer 390 may employ a patient module 360. The patient module 360 ​​may comprise a compact electronics package (circuitry) mounted on an adhesive patch 362 and configured for bidirectional data communication with the leadless sensor module 34. The patient module 360 ​​may include, for example, an inductive coil, an application specific electronics package, a battery, and an RF transceiver. The electronics package may be programmed to transmit power and instructions to the leadless sensor module 34 via the inductive coil and / or the RF transceiver. The electronics package of the patient module 360 ​​may also be programmed to download physiological data stored on or generated in real time by the leadless sensor module 34 and transmit the data for processing and display in a window 372 of the patient display device 370. An adhesive patch 362 including the patient module 360 ​​may be applied to the patient's chest or upper torso to maintain proximity to and ensure uninterrupted transfer from the leadless sensor module 34. More specifically, use of the patient module 360 ​​may reduce the risk that the distance between the patient display device 370 and the leadless sensor module 34 will exceed a predetermined distance at which such intercommunication is impaired. Advantageously, the patient module 360 ​​may include a rechargeable battery that may be used to recharge or power the electronics in the leadless sensor module, providing a more predictable power supply than a conventional smartphone battery in the patient display device 370.

[0176] In an alternative embodiment described below with respect to Figures 6A and 6B, the sensor module may include electrical leads. In such an embodiment, instead of the optional patient module 360 ​​as described above, the sensor may be connected directly via electrical leads to an implantable module configured to communicate to an external device, such as a patient display module 370. In that case, the implantable module may communicate directly with the patient display device 370, which may be programmed to display messages to the patient and / or communicate physiological data and alerts to a physician, as otherwise described in Figure 3.

[0177] In one preferred embodiment of the embodiment of FIG. 3, the support structure 35 preferably positions the sensor 34 generally coaxial with the longitudinal axis of the shunt 30 such that the sensing surface 32 of the sensor is spaced from the shunt orifice. In this way, the measured parameter is indicative of the parameter within the left atrial cavity and is not significantly affected by the increased flow velocity characteristics in the region of the shunt orifice. In a preferred embodiment, the support struts 36 are integrally formed with the anchor structure of the shunt 30, extending from alternating longitudinal struts and terminating in collars 38 that receive the sensor module 34. The support struts 36 and collars 38 may be a unitary structure, for example, laser cut, heat set, and electropolished from a single piece of superelastic Nitinol tubing. Alternatively, the struts and / or collars may be welded or attached to the anchors of the shunt 30 by other means. The support struts 36 may alternatively be formed from a suitable biocompatible polymer composition. The sensor 34 and support structure 35 are preferably configured so that they can be crimped and constrained within a loading cartridge or delivery introducer sheath for transvascular delivery and then expanded to their final configuration during the delivery process.

[0178] The sensing surface 32 of the sensor 34 is preferably positioned such that during post-implant healing, the distance that reactive migratory tissue growth extends from any point where the shunt contacts the cardiac structure and grows across the support structure to reach the sensing surface exceeds a total linear distance of 2.5 mm. From prior experiments performed by the inventors, this distance should limit tissue growth across the sensing surface to <300 μm. Alternatively, the support struts 36 may contact the collar 38 at an angle that is <±45 degrees from perpendicular to the axis of the sensing surface and contact the collar at a minimum distance of 2.5 mm from the sensing surface. This would effectively mechanically isolate the sensing surface from reactive tissue growth and reduce tissue bridging to the sensing surface. Furthermore, such an arrangement would minimize transmission of changes in ventricular wall tension due to cardiac contraction or relaxation to the sensing surface. As a result, sensing surface movement would accurately reflect the left atrial pressure waveform and would not be substantially artifactually degraded or otherwise rendered uncorrectable to be diagnostically useful.

[0179] In alternative embodiments, the body of the sensor module may extend proximally into or through the neck portion of the shunt lumen. Wireless LFPSs tend to be elongated structures to accommodate RF coils of various configurations. The CardioMEMs sensor has a rectangular solid form factor, approximately 15 mm long x 3.4 mm wide x 2 mm thick. The V-LAP sensor is cylindrical, approximately 14 mm long with a diameter of 2.5 mm. To minimize distal end protrusion into the left atrium, LFPSs of these or similar form factors can be mounted such that their proximal portion extends into the shunt lumen, including the shunt neck, and even into the right atrial portion of the shunt. To maintain similar flow characteristics, the cross-sectional area of ​​the shunt neck should be enlarged by approximately the cross-sectional area of ​​the sensor. For example, for a sensor with a form factor such as a V-LAP that would extend through the neck region, having a shunt pressure / flow relationship similar to a stand-alone hourglass shunt with an internal minimum diameter of 5 mm may involve expanding the neck to about 5.6 mm in diameter. Similarly, the neck may expand to 5.8 mm when a sensor with a form factor such as a CardioMEMs is placed through it. These dimensions are first order approximations and may be suitably modified based on the results of pressure / flow testing or computational flow dynamic analysis based on the actual shunt / sensor geometry.

[0180] With reference to Figures 4A and 4B, further aspects of the inventive shunt of Figure 3 are described. Figure 4B shows that the sensor support structure illustratively includes three support struts 45 equally spaced around the circumference of the anchor frame 40 adjacent to the sensor collar 48. The extent to which the sensor 44 protrudes into the left atrial cavity is generally limited by the size of the LV cavity, which is generally about 55 mm in diameter in patients with HF. The axial dimension of the left protrusion from the center of the shunt neck to the left end of the sensor is approximately 55 mm in diameter, as shown in Figure 4A. maxThis dimension should be short enough so that there is no contact between the shunt and critical or adjacent structures of the left atrium, such as the mitral valve, pulmonary veins, left atrial appendage, left atrial wall, etc., that could cause trauma or thrombus formation. In one embodiment, L refers to the chamber diameter measured from the middle of the fossa ovalis to the ostium of the left atrial appendage. max is limited to not more than 50% of that distance. Thus, for a small diameter left atrium such as that found in patients with PAH, e.g., for a diameter of 20 mm, L max should not exceed 10 mm.

[0181] 5A and 5B, an alternative embodiment is described in which the sensor 54 is mounted substantially non-coaxially with the long axis of the shunt 50. The sensor may be an LFPS or SFPS type, or a non-pressure sensor, as described above. The long axis of the sensor 54 may extend parallel to the long axis of the shunt 50, but it is not necessary that it be so arranged. The sensor 54 may be attached to the shunt using a support structure, including a support post 55 and a collar 58, similar to that described with respect to FIGS. 4A-4B, but which supports the sensor off-center from the lumen 22 of the shunt 50. One advantage of the embodiment of FIGS. 5A-5B is that if future access to the left atrium is required for a large diameter catheter, such a catheter may be advanced through the shunt unobstructed by the sensor.

[0182] In embodiments such as those described with reference to Figures 4A-4B and 5A-5B, as well as other embodiments provided herein, the shunt anchor may be of the type described in the above-incorporated U.S. patent application Ser. No. 16 / 875,652, entitled "Devices with dimensions that can be reduced and increased in vivo, and methods of making and using the same." Thus, the neck region of the anchor is adapted to receive a temperature above body temperature, A fThe anchor may have shape memory properties with a thermal expansion coefficient of 0.1, 0.1, 0.2, 0.3, 0.4, 0.5, 1. 1, 2. 2, 3. 3, 4. 4, 5. 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 70, 72, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 114, 115, 120, 121, 122, 123, 124, 125, 136, 140, 142, 150, 166, f Similarly, the support posts (e.g., posts 45 or 55) that affix the sensor to the shunt anchor frame may be heated to above a similar transition temperature A f A balloon or other source of expansive force can be used to deform the support structure and push the sensor further out of the way, allowing for wider left atrial access. f In response to transient heating above .gamma., the sensor and its supporting structure return to their pre-deformed configuration.

[0183] In Figures 6A and 6B, an embodiment is described with an encapsulated shunt anchor 60 and a sensor support structure with posts 65 and collar 68 similar to those of Figures 4A-4B. The sensor depicted in this embodiment is a wired LFPS type, with the wire 66 extending from the proximal side of the sensor module 64 to a venous access site near the left or right shoulder (not shown). The wire 66 may be or include a conventional pacing type wire design with an inner stylet lumen, trifilar coiled inner and outer conductors, and interposition and outer insulation made from silicone or other suitable polymeric material. The wires may typically range in size from 5Fr to 8Fr (1.7 to 2.7 mm diameter). The conductors may be coiled or braided wire, depending on the size and number of conductor requirements. Alternatively, the wire 66 may have multiple separately insulated conductors. A strain relief section may be employed to connect the sensor module 64 to the outer insulation. As in the embodiment of FIGS. 4A-4B, the shunt lumen 22 can be adjusted according to the size of the lead 66 to achieve the desired pressure / flow relationship.

[0184] 6A-6B, the lead 66 may additionally include an indifferent sensing electrode 67 to measure the IEGM for a vector between an electrode on the sensor module 64 and an indifferent electrode 67. The lead / sensor geometry may be selected such that lead contact with the shunt neck or other shunt structure is sufficiently low or minimized, thereby inhibiting or preventing abrasion of the outer lead insulation and reducing the risk of possible abrasion fracture of the conductor. The lead 66 may include a proximal connector, such as an IS-1 or IS-4 connector, and the lead may be connected to a stand-alone antenna coil / capacitor or to an implanted pacemaker or defibrillator generator. In one embodiment, the shunt 60 is placed after conventional transfemoral transseptal catheterization, and the lead may subsequently be transported to a site of superior venous access as described above. Alternatively, transseptal catheterization and shunt / lead placement can be performed directly from a site of superior venous access, such as the subclavian, axillary, or jugular vein.

[0185] 7A-7F, a further embodiment of a shunt 70 of the present invention having a wired LFPS sensor 74 is described. In this embodiment, a shunt 70 including only a sensor support structure with struts 75 and 78, and not including any wired sensor, is first positioned across the fossa ovalis in the manner as illustrated in FIGS. 7A-7B. With a guidewire 79 extending through a sensor fixation collar 78, a sensor delivery introducer sheath 71 is then positioned across the collar in the manner as shown in FIGS. 7C-7D. The sensor module 74 preferably includes one or more proximal and one or more distal superelastic retention tabs 72 that fold generally flat when restrained within the sensor delivery sheath 71. In one non-limiting embodiment, there are two or more (e.g., three) proximal retention tabs 72 and two or more (e.g., three) distal retention tabs 72'. The distal tab 72' secures the shunt in place when the distal tab is exposed and the sheath 71 and sensor 74 are retracted proximally, aligning the distal tab 72' against the fixation collar 78. When the sheath 71 is retracted further proximally, the proximal tab 72 is deployed proximally of the collar in the manner illustrated in Figures 7E-7F. Following deployment, the lead 76 may be delivered to the site of superior venous access in the manner described with respect to Figure 6.

[0186] In another embodiment, the lead 76 may be pre-positioned within the sensor fixation collar 78 and deployed in the manner described with respect to FIGS. 6A-6B. An advantage of this two-part structure is that the sensor 74 may be easily removed and replaced later if it becomes infected or inoperable. To do so, the proximal portion of the lead 76 may be surgically released and a locking stylet (not specifically shown) may be placed over the lead. A mechanical or excimer laser lead removal device may be used to detach the adhered portion of the lead from the venous structure. A sheath (not specifically shown) may be advanced over the lead just proximal to the collar to provide additional support. The lead and sensor may then be retracted into the sheath, removed, and replaced with a new lead-loaded sensor 74 if desired.

[0187] In the foregoing embodiment as described with reference to Figures 3-7F, the sensor may be attached to the shunt by a support structure including one or more support posts and a collar. In alternative embodiments, the sensor may be disposed between layers of biocompatible encapsulation such as ePTFE, which are bonded to the shunt anchor frame by a heat or pressure mediated sintering or welding process, or the encapsulation is accomplished by electrospinning of nanofibers of biomaterial. As described above, the biocompatible material may be or include a polymer such as expanded polytetrafluoroethylene (ePTFE), PTFE, polyurethane, Dacron (polyethylene terephthalate), silicone, polycarbonate, urethane, ultra-high molecular weight polyethylene (UHMWPE), or carbon fiber. Alternatively or in addition, the biocompatible material may be or include a metal, ceramic, carbon nanotube array, or any other suitable biocompatible material. Additionally, the sensor may be adhered to the shunt by adhesive bonding, such as with an epoxy, or the sensor may maintain its location by friction or interference fit with other structural members, or a hybrid combination of the foregoing. This list of fixation methods is intended to be illustrative and not exhaustive. Other means of sensor fixation to the shunt will be apparent to those skilled in the art and are understood to be incorporated within the scope of this disclosure.

[0188] Other embodiments of the shunts of the present invention may employ shunt designs such as those shown in Figures 10-15 of commonly assigned U.S. Pat. No. 10,251,740 (hereby incorporated by reference) that may incorporate LFPS-type sensors with an elongated cylindrical profile. In such embodiments, a hybrid fixation mechanism may be employed, for example, the sensor is affixed both by the support structure 45, 48 in the manner described with reference to Figures 4A-4B and by incorporation between the biocompatible bilayers of the encapsulating material. Alternatively, the sensor may simply be attached to the shunt by adhesion and interference fit with the encapsulating material. As a further alternative, the shunts of the present invention may include injection molded silicone rubber forming a one-piece self-expanding shunt in which the sensor is embedded. Other non-limiting examples of structures and methods for coupling the sensor to the shunt are provided elsewhere herein.

[0189] 8A-10B, additional variations of the shunt of the present invention are described. In the embodiment of Figs. 8A and 8B, a shunt 80 is depicted in which a sensor 84 is affixed between a shunt frame 81 and an outer layer 82 of biocompatible material. An inner layer 83 of biocompatible material may be provided on the inside of the shunt frame 81. The shunt frame 81 may be deformed inwardly toward the lumen 22 to accommodate the sensor 84 and maintain an axially symmetric outer profile of the shunt, and the left atrial inlet cone may be deformed inwardly asymmetrically in the region of the sensor. In Figs. 9A and 9B, another embodiment is depicted in which a sensor 94 is affixed between the shunt frame 91 and an inner layer 93 of biocompatible material. An outer layer 92 of biocompatible material may be provided on the outside of the shunt frame 91. In this embodiment, the shunt frame 91 is not deformed, but instead substantially maintains the axial symmetry of its outer profile, while the left atrial inlet cone is deformed inwardly asymmetrically in the region of the sensor 94. In Figures 10A and 10B, another shunt embodiment 1000 is shown in which the outer profile of the shunt frame 1001 is deformed to accommodate a sensor 1004 with a relatively large diameter RF coil 1006, improving wireless power reception and telemetry. The sensor 1004 may be affixed between the shunt frame 1001 and an inner layer 1003 of biocompatible material. An outer layer 1002 of biocompatible material may be provided on the outside of the shunt frame 1001. The left atrial inlet cone is deformed inwardly asymmetrically in the region of the sensor 1004, and both the inner and outer profiles of the shunt 1000 are deformed asymmetrically. Nevertheless, the shunt can still be crimped to fit inside the loading tube and delivery introducer sheath.

[0190] FIG. 11 illustrates an embodiment of a shunt 1100 of the present invention in which a sensor 1104 is affixed within an axially asymmetric shunt in a manner generally as described in FIG. 8 of the above-incorporated U.S. Patent Application Publication No. US2019 / 0262118 A1. The shunt 1100 in this embodiment incorporates a leadless LFPS 1104 with a form factor like that of the V-LAP system. In a preferred embodiment, the internal anchor framework can be adjusted to place the LFPS 1104 internal to the frame near the LA inlet 1107, but external to the frame in the region of the neck and right atrial outlet cone 1108. In this embodiment, the sensor 1104 can be fully or partially encapsulated with a biocompatible cover such as ePTFE.

[0191] Still referring to FIG. 11 , in accordance with the principles of the present disclosure, the minimum distance X along the inner curve of the left atrial shunt cone 1107 to reach its junction with the sensor body 1104 plus the minimum distance Y from the junction to the sensing surface 1104′ of the sensor 1104 is at least 2.5 mm. Maintaining such a distance helps ensure that tissue overgrowth on the sensing surface is unlikely to exceed 300 μm in thickness, thus reducing or minimizing LAP waveform artifacts. In another embodiment, the dimensions X and Y and the angle between X and Y are selected such that any tissue overgrowth of the sensing surface 1104′ that is contiguous with any cardiac tissue is sufficiently mechanically isolated such that artifacts in the sensed LAP waveform associated with changes in cardiac wall tension will not be substantial. In yet another embodiment, a ring or other collar-like member 1109 may be disposed around the sensor body proximal to the sensing surface 1104′ of the sensor 1104 to provide further mechanical isolation from artifacts due to changes in cardiac wall tension.

[0192] 12A and 12B, a shunt 1200 of the present invention is described that is equipped with a generally coaxially oriented leadless LFPS sensor 1204 affixed to a shunt frame by a support structure including a strut 1205 and a collar 1208, similar to that described with respect to FIGS. 4A-4B. In this embodiment, the support structure extends from the right atrial cone of the shunt 1200 so that the LFPS 1204 can measure the RAP. This shunt design may be particularly beneficial for patients with PAH who have an enlarged right atrium and suffer primarily from right-sided HF. It will be further apparent that such a sensor fixation method, in which the strut 1205 occupies the RA entrance, may be constructed to prevent the passage of embolic material through the shunt from one atrium to the other.

[0193] 13A and 13B depict an additional embodiment of a shunt 1300 in which a generally non-coaxial, wire-free LFPS sensor 1304 extends from the right atrial cone of the shunt to measure RAP, off-center in the lumen 22, and is affixed to the shunt anchor frame by a support structure including a strut 1305 and a collar 1308, in a manner similar to that of FIGs. 5A-5B. This shunt design may also be particularly beneficial for patients with PAH who have an enlarged right atrium and suffer primarily from right-sided HF. This arrangement also improves the ability to later pass through the shunt into the LA.

[0194] 14A and 14B, another embodiment 1400 of a shunt of the present invention is illustrated in which the end 1402 of the sensor 1404 opposite the sensing surface 1401 has a streamlined profile. As will be recognized by one of ordinary skill in the art, modifying the sensor body to streamline any surface features exposed to the blood flow can be beneficial to optimize the pressure / flow relationship and reduce turbulence and high shear forces that may activate platelets or otherwise enhance clot formation.

[0195] 15A-15D, devices and methods that may be useful in treating HF, PAH, and other cardiovascular and cardiopulmonary disorders are described. In FIG. 15A, an exemplary shunt 1500 includes any of the shunt configurations provided herein and includes a leadless LFPS 1504 disposed on the RA side of the shunt, e.g., via a strut 1505 and a collar 1508, in a manner as described with respect to FIGS. 12A-12B, 13A-13B, and 14A-14B. In one preferred embodiment, the sensor 1504 is a dual sensor with circuitry for measuring at least two different physiological parameters. In the illustrated example, a pressure-sensing surface P is disposed near the proximal end of the sensor module, and a Doppler piezoelectric acoustic transducer D is positioned near the distal end of the sensor module. Sensor D measures the velocity profile along the longitudinal axis of the shunt, while sensor P measures the RAP. In one preferred embodiment, sensor D measures a continuous wave Doppler time-varying signal. Alternatively, Sensor D may use pulsed Doppler techniques to measure a time-varying velocity signal along the longitudinal axis of the shunt in a volume at a defined distance from the transducer. In yet another embodiment, Sensor D may be capable of using either continuous wave or pulsed Doppler signals.

[0196] 15B depicts an example of a velocity profile through one half of the longitudinal lumen of a V-Wave Ventura® interatrial shunt under static pressure / flow conditions when the LAP is 38 mmHg, the RAP is 8 mmHg, and the interatrial pressure gradient is 30 mmHg. It can be seen from the figure that the peak velocity is largely localized in the central portion of the jet exiting the neck throat orifice of the shunt and extending beyond the exit of the RA cone.

[0197] FIG. 15C is an example of a continuous wave Doppler time-varying signal acquired in an animal from an intracardiac echocardiographic probe located in the RA, aimed through the central lumen of a V-Wave Ventura® interatrial shunt. The image shows a peak velocity V maxand an average velocity V over multiple cardiac cycles of approximately 0.90 M / s mean The pressure gradient across the shunt is given by the formula ΔP = 4V 2 It will be appreciated by those skilled in the art of echo / Doppler imaging that the peak and mean pressure gradients for this example are shown in the table adjacent to the image in FIG. 15C.

[0198] FIG. 15D is an example of a RAP pressure trace taken with a catheter over multiple cardiac cycles, showing an average RAP of about 5 mmHg. This is representative of the type of signal waveform that can be obtained by the LFPS shown in FIG. 15A. With the dual sensor configuration of FIG. 15A, located generally near the RA end of the shunt, it is clear that the instantaneous or average pressure in each atrium can be measured simultaneously. The RAP is measured directly by the LFPS, and the LAP is estimated by the total RAP+|ΔP|. It should be appreciated that the present shunt design can be used to guide therapy in patients with HF and the like, with a primarily left-to-right shunt flow, or alternatively, in PAH and the like, with a primarily right-to-left shunt flow. One advantage of the configuration shown in FIG. 15A is that the LAP can be measured without the need for an additional sensor located on the left atrial side of the shunt. This can be particularly advantageous in PAH, where the LA tends to be small relative to the dimensions of the RA.

[0199] Figures 16A-16C illustrate another exemplary embodiment with similar features to Figures 15A-15D. However, in this embodiment, the dual function sensor 1604 is inverted and placed on the LA side of the shunt 1600 using a strut 1605 and collar 1608, so that the pressure sensing surface P is oriented toward the mid-LA cavity and the piezoelectric acoustic Doppler transducer D is oriented along the longitudinal axis through the shunt. The image in Figure 16B is a short-axis transesophageal echocardiogram (TEE) color Doppler view of a V-Wave Ventura® interatrial shunt positioned across the fossa ovalis of a patient with HF. The image shows a prominent left atrium to right atrium high velocity jet exiting the shunt into the RA. FIG. 16C is the corresponding continuous Doppler waveform over multiple cardiac cycles showing a peak velocity through the LA to RA shunt of 2.5 M / sec and an average velocity of 1.7 M / sec, corresponding to a peak ΔP of 25 mmHg and an average ΔP of 12 mmHg, respectively. RA pressure can be calculated as RA=LAP-|ΔP|. This embodiment 1600 of the shunt of the present invention can be used to induce therapy in patients with HF and the like, with a shunt flow primarily from left to right, or alternatively, in PAH and the like, with a shunt flow primarily from right to left. In one preferred embodiment, the configuration may be most advantageous when LAP-inducing therapy is most relevant, such as in HF. The shunt 1600 of FIG. 16A may also be advantageous when the LA cavity is enlarged, as in HF and the like.

[0200] 17A-17C, additional preferred embodiments of the shunts of the present invention are described. FIG. 17A shows a shunt 1700 similar to that of FIGS. 1A-1C, in which various features may be optimized for different anatomies. For example, the rake angle θ of the left atrial cone Lcan be increased so that for the same base diameter of the LA cone, there is less protrusion into the LA cavity. This feature can be advantageous in treating RV failure in PAH and equivalents, where the LA is small and underfilled. The neck length N can be extended to accommodate a thicker fossa ovalis. Although a thicker fossa ovalis may be more common in PAH, lipomatous infiltration of the interatrial septum can increase the minimum thickness of the fossa ovalis up to 10 mm or so in the absence of other disease processes. Furthermore, the rake angle θ of the RA cone R may be reduced for the same diameter of the RA cone base, providing further projection into the RA. Further projection of the RA cone may be advantageous in PAH and equivalents, where the RA is enlarged and the fossa ovalis bends toward the LA due to RAP>LAP, and thus the fossa ovalis from the RA perspective appears as a distinct depression or crater. In this situation, it may be more advantageous for the RA cone to be longer and therefore to project into the RA beyond the level of the limbus surrounding the fossa ovalis. This extension of the inlet cone in the setting of a right-to-left shunt may reduce the risk of entrainment of thromboemboli into the left atrium, and therefore the risk of stroke. Any combination of the above features may be utilized to create an interatrial shunt optimized for specific anatomical or physiological conditions.

[0201] FIG. 17B depicts the use of an anatomically optimized shunt 1701 with a lead-free transit-time flow probe 1702 that surrounds the neck region of the shunt. In this embodiment, the flow probe has dual piezoelectric acoustic transducers such that a first transducer 1703 transmits a pulse that is reflected by the neck region of the shunt 1700 and received by a second transducer 1704. The next pulse is transmitted from the second transducer 1704, reflected by the neck region of the shunt 1700, and received by the first transducer 1703. The difference in transit time between transmission and reception in each direction indicates the direction and velocity of blood flow. The transducers may be arranged in different locations on opposite sides of the neck (not shown), or the pattern of sound transmission and reflection may be "V-shaped" (as shown in FIG. 17B) or even "W-shaped" (not shown), as is well known to those skilled in the art of transit-time flowmeters. In another embodiment, the transducers 1703, 1704, control electronics, and RF coils for external power reception and telemetry are housed within a hermetically sealed cylindrical collar 1705 with an acoustic window for the transducers. The collar 1705 can be slid over the constrained shunt portion (neck) and can be affixed to the shunt 1700 by the various described above.

[0202] The embodiment 1701' depicted in FIG. 17C is similar to that of FIG. 17B, except that the flow sensor 1702' is wired and includes first and second transducers 1703', 1704'. In one embodiment, the lead 1706 traverses the wall of the RA cone, creating a more coaxial system that may be beneficial for constraining the shunt within a loading tube or introducer sheath prior to deployment. In another embodiment, the lead and internal electronics (circuitry) may be optimized so that the lead can be connected to a pacemaker generator. A pacing electrode or electrodes may be placed externally on the collar for atrial pacing and / or IEGM sensing from the fossa ovalis location. Alternatively, the lead may contain a more proximal indifferent electrode (not shown) for bipolar pacing and / or IEGM sensing.

[0203] 18A and 18B are illustrations of computational flow dynamics analysis of gauge pressure fields across a half model of a V-Wave Ventura® interatrial shunt corresponding to two sets of boundary conditions. FIG. 18A simulates the average or typical observed condition in HF, where a fixed gauge pressure of 18 mmHg is applied on the LA side (inlet) and 8 mmHg is applied on the RA side (outlet). Thus, ΔP=10 mmHg. FIG. 18B illustrates an extreme condition corresponding to decompensated HF, where a fixed gauge pressure of 38 mmHg is applied on the LA side (inlet) and there is no change in the RA side (outlet) pressure, which remains constant at 8 mmHg. In this case, ΔP=30 mmHg. In both scenarios, the pressure at the distal half of the LA cone is essentially the same as the LAP due to minimal acceleration of flow at that location. Additionally, in both graphs, the pressure is lowest in the region of the shunt neck throat orifice, substantially lower than that at RA. This is consistent with the Venturi effect in classical fluid dynamics, whereby a fluid gains kinetic energy when there is a reduction in pressure (potential energy), according to Bernoulli's principle of conservation of energy.

[0204] With increasing pressure gradient ΔP, the pressure at the neck drops dramatically from 6.24 mmHg to 2.37 mmHg. If the encapsulated shunt body has substantially impermeable walls, is elastically deformable, and has the proper frequency response, the transition from lower ΔP to higher ΔP as shown in FIG. 18B can be measured by assessing the change in shunt geometry. One example of changing geometry is the inward displacement of the shunt neck (arrows), while another example is the change in the rake angle θ of the LA cone. L The bending moment is measurable as an increase in force. If these conditions are met, the shunt itself can be used as a force gauge, similar to a pressure sensitive diaphragm. Sensor types that measure linear or angular displacement are well known and can be directly coupled to a force collector, in this case the shunt.

[0205] Referring now to FIG. 18C, an embodiment 1800 having one or more flexible sealed strain gauges in an SFPS sensor configuration is described. In FIG. 18C, the sensing element 1801 may be arranged to measure bending moment of the shunt frame 1810 near and at multiple locations around the circumference of the shunt neck. The sensor includes piezoresistive strain gauges, associated application specific processing circuitry, and circuitry such as an external inductor coil for remote RF power reception and telemetry. The electronics may be potted with a flexible polymeric material that inhibits or prevents the ingress of moisture to the sensitive electronics in the implanted environment. It will be apparent to one skilled in the art of implantable sensors that other suitable arrangements of components may be used to create a sensor that would measure displacement within the shunt itself.

[0206] 19A and 19B depict an exemplary embodiment employing SFPS technology. More specifically, FIG. 19A shows a shunt anchor frame 1901 as described elsewhere herein, with the anchor cut longitudinally and laid out in a flat plan view for easy understanding. Multiple 1×1×0.1 mm SFPS sensors 1904 are disposed on a biocompatible material 1920 that encapsulates the shunt anchor frame on both the RA and LA sides of the shunt. FIG. 19B depicts an exemplary location for multiple SFPS 1904 on the luminal aspect of the RA cone of a V-Wave Ventura® interatrial shunt. In one embodiment, the sensors may be bonded directly to the luminal surface of the ePTFE encapsulation 1920. Alternatively, the sensors 1904 may be disposed between a bilayer of ePTFE that is sintered together to sandwich the shunt anchor frame. Additionally or alternatively, the minimum distance from each sensor 1904 to the respective atrial cone edge that may contact a cardiac structure may be about 2.5 mm in some examples. The pressure sensor 1904 is preferably located on the lumen wall at a location between the distal left or right atrial cone base and the neck region of the shunt.

[0207] From Figures 15B and 18A and 18B, it is apparent that the regions of blood adjacent to the shunt lumen wall other than those at the shunt neck may have relatively low rates of flow and pressure indicative of the ventricle immediately adjacent to the respective pressure sensor. In one embodiment, multiple sensors are provided on each side of the shunt, all of which may be or include pressure sensors. For example, if LC-type SFPS sensors are used, each sensor may have a different fundamental resonant frequency and may be activated in sequence or read simultaneously by an appropriately multiplexed RF signal. For example, pressure changes may cause the resonant frequency to shift from the zero frequency. If the sensors each have different zero frequencies and these frequencies are spaced far enough apart, the sensors may be read all at once without multiplexing and the spectrum may cover all frequencies of the sensors that can be distinguished from one another. Alternatively, the sensors may be multiplexed and read out, for example, one at a time. The sampling rate to faithfully reproduce the cardiac pressure signal is approximately twice the tenth harmonic of the fundamental frequency of the heart rate. Most HF patients have a HR or fundamental frequency of 0.8-1.3 Hz. Even with a tachycardial HR of 2 Hz, a sampling rate of 40 Hz would be adequate. A device capable of frequency switching and sampling pressure at at least 240 Hz would be adequate for multiplexing up to six pressure sensors. Being able to properly reproduce the 20th harmonic would also allow for faithful calculation of dP / dt. For six sensors multiplexed, this could utilize sampling at 480 Hz, which is well within the sampling capability for practical RF carrier frequencies of 100 kHz or greater.

[0208] Having multiple LAP sensors as described herein may also be beneficial to reduce noise by allowing signal averaging. Furthermore, if a sensor were to fail or develop artifacts due to mechanical connections caused by tissue overgrowth or chamber wall tension, the information from that sensor may be ignored and the redundant sensor would allow continued access to the important pressure data. In another embodiment, individual sensors that individually measure one of multiple physiological or biochemical parameters, for example, shunts with multiple sensor types (e.g., pressure, oximetry, pH, acceleration, etc.), may be employed.

[0209] With reference to Figures 20A-20C, 21A-21C, and 22, illustrative examples are described showing how an implanted pressure sensor, such as an LFPS or SFPS pressure sensor, can be used to guide drug and device therapy in an HF patient.

[0210] 20A-20C depict data from a patient with idiopathic cardiomyopathy with LVEF of 25% who was previously hospitalized with ADHF and then implanted with a wired LAP sensor. FIG. 20A is a LAP waveform tracing corresponding to an episode when the patient was out of breath. The mean LAP was substantially elevated at 36 mmHg with a V wave of 60 mmHg. FIG. 20B is a waveform tracing taken at a later time point and shows a normal mean LAP of 11 mmHg. FIG. 20C is a time trend plot of daytime LAP measurements (open circles=morning, closed circles=evening) and a 7-day moving average. During the first 4 months of monitoring, there were two episodes of acute decompensated HF. Physician-directed patient self-management was initiated with sequential titration of ACE inhibitors and beta antagonists. Diuretics and long-acting nitrates were adjusted according to the just measured LAP using the DynamicRx algorithm described above. During the final 8 months of the plot, LAP largely normalized, averaging 10-12 mmHg, and the patient became asymptomatic.

[0211] Figures 21A-21C are LAP waveform traces and trend plots from an elderly patient with HFrEF who had four prior hospitalizations for ADHF. During the first year after sensor implantation, the patient continued to have brief episodes of severely elevated LAP readings associated with giant v-waves (Figure 21A). These episodes correlated with severe functional mitral regurgitation as observed on echocardiography. The patient underwent successful MitraClip implantation with transseptal catheter placement performed posterior to the location of the LAP pressure sensor on the fossa ovalis. The patient's symptoms improved with prevention of the most significant LAP outliers. Subsequent intensification of medical therapy resulted in excellent control of LAP.

[0212] FIG. 22 shows a trend plot of pulmonary artery pressure and heart rate in a patient with HFpEF implanted with a CardioMEMS pressure sensor. The patient had NYHA Class III symptoms with severe and sustained elevation of PA pressure. A V-Wave Ventura® interatrial shunt was implanted and heart rate was reduced using a beta antagonist to improve the efficiency of left atrial shunt decompression. These steps resulted in an immediate and sustained reduction in PA pressure with a concomitant improvement in symptoms.

[0213] FIG. 23 is an embodiment of the shunt of the present invention in which the electrical components of the sensor are located on the retention members (legs) of the shunt anchor 2300. In FIG. 23, an anchor frame 2301 similar to that depicted in FIG. 12 of commonly assigned U.S. Patent No. 10,251,740 is illustrated. More specifically, in FIG. 23, an anchor 2300 suitable for use in the shunt of the present invention includes a flared region 2306 configured for deployment in the left atrium and a generally cylindrical region 2307 extending through the atrial septum into the right atrium. The flexible struts 2308 include U-shaped inverted ends 2309 that bend distally, i.e., toward the septum, when the anchor is released from its delivery sheath, and preferably contact but do not penetrate the right atrial wall in the fully deployed position, as depicted in FIG. Preferably, anchor 2300 includes a conduit formed by encapsulating the anchor with a polymeric material that inhibits or prevents tissue ingrowth from occluding the lumen of cylindrical region 2307, other than flexible struts 2308, and may include or be made from a biocompatible shape memory alloy, as described with respect to the previous embodiment. In the embodiment of FIG. 23, at least one of the flexible struts 2308 includes a sensor element 2304. Depending on the height of the flexible struts 2308 when deployed and whether the struts are likely to be overgrown by pannus, the sensor element 2304 may include the sensor itself or any suitable combination of one or more of a sensor circuitry, e.g., a sensor antenna and / or a sensor electronics package. In some examples, sensor element 2304 includes a temperature sensor, a biochemical sensor, or other suitable sensor type.

[0214] 24A and 24B are end and side views, respectively, of an inter-atrial shunt 2400 formed from a wire braid configured in a manner as described in U.S. Patent No. 6,468,303, the entire contents of which are incorporated herein by reference. The shunt 2400 may be covered with a biocompatible covering (specifically not shown) and may include a sensor 2404 that is affixed within the flow lumen 22' of the shunt. The sensor 2404 may be provided in a secondary lumen 22″ located within lumen 22′. FIG. 24C depicts deployment of the shunt of FIGS. 24A-24B within the atrial septum. For example, the shunt 2400 (some details omitted for clarity), including the sensor 2404, may be compressed into a delivery sheath 2405, which may be extended across the atrial septum. Structure 2406 may be used to hold the shunt 2400 in place while the sheath 2405 is retracted so that the first flange 2402 may self-expand into one of the atria. The sheath 2405 may then be further retracted to allow the second flange 2403 to self-expand into the other atrium in a manner to anchor the sensor 2404 across the atrial septum. The sensor 2404 may measure the LAP, the RAP, or both the LAP and the RAP. 24A may suggest that the sensor 2404 has a generally circular cross-section, it is noted that the sensor 2404 may have any suitable cross-sectional shape, such as semicircular, crescent, or other, and may have a cross-sectional shape that varies along the length of the sensor, for example, in a manner as described in more detail with reference to FIGS. 31A-31E and 32A-32D. By way of example, the sensor 2404 may have at least a partially annular cross-section through which blood may flow, and the sensor may include circuitry for measuring the flow rate of blood therethrough. It is also to be understood that while the sensor 2404 may be positioned adjacent the inner wall of the lumen 22', the shunt 2400 may instead include struts and collars configured to concentrically support the sensor 2404 and spaced from the inner wall of the lumen 22'.

[0215] 25A and 25B illustrate a further alternative embodiment of the shunt of the present invention in which the mid-region 2501 of the shunt anchor 2500 has a coil structure that serves as a circuit element of the sensor 2504. In this embodiment, the frame neck 2501 (mid-region) may be laser cut to a coil geometry, thus forming an inductor or telemetry coil, in a manner similar to that described in Luo, "Selective and regulated RF heating of stent toward endohypothermia treatment of in-stent restenosis," Master's Thesis, University of British Columbia (Vancouver), 2014, the entire contents of which are incorporated herein by reference. A sensor 2504, e.g., a capacitor, may be provided at one or both edges of the flanges 2502, 2503 and, together with the neck 2501 (which may provide an inductor), may form an LC circuit that may be used as a passive resonant circuit. By way of example, the frame neck 2501 may form a fully encapsulated, multi-turn coil, have an outer diameter of about 6 mm, and be deployable through an 18 Fr or 24 Fr sheath. In some examples, the frame neck 2501 may include or be formed from a composite Nitinol / silver wire to have superelastic properties and / or may be plated with platinum or silver to inhibit corrosion. In this regard, the frame neck 2501 may not necessarily be integrally formed with the flanges 2502 and 2503, but instead may be welded or otherwise coupled thereto.

[0216] It should be noted that the inductance of the coil-shaped frame neck 2501 may be relatively small, and such inductance may change in response to changes in the cross-sectional area and / or length of the coil, for example, between beats, or over time due to healing or remodeling. An active sensor using the aforementioned changes in inductance in the present neck strut ring coil could potentially measure flow through the shunt, since pressure in the neck would decrease with increasing flow due to the Venturi effect, thus reducing the cross-sectional area of ​​the coil and therefore its inductance. Due to the relatively high resonant frequency of the LC circuit using a reasonably sized capacitor, an active circuit for measuring inductance and performing telemetry could be provided.

[0217] 26A-26B illustrate an alternative embodiment of the shunt of FIGS. 19A and 19B in which a sensor is disposed in a laser cut frame element formed in the shunt anchor. In the embodiment of FIGS. 19A and 19B, multiple leadless sensors may be disposed on or in a biocompatible material encapsulating the shunt anchor frame, while in the shunt 2600 of FIGS. 26A-26B, the anchor frame 2602 includes one or more receptacles 2603 formed in circumferential struts 2605 configured to individually receive and anchor a sensor 2604. The multiple receptacles 2603 may be equally spaced around the circumference of the anchor frame 2602, and the receptacles may be located in one or both atria of the anchor frame and / or at the shunt neck location. The receptacles 2603 may be formed by any suitable process, including laser cutting or subsequent welding during manufacture of the anchor frame. The sensors 2604 may be affixed on or within the respective receptacles 2603 via any suitable process, for example, using a biocompatible adhesive or crimping. Alternatively, the sensors 2604 may be located in eyelets formed at one or both ends of the anchor frame, such as in the eyelets 64 depicted in Figures 4 and 5 of commonly assigned U.S. Patent No. 10,251,740. Advantageously, the receptacles 2603 may be positioned within the length of the anchor frame and thus may be less susceptible to potential bending during deployment of the shunt. For example, Figure 26B illustrates a shunt 2600 compressed into a delivery configuration in which the receptacles 2603 generally follow the outer contour of the compressed shunt. Other exemplary locations for the receptacles are also described with reference to Figures 28-30, as well as elsewhere herein.

[0218] FIG. 27 illustrates a further alternative embodiment of a shunt of the present invention in which an intermediate region of the shunt anchor 2700 has a coil structure 2701 that may form circuit elements of a sensor 2704 in a manner similar to that described with reference to FIGS. 25A-25B.

[0219] It should be understood that the shunts provided herein may include one or more sensors, each of which may be located at any suitable location on the shunt. For example, Figures 28-30 illustrate alternative embodiments of the shunts of the present invention in which sensors are located at various regions on the shunt anchor. For example, the shunt anchor 2800 illustrated in Figure 28 includes a receptacle 2803 for a sensor 2804 that is coupled to a longitudinal strut 2806 and extends beyond the periphery of the flange 2802. As another example, the shunt anchor 2900 illustrated in Figure 29 includes a receptacle 2903 for a sensor 2904 that is coupled to a longitudinal strut 2906 and is located within the length of the anchor frame in a manner similar to that described with reference to Figures 26A-26B. As yet another example, the shunt anchor 3000 illustrated in Figure 30 includes one or more receptacles 3003 for each sensor 3004 coupled to circumferential struts 3005 and one or more receptacles 3003' for each sensor 3004' coupled to longitudinal struts 3006. Any suitable one of the receptacles 3003, 3003' may be located within the length of the anchor frame (e.g., receptacle 3003 in the example shown in Figure 30), and any suitable one of the receptacles 3003, 3003' may extend beyond the periphery of the flanges 3001 and / or 3002.

[0220] As further described above with reference to Figures 24A-24C, the sensor may have any suitable cross-sectional profile, and in some embodiments, may have a cross-sectional profile that varies along the length of the sensor. For example, Figures 31A-31E illustrate alternative embodiments of a shunt 3100 of the present invention in which the cross-sectional profile of the sensor varies. As illustrated in Figure 31A, the sensor 3104 may include a pressure sensor or other sensor type as described elsewhere herein. The sensor 3104 may be generally circular and may include a sensor surface 3104', such as a pressure-sensing diaphragm, that may be configured to be disposed within or adjacent either the first flared end region 3102 or the second flared end region 3103 to measure pressure within that region, a concave section 3107 disposed within the neck region 3101 of the shunt frame 3110 and configured to have a relatively low profile therein, and a tapered section 3106 extending between the sensor surface and the concave section. In some embodiments, the recessed section 3107 may house the circuitry of the sensor 3104.

[0221] The sensor 3104 may be positioned in any suitable location within the shunt 3100. For example, as illustrated in FIGS. 31B-31E, the sensor 3104 may be centrally positioned along a first dimension of the shunt frame 3110 and off-center positioned along a second dimension of the shunt frame. By way of illustration, the sensor 3104 may be coupled to the shunt frame 3110 along an inner surface of the shunt frame in a manner that reduces or minimizes the extent to which the sensor 3104 blocks blood from flowing through the lumen 22. The concave section 3107 may have a similar profile as the interior of the neck 3101 to reduce or minimize turbulence through the lumen 22. Thus, the sensor 3104 circuitry may be positioned coaxially with the inner lumen 22 of the shunt 3100. It should be understood that in embodiments such as those illustrated in Figures 31A-31B, blood may flow only along a single side of the concave section 3107 and the tapered section 3106, while the other sides of those sections may be coupled to the shunt frame 3110 in a manner that prevents blood flow between those sections and the shunt frame.

[0222] 32A-32D illustrate another alternative embodiment of a shunt 3200 of the present invention in which the cross-sectional profile of the sensor varies and includes a telemetry coil. As illustrated in FIG. 32A, the sensor 3204 may include a pressure sensor or other sensor type as described elsewhere herein. As perhaps seen in most detail in FIG. 32D, the sensor 3204 may be generally circular and may include a sensor surface 3204', such as a pressure-sensing diaphragm, that may be configured to be disposed within or adjacent either the first flared end region 3202 or the second flared end region 3203 to measure pressure within that region, a reduced diameter section 3207 disposed within the neck region 3201 of the shunt frame 3210 and configured to have a relatively low profile therein, optionally extending beyond the outer periphery of the shunt frame, and a tapered section 3106 extending between the sensor surface and the concave section. In some embodiments, the reduced diameter section 3207 may house the circuitry of the sensor 3204. The shunt 3200 may further include a telemetry coil 3220.

[0223] The sensor 3204 may be positioned at any suitable location within the shunt 3200. For example, as illustrated in FIGS. 32A-32D, the sensor 3204 may be centrally located along one or more dimensions of the shunt frame 3210. For example, the sensor surface 3204' may be located generally symmetrically within the flared end region 3202 or within the flared end region 3203. By way of illustration, the sensor 3204 may be coupled to the shunt frame 3210 via a collar 3208 into which the sensor 3204 may be inserted and posts 3205 that couple the collar 3208 to longitudinal posts 3212 of the shunt frame 3210. Thus, blood may flow generally symmetrically around and past the sensor 3204 through the annular gap 3230 in a manner as suggested by the unlabeled arrows in FIG.

[0224] In some embodiments, the location of the sensor 3204 within the shunt frame 3210 may be adjustable in vivo or ex vivo to regulate the rate of blood flow through the annular gap 3230. For example, the outer surfaces of the collar 3208 and reduced diameter section 3207 may each be threaded and may interlock with one another such that when the sensor 3204 is rotated in a first direction, as suggested by arrow 3240 in FIG. 32D, the sensor moves laterally in a first direction, as suggested by arrow 3231, reducing the size of the gap 3230 and causing a decrease in blood flow through the gap. Similarly, when the sensor 3204 is rotated in a second direction, as suggested by arrow 3241 in FIG. 32D, the sensor moves laterally in a second direction, as suggested by arrow 3232, increasing the size of the gap 3230 and causing an increase in blood flow through the gap.

[0225] 33A-33D illustrate yet another alternative embodiment of a shunt 3300 of the present invention in which the sensor may be deployable. As shown in FIG. 33A-33C, the shunt 3300 may include a Nitzan type hourglass or diabolo shaped nitinol anchor such as those described in FIG. 1A-1C and 2, which may be fully or partially encapsulated with a biocompatible material such as those described with respect to FIG. 1A-1C and 2. For example, the anchor may include a first flared region 3302, a second flared region 3306, and a neck region 3304 disposed between the first flared region 3302 and the second flared region 3306. Additionally, the anchor may be formed by a plurality of longitudinal struts 3308 interconnected by a plurality of circumferential struts 3310.

[0226] As shown in Figures 33A-33D, the sensor 3400 may be pivotally coupled to an end of an anchor, for example, at an end of the first flared region 3302, such that the sensor 3400 may pivot about the end of the anchor (as shown in Figures 33A-33D) and transition between a delivery configuration and a deployed configuration, as described in more detail below. For example, as shown in Figure 33D, which is a close-up view of boxed portion D of Figure 33C, the sensor 3400 may be coupled to the anchor via a support structure, for example, a torsion spring 3312. The torsion spring 3312 may be biased to a folded configuration, thereby biasing the sensor 3400 toward a deployed configuration in which a sensing surface of the sensor 3400 is in fluid communication with a lumen of the anchor.

[0227] As shown in FIG. 33D, a first end of the torsion spring 3312 may be secured to the longitudinal strut 3308 of the anchor, and a second end of the torsion spring 3312 may be secured to the sensor 3400 such that a portion of the torsion spring 3312 between the first and second ends wraps around the outermost circumferential strut 3310 of the anchor. In the biased, folded configuration of the torsion spring 3312, the first and second ends of the torsion spring 3312 are adjacent to one another, as shown in FIG. 33D. Thus, the torsion spring 3312 causes the sensor 3300 to transition between the delivery configuration and the deployed configuration by pivoting the sensor 330 around the outermost circumferential strut 3310 of the anchor. FIG. 33D illustrates the torsion spring 3312 wrapping two and a half times around the circumferential post 3310, however, as would be understood by one of ordinary skill in the art, the torsion spring 3312 may be wrapped around the circumferential post 3310 more or less times.

[0228] As shown in FIG. 33D, the shunt 3300 may include, for example, two torsion springs, one on each side of the sensor 3400, to stabilize the sensor 3400 as it transitions between the delivery configuration and the deployed configuration. Thus, each torsion spring may be coupled to an adjacent longitudinal strut of the anchor such that the sensor 3400 is positioned between two adjacent longitudinal struts of the anchor in the deployed configuration. In this manner, the sensing surface of the sensor 3400 may be in fluid communication with the lumen of the anchor in the deployed configuration without obstruction or interference from any longitudinal struts. Preferably, the anchor is not encapsulated with a biocompatible material where the sensing surface of the sensor 3400 is in fluid communication with the lumen of the anchor. For example, the opening in the biocompatible material may be a cutout. Additionally, the circumferential and / or longitudinal struts adjacent the sensor 3400 may be structured to be positioned around the sensor 3400 when the sensor 3400 is in its deployed configuration, such that the sensor 3400 does not interact with any circumferential or longitudinal struts except via the torsion spring 3312.

[0229] As with the sensors described herein, the sensor 3400 may include circuitry for measuring mechanical parameters including pressure, force, flow, velocity, acceleration, wall shear stress, temperature, etc., or electrical properties exemplified as IEGMs, resistance, impedance, current, inductance, capacitance, or chemical properties including pH, osmolality, chemical speciation, molecular concentration, reaction rates, or any other desired physiological parameters for which acceptable sensors have been developed. For example, the sensor 3400 may include a MEMS sensor disposed within a sensor housing, such as a Wurth, TDK, or Fraunhoffer sensor. Additionally or alternatively, the sensor 3400 may include a strain gauge. Although FIGS. 33A-33D illustrate a shunt 3300 having a single sensor, as would be understood by one of ordinary skill in the art, the shunt 3300 may have additional sensors (e.g., in the space around the end of the first flared region 3302 and / or the space around the end of the second flared region 3306).

[0230] 34A-34G, the sensor 3400 will be described in further detail. As shown in FIG. 34A-34G, the sensor 3400 may include a housing 3402 (e.g., a ceramic sensor can) and a sensing surface 3404 (e.g., a titanium plate hermetically sealed to the housing 3402), the sensing surface 3404 having a sensing diaphragm 3406 (e.g., a flexible and compressible pressure sensor diaphragm). The sensor housing 3402, and accordingly the sensing surface 3404, may have a generally rectangular shape with rounded corners. In some embodiments, the sensor housing 3402 may be approximately 4 mm long, 3.5 mm wide, and 2.2 mm thick. The sensor housing 3420 has an internal cavity sized and shaped to store the internal components of the sensor 3400.

[0231] FIG. 34F is a cross-sectional view of the sensor 3400 along line FF of FIG. 34E, and FIG. 34G is an exploded view of the sensor 3400. As shown in FIGS. 34F and 34G, the internal components may include a sensor electronics housing 3416 for housing the sensor electronics (e.g., electronic circuitry) and a ferrite core 3412 wrapped over with a telemetry coil 3414 (e.g., a copper wire coil), all disposed on a plate 3410. In some embodiments, the ferrite core 3412 may have an approximately 0.7 mm diameter and 2.5 mm length, and the telemetry coil 3414 may have a 0.025 mm diameter. Thus, placing at least the ferrite core 3412 and the telemetry coil 3414 within the housing 3402 minimizes the gas volume within the housing 3402, thereby maximizing the internal pressure change for a given diaphragm displacement of the sensing diaphragm 3406. The plate 3410 may have the same shape as the sensing surface 3404, and the sensing diaphragm 3406 may be positioned adjacent to the sensing surface 3404 within the sensor housing 3402 such that the sensing diaphragm 3406 changes the volume between the sensing surface 3404 and the plate 3410 in response to pressure changes across the shunt 3300. It should be understood that the three-dimensional geometry of the sensor 3400 is not limited in overall size and dimensions as long as it does not sufficiently impede shunt flow or substantially reduce the clinical effectiveness of the shunt.

[0232] By way of example, the circuitry may generate data indicative of left atrial pressure (e.g., in embodiments such as those illustrated in FIG. 3 or described with reference to FIGS. 4A-10 or 16A), right atrial pressure (e.g., in embodiments described with reference to FIGS. 12A-15A), or the rate of blood flow through the lumen. Additionally, the sensor 3300 may include circuitry for measuring multiple characteristics or may include multiple sensors, each of which includes circuitry for measuring a respective characteristic and is included in an integral housing with the other sensors. Alternatively, multiple independent sensors may be pivotally coupled to the anchor of the shunt 3300. The circuitry may further communicate with a patient display device described herein, thereby transmitting data therebetween. For example, the sensor 3300 may include an RF transceiver circuit configured to directly exchange physiological data and programming instructions with a patient display device.

[0233] 35A-35C illustrate the shunt 3300 in a delivery configuration, with the anchor in a folded delivery state and the sensor 3400 in its delivery configuration. As shown in FIG. 35A-35C, the sensor 3400 may be folded such that it pivots around the outermost circumferential strut of the anchor via the torsion spring 3312, substantially aligned with the folded anchor and extending axially therefrom, thereby providing a minimum profile of the shunt 3300 for delivery through the delivery sheath 3500. As explained above, the torsion spring 3312 is biased toward its folded state such that the sensor 3400 is biased toward the delivery configuration. Thus, the inner wall of the delivery sheath 3500 maintains the sensor 3400 in its delivery configuration when the shunt 3300 is in its folded delivery state within the delivery sheath 3500. Upon exiting the delivery sheath 3500, the anchor may self-expand to its expanded deployed state and the sensor 3400 transitions to its deployed configuration via the torsion spring 3312, as shown in Figures 33A-33C.

[0234] FIG. 36 illustrates an alternative embodiment of the shunt of FIGS. 33A-33D in which the sensor 3612 of the shunt 3600 is encapsulated with a biocompatible material 3614. For example, a pocket may be formed in the biocompatible material 3614 to house the sensor 3612. However, the sensing surface of the sensor 3612 may not be covered with a biocompatible material 3614 such that the sensing surface may be in fluid communication with the lumen of the anchor of the shunt 3600. Like the anchor of the shunt 3300, the anchor of the shunt 3600 may include a first flared region 3602, a second flared region 3606, and a neck region 3604 disposed between the first flared region 3602 and the second flared region 3606, and may be formed by a plurality of longitudinal struts 3608 interconnected by a plurality of circumferential struts 3610. As shown in FIG. 36, the sensor 3612 may be positioned between adjacent longitudinal posts 3608 and adjacent circumferential posts 3610 such that the sensing surface of the sensor 3612 is not obstructed by any longitudinal or circumferential posts.

[0235] The shunt 3600 need not include a torsion spring to pivotally couple the sensor 3612 to the first flared region 3602, whereby the sensor 3612 is fixed in position relative to the anchor. For example, the sensor 3612 may be secured to the anchor via one or more support structures. Alternatively, the biocompatible material 3614 may encapsulate at least a portion of the sensing surface of the sensor 3612, for example, around a peripheral edge of the sensing surface, while not obstructing the sensing diaphragm of the sensing surface so as not to interfere with the sensing capabilities of the sensor 3612.

[0236] In addition, when multiple receptacles are provided for the sensors, it should be understood that such receptacles may, but need not necessarily, be spaced approximately equally around the circumference of the anchor frame. Additionally or alternatively, the receptacles may be located in one or both atria of the anchor frame and / or at the location of the shunt neck. The receptacles may be formed by any suitable process, including laser cutting during manufacture of the anchor frame or subsequent welding to the anchor frame. Additionally or alternatively, one or more sensors may be placed between two layers of biocompatible material (e.g., ePTFE) at the neck, left atrial side, or right atrial side of the shunt. By way of illustration, the sensor may be placed inside a "pocket" previously created by the two layers of biocompatible material and then sealed using any suitable combination of heat, biocompatible adhesive, and / or suitable sutures. Alternatively, the sensor may be positioned on one layer of biocompatible material and another layer of biocompatible material folded over it.

[0237] In various configurations provided herein, the connection between the sensor and the shunt may not substantially increase the crimping strain in the shunt frame. For example, the encapsulated sensor may be configured to be relatively easily folded or compressed into a delivery configuration with the shunt frame without substantially causing plastic deformation to the structure, and may also have a fail-safe release mechanism when deployed. The sensor encapsulation (e.g., using parylene or the like) may provide relatively long-term durability against temperature changes, for example, to ensure that the sensor remains functional even when temporarily exposed to relatively high heat (e.g., saline heated above 45 degrees Celsius).

[0238] Certain mechanisms and methods of delivering the shunt are described herein and in the incorporated references, however, it should be understood that any suitable mechanism and method may be used, such as a threaded delivery cable, a hookless design, a clamp around the sensor body, etc., as previously used to deliver Amplatzer shunt designs.

[0239] The above real-world patients demonstrate the clinical feasibility and potential synergistic benefits achievable by combining an interatrial shunt that rapidly and automatically re-equilibrates pathological cardiac pressures with implantable sensors that assess key physiological parameters and provide actionable data to guide therapeutic decisions.

[0240] Thus, some embodiments herein provide a system for treating heart failure (HF) or pulmonary arterial hypertension (PAH) by monitoring at least one atrial physiological parameter and displaying information indicative of the at least one atrial physiological parameter on a patient display device. The system may include an interatrial shunt comprising: (i) an anchor having a first flare region, a neck region, and a second flare region, the neck region being disposed between the first flare region and the second flare region; and (ii) a biocompatible cover disposed on the anchor and forming a lumen extending from the first flare region to the second flare region. The system may further include a sensor comprising circuitry for generating data indicative of the at least one atrial physiological parameter, and a support structure for coupling the sensor to the interatrial shunt. The support structure may position the sensor relative to the lumen for monitoring the at least one physiological parameter, where post-implantation tissue growth does not exceed 300 microns. The system may include a computer-readable medium storing programming to be executed by a processor of a patient display device, the programming including instructions for receiving data from a sensor and processing the data for viewing on the patient display device. A non-limiting example of such a system is described with reference to FIG. 3, and non-limiting examples of inter-atrial shunts and sensors for use in such a system are described with reference to FIGS. 1-2, 4A-4B, 5A-5B, 6A-6B, 7A-7F, 8A-8B, 9A-9B, 10A-10B, 11, 12A-12B, 13A-13B, 14A-14B, 15A, 16A, 17A-17C, 18C, 19A-19B, 23, 24A-24C, 25A-25B, 26A-26B, 27, 28, 29, 30, 31A-31E, 32A-32D, 33A-33D, 34A-34G, 35A-35C, and 36.

[0241] Some examples herein provide an interatrial shunt for treating heart failure (HF) or pulmonary arterial hypertension (PAH) by shunting blood to relieve high pressure and monitoring at least one atrial physiological parameter. The shunt may include an anchor, the anchor having a first flared region, a neck region, and a second flared region, the neck region being disposed between the first flared region and the second flared region. In some embodiments, the inlet of the first flared end region may be in a first plane and the outlet of the second flared end region may be in a second plane such that the first plane intersects with the second plane in the expanded deployed state, as described in U.S. Patent No. 2019 / 0262118 to Eigler, the entire contents of which are incorporated herein by reference. Additionally, the shunt may include a biocompatible cover, the biocompatible cover disposed on the anchor and forming a lumen extending from the first flared region to the second flared region. The shunt may include a sensor with circuitry for generating data indicative of at least one atrial physiological parameter. The sensor may be positioned relative to the lumen such that tissue growth after implantation does not exceed 300 microns. Non-limiting examples of inter-atrial shunts and sensors are described with reference to Figures 1-2, 4A-4B, 5A-5B, 6A-6B, 7A-7F, 8A-8B, 9A-9B, 10A-10B, 11, 12A-12B, 13A-13B, 14A-14B, 15A, 16A, 17A-17C, 18C, 19A-19B, 23, 24A-24C, 25A-25B, 26A-26B, 27, 28, 29, 30, 31A-31E, 32A-32D, 33A-33D, 34A-34G, 35A-35C, and 36.

[0242] It should be understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. While various illustrative embodiments of the invention are described above, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the invention. Thus, the full scope of the invention should be ascertained with reference to the appended claims, along with the full scope of equivalents to which such claims are legally entitled.

[0243] In the foregoing disclosure, embodiments have been described with reference to specific exemplary implementations thereof. It will be apparent that various modifications can be made thereto without departing from the broader spirit and scope of the present disclosure as set forth in the following claims.

Claims

1. 1. An inter-atrial shunt for treating heart failure (HF) or pulmonary arterial hypertension (PAH) by shunting blood to relieve high pressure and monitoring at least one atrial physiological parameter, the inter-atrial shunt comprising: an anchor having a first flared region, a second flared region, and a neck region disposed between the first flared region and the second flared region; a biocompatible covering disposed over the anchor, the biocompatible covering forming a lumen extending from the first flaring region to the second flaring region; a sensor comprising a housing, a sensing surface and circuitry disposed within the housing; Equipped with The circuitry generates data indicative of the at least one atrial physiological parameter and communicates the data, and the sensor is pivotally coupled to the first flared region and configured to transition between a delivery configuration and a deployed configuration in which the sensing surface is in fluid communication with the lumen.

2. The inter-atrial shunt of claim 1 , wherein the anchor comprises a plurality of longitudinal struts interconnected by a plurality of circumferential struts.

3. 3. The inter-atrial shunt of claim 2, wherein in the deployed configuration, the sensor is positioned between adjacent pairs of longitudinal struts of the plurality of longitudinal struts and between adjacent pairs of circumferential struts of the plurality of circumferential struts such that the sensing surface of the sensor is not obstructed by the plurality of longitudinal and circumferential struts.

4. The inter-atrial shunt of claim 1 , wherein the anchor is configured to transition between a collapsed delivery state and an expanded deployed state.

5. + 5. The inter-atrial shunt of claim 4, wherein an inlet of the first flared end region lies in a first plane and an outlet of the second flared end region lies in a second plane such that the first plane intersects with a second plane in the expanded deployed state.

6. The inter-atrial shunt of claim 1 , wherein in the delivery configuration, the sensor extends axially away from the anchor.

7. The interatrial shunt of claim 1 , wherein the sensor is pivotally coupled to the first flared region via a torsion spring.

8. The inter-atrial shunt of claim 7 , wherein the torsion spring is configured to bias the sensor toward the deployed configuration.

9. 9. The inter-atrial shunt of claim 8, wherein during delivery of the inter-atrial shunt within a delivery sheath, the sensor is configured to be retained in the delivery configuration by an inner wall of the delivery sheath such that upon exiting the delivery sheath, the sensor transitions to the deployed configuration.

10. 8. The inter-atrial shunt of claim 7, wherein the torsion spring is coupled to an outermost circumferential strut of the first flared region such that the torsion spring is configured to pivot the sensor about the outermost circumferential strut.

11. 11. The inter-atrial shunt of claim 10, wherein a first end of the torsion spring is coupled to a housing of the sensor and a second end of the torsion spring is coupled to a longitudinal strut of the first flared region such that a portion of the torsion spring between the first and second ends wraps around the outermost circumferential strut.

12. The inter-atrial shunt of claim 1 , wherein the sensing surface comprises a flexible sensing diaphragm.

13. The interatrial shunt of claim 1 , wherein the sensor comprises a ferrite core wound over a telemetry coil disposed within the housing.

14. The inter-atrial shunt of claim 1 , wherein the sensor comprises a MEMS sensor disposed within the housing.

15. 15. The inter-atrial shunt of claim 14, wherein the MEMS sensor is selected from the list consisting of a Wurth, TDK, or Fraunhoffer sensor.

16. The inter-atrial shunt of claim 1 , wherein the sensor comprises a strain gauge disposed within the housing.

17. The inter-atrial shunt of claim 1 , wherein the data generated by the sensor is indicative of left atrial pressure, right atrial pressure, or a rate of blood flow through the lumen.

18. 2. The inter-atrial shunt of claim 1, wherein the biocompatible covering comprises an opening sized and shaped to expose the sensing surface of the sensor when the sensor is in the deployed configuration such that the sensing surface is in fluid communication with the lumen.

19. 1. A system for treating heart failure (HF) or pulmonary arterial hypertension (PAH) by monitoring at least one atrial physiological parameter and displaying information indicative of the at least one atrial physiological parameter on a patient display device, the system comprising:

1. An interatrial shunt, comprising: an anchor having a first flared region, a second flared region, and a neck region disposed between the first flared region and the second flared region; a biocompatible covering disposed over the anchor, the biocompatible covering forming a lumen extending from the first flaring region to the second flaring region; an interatrial shunt comprising: a sensor comprising a housing, a sensing surface, and circuitry disposed within the housing, the circuitry generating data indicative of the at least one atrial physiological parameter, the sensor being pivotally coupled to the first flared region and configured to transition between a delivery configuration and a deployed configuration in which the sensing surface is in fluid communication with the lumen; A computer-readable medium having instructions; Equipped with The instructions, when executed by a processor of the patient display device, cause the processor to receive the data from the sensor and process the data for viewing on the patient display device.

20. 20. The system of claim 19, wherein the sensor is pivotally coupled to the first flared region via a torsion spring.

21. 20. The system of claim 19, further comprising a delivery sheath configured to receive the anchor in a collapsed delivery state and the sensor in the delivery configuration.

22. 22. The system of claim 21, wherein the sensor is biased toward the deployed configuration such that upon exiting the delivery sheath, the sensor transitions to the deployed configuration.

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