System for cardiac treatment

Abstract

A method of cardiac treatment to provides a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient. The method may include ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure, delivering cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart, and stimulating a vagus nerve of the patient to induce an anti-inflammatory reflex in the patient's heart. The method may include ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure, and stimulating carotid baroreceptors of the patient to downregulates sympathetic tone and upregulates parasympathetic tone.

Description

Attorney Docket No. A0012932W001SYSTEM AND METHOD FOR CARDIAC TREATMENTFIELD

[0001] The present disclosure generally relates to a method and system of treating coronary microvascular disease and reducing heart failure with preserved ejection.BACKGROUND

[0002] Heart failure (HF) is a complex disease state broadly defined by an inability of the heart to pump sufficiently to cope with its venous return and / or to deliver sufficient output to meet the metabolic demands of the body. Heart failure is an increasingly common, life-threatening cardiovascular disorder, characterized by marked disability, frequent hospitalization and high mortality. HF is increasingly prevalent in older individuals (up to 10% of the population) and it has become the most common cause for hospitalization in people >65 yrs. HF is a leading cause or contributor to hospitalization and therefore is emerging as a substantial contributor to healthcare spending. The particular clinical manifestations of HF are determined by the underlying cause of the heart failure.

[0003] The term heart failure (HF) refers broadly to a pathophysiologic disorder in which cardiac performance is incapable of delivering sufficient blood to meet metabolic demand (e.g. during physical activity or in severe cases at rest), or to accommodate venous return. A range of further sub-classifications and / or structure of the heart, can then be applied, based on the symptoms exhibited by the patient. Exemplary classifications of heart failure by symptoms or objective assessments are provided by the New York Heart Association (classes LIV, classes A-D)). Heart failure can also be defined by ejection fraction. Generally, patients exhibiting an ejection fraction of less than or equal to 0.35 are classified as having heart failure with reduced ejection fraction (HFrEF) while an ejection fraction above 0.35 is considered to be heart failure with preserved ejection fraction (HFpEF).

[0004] Congestive heart failure symptoms are indicative of congestive heart failure. Exemplary congestive heart failure symptoms include reduced cardiac output leading to easy fatigue and organ dysfunction (e.g. renal), and to symptoms related to congestion either in the lungs (causing breathlessness) or peripherally (leading to swelling of the lower limbs and abdomen).Attorney Docket No. A0012932W001

[0005] A possible correlation has been identified between sedentary lifestyle and risk of ventricular arrhythmias based on a comparison of occurrences of ventricular arrhythmias in healthy active vs. sedentary men, and men with previous myocardial infarction. One result of a sedentary lifestyle is that the size of the chambers of the heart may decrease, which often occurs as a result of increased muscle thickness. Accordingly, the greatest number and highest grades of ventricular arrhythmias during exercise were found in healthy sedentary men.

[0006] Nearly half of all patients with heart failure have a normal ejection fraction (EF), commonly referred to as heart failure with preserved ejection fraction (HFpEF). Further, a large subset of HFpEF population has underlying microvascular disease (MVD) with hypertension and inflammation at foundation. In congestive heart failure patients with HFpEF the amount of blood pumped from the heart's left ventricle with each beat (ejection fraction) is greater than 50%. Some invasive studies demonstrate the prevalence of MVD in HFpEF is consistently high, ranging between 70 - 85% depending on the diagnostic thresholds used, such as CFR <2 to < 2.5, IMR >23 to >25.

[0007] HFpEF is also commonly known as diastolic heart failure or diastolic dysfunction, as the deficit in function frequently relates to changes occurring during diastole and filling of the ventricles. Approximately half of people with heart failure have HFpEF, while the remainder display a reduction in ejection fraction, or heart failure with reduced ejection fraction (HFrEF). The prevalence of HFpEF continues to increase, likely because of the increasing prevalence of common risk factors, including older age, hypertension, metabolic syndrome, renal dysfunction and obesity. HFpEF is characterized by abnormal diastolic function, which manifests as an increase in the stiffness of the heart's left ventricle, a decrease in left ventricular relaxation when filling with blood before the next beat, and decreased chamber volume, which often occurs as a result of increased muscle thickness. There is an increased risk for atrial fibrillation and pulmonary hypertension for patient's experiencing HFpEF.

[0008] Changes from MVD can mediate thickening and stiffening of the left ventricle (LV) wall, or concentric remodeling, which are characteristic of HFpEF. In patients with hypertension or aortic stenosis, these remodeling processes are believed to be partly induced by a state of LV pressure overload. Specifically, wall stress increases to maintain ejection performance under an elevated load that the heart pumps against during systole (e.g., afterload). In this context, concentric remodeling occurs to minimize the changes in wall stress, as predicted by the law of Laplace.Attorney Docket No. A0012932W001

[0009] In healthy vessels, coronary blood flow and myocardial perfusion are regulated by coronary arteriolar tone. Coronary blood flow remains constant over a wide range of coronary perfusion pressures through dynamic changes in resistance vessel tone. These dynamic changes result from a series of partially redundant mechanisms, including adrenergic stimuli, changes in local oxygen tension, and the response to changes in transmural pressure. Such redundant control of coronary blood flow helps to mitigate myocardial ischemia during the development and progression of epicardial atherosclerosis. Because myocardial oxygen extraction is near-maximal at rest, myocardial oxygen delivery is almost completely dependent on coronary blood flow. Consequently, an increase in myocardial oxygen demand must be matched by a proportional increase in coronary blood flow to prevent myocardial ischemia. Coronary microvascular disease (CMD) attenuates coronary flow augmentation in response to stress and, if severe enough to lead to demand-supply mismatch, may lead to subclinical or clinical myocardial ischemia. With the development of CVD risk factors and atherosclerosis, the vascular endothelium becomes dysfunctional and the vasodilator response to pharmacological and physiological interventions is attenuated, resulting in blunted coronary blood flow augmentation or vasoconstriction with frank reduction in blood flow. There is evidence that more than one-half of atherosclerotic coronary arteries without focally obstructive stenoses display a significant longitudinal pressure gradient affecting coronary blood flow and myocardial perfusion, which can contribute to myocardial ischemia and symptoms. This may help to explain the discrepancy between ischemic symptoms and the low frequency of obstructive coronary artery disease (CAD) in large registries of invasive coronary angiography and recent diagnostic clinical trials with cardiac computed tomography angiography as provided in Viviany R. Taqueti, Marcelo F. Di Carli, Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review, Journal of the American College of Cardiology, Volume 72, Issue 21, 2018, Pages 2625- 2641, ISSN 0735-1097. Second, recognition that symptoms in patients with nonobstructive CAD may be related to CMD offers an opportunity for directing additional investigations to improving diagnosis and management. Viviany R. Taqueti, Marcelo F. Di Carli, Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the- Art Review, Journal of the American College of Cardiology, Volume 72, Issue 21, 2018, Pages 2625-2641, ISSN 0735-1097.

[0010] Obesity, especially visceral obesity, is associated with microvascular disease MVD, including impairments in functional capillary density, endothelium-dependentAttorney Docket No. A0012932W001 vasodilation, vasomotion, and insulin-induced microvascular dilation and recruitment. An important consequence of MVD in obesity is that it contributes to impairment of insulin- mediated glucose disposal. Experimental evidence indicates that obesity shifts this balance toward less vasodilation, or even vasoconstriction, through adverse changes in adipokines, such as adiponectin, free fatty acids, and tumor necrosis factor-a. These changes impair insulin signal transduction in endothelial cells, resulting in less nitric oxide synthesis.

[0011] A second consequence of MVD in obesity is an increase in peripheral resistance and, other things being equal, blood pressure. Hypertension is characterized by multiple abnormalities of microvascular structure and function in many organs, such as reduced density (rarefaction) of arterioles, capillaries, and venules; enhanced constriction and reduced dilation of arterioles, including reduced endothelium-dependent vasodilation induced by insulin and other mediators; decreased arteriolar diameter; and increased wall-to-lumen ratio of small arteries (remodeling). Hypertension undoubtedly causes MVD, but, as reviewed elsewhere, MVD is currently thought to be both cause and consequence of high blood pressure.

[0012] Traditionally, CMD pathophysiology was thought to be a combination of microvascular architectural changes and endothelial dysfunction. Microvascular architectural changes include microvascular obstruction, with luminal narrowing of the arterioles and capillaries, and capillary rarefaction. Alternatively, or concurrently, endothelial or vascular smooth muscle (VSM) dysfunction may lead to an attenuated vasodilatory response or a pathological vasoconstrictive response to stimuli, leading to a blunted augmentation of, or reduction of, coronary blood flow (CBF) in response to stress. This can lead to a supplydemand mismatch in CBF, therefore leading to ischaemia and symptoms of angina. Patients with structural CMD appear to have more established cardiovascular risk factors, including poorly controlled hypertension, type 2 diabetes mellitus (T2DM) and a higher prevalence of exercise-induced hypertension as provided in Weerts, J.; Mourmans, S.G.J.; Barandiaran Aizpurua, A.; Schroen, B.L.M.; Knackstedt, C.; Eringa, E.; Houben, A.J.H.M.; van Empel, V.P.M. The Role of Systemic Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction. Biomolecules 2022, 72, 278.SUMMARY

[0013] It is believed a heightened sympathetic response contributes to both microvascular disease (MVD) and heart failure (HF) pathologies (e.g., HFpEF ). The techniques of this disclosure generally relate to systems and methods of cardiac treatment toAttorney Docket No. A0012932W001 provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies (e.g., HFpEF) and promoting cardiac remodeling of left ventricular hypertrophy in the patient.

[0014] In one aspect, the present disclosure provides a method of cardiac treatment to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient. The method includes ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; delivering cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart; and stimulating a vagus nerve of the patient to induce an anti-inflammatory reflex in the patient's heart.

[0015] In another aspect, the disclosure provides a method of cardiac treatment to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient. The method includes ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; and stimulating carotid baroreceptors of the patient to downregulates sympathetic tone and upregulates parasympathetic tone.

[0016] The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the techniques described in this disclosure will be apparent from the description and drawings, and from the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 is a schematic diagram that illustrates a cardiac therapy system of the present disclosure;

[0018] FIG. 2 is an illustration of a renal denervation system of the present disclosure;

[0019] FIG. 3 is an illustration of therapeutic targets of a patient for a pacing system of the present disclosure;

[0020] FIG. 4 is an illustration of the patient's coronary sinus ostium for a lead placement of a frequency stimulation system;

[0021] FIG. 5 is a graphical illustration of a reduction of post-CAGB inflammation for a 50 Hz stimulation of the frequency stimulation system;Attorney Docket No. A0012932W001

[0022] FIG. 6 is a schematic diagram that illustrates a method of cardiac therapy of the present disclosure;

[0023] FIG. 7 is a schematic diagram that illustrates a method of delivering renal denervation of the present disclosure;

[0024] FIG. 8 is a schematic diagram that illustrates a method of delivering cardiac pacing of the present disclosure;

[0025] FIG. 9 is a schematic diagram that illustrates an alternative cardiac therapy system of the present disclosure;

[0026] FIG. 10 is a schematic diagram that illustrates an alternative method of cardiac therapy of the present disclosure;

[0027] FIG. 11 is an illustration of a baroreflex activation therapy system of the present disclosure;

[0028] FIG. 12 is an illustration of the baroreflex activation therapy system of the present disclosure in a patient; and

[0029] FIG. 13 is an illustration of the baroreflex activation therapy system of the present disclosure and a pacemaker in a patient.

[0030] Corresponding parts are given corresponding reference numbers throughout the drawings.DETAILED DESCRIPTION

[0031] The present disclosure provides systems and methods for treating microvascular dysfunction and heart failure. The systems and methods for treating microvascular dysfunction and heart failure provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promote cardiac remodeling of hypertrophy in a patient.

[0032] Referring to FIG. 1, a schematic diagram of an exemplary cardiac therapy system that may be used to deliver a cardiac therapy to a patient according to the present disclosure is indicated at reference number 10. The system 10 is generally used to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies (e.g., HFpEF) and promoting cardiac remodeling of left ventricular hypertrophy in the patient.

[0033] The system 10 includes a renal denervation system, generally indicated at reference number 12, a cardiac pacing system generally indicated at reference number 14,Attorney Docket No. A0012932W001 and a vagus nerve stimulation system generally indicated at reference number 16. Using the combination of the renal denervation system 12, the cardiac pacing system 14, and the vagus stimulation system 16, the system 10 provides a synergetic therapeutic effect to lower the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies (e.g., HFpEF) and promote cardiac remodeling of left ventricular hypertrophy in the patient.

[0034] The renal denervation system 12 is configured to ablate renal nerves (e.g., nerves of a renal artery) to reduce sympathetic afferent and efferent activity to the kidney, which decreases blood pressure in the patient. For example, the system 12 may be configured to ablate neural fibers surrounding or in proximity to the renal artery, such as at least partially denervating the kidney(s) innervated by the renal neural fibers. For example, neural fibers of sympathetic nerves are typically between 1 to 10 mm away from the wall of the renal artery and can be ablated using the renal denervation system 12.

[0035] Referring to FIG. 2, in one suitable example, the renal denervation system 12 includes a renal denervation catheter 18 and a renal denervation generator 20. The renal denervation generator delivers energy through the renal denervation catheter 18. The renal denervation catheter 18 is positioned in a renal artery of the patient. In a preferred embodiment, the renal denervation catheter 18 is a six French compatible catheter with a plurality of electrodes 22 spaced along the catheter and a .014 guidewire 24. In an embodiment, the renal denervation catheter 18 is delivered to a renal artery of one of the kidneys (e.g., left kidney) of the patient using a rapid exchange system with the guidewire 24. Once positioned in the renal artery, the guidewire 24 is retracted such that the renal denervation catheter 18 conforms to the patient's renal artery without occluding blood flow. A helical ablation pattern is then performed through the renal denervation catheter 18 with energy delivered to electrodes of the renal denervation catheter to ablate renal nerves or bundles. RF energy delivered from the electrodes is monitored by impedance and temperature measurements of the electrodes. After the energy is delivered and the helical ablation pattern is performed through the renal denervation catheter 18, the renal denervation catheter may be repositioned to a contralateral renal artery of the patient to treat the other kidney (e.g., right kidney). Once repositioned, the helical ablation pattern is performed in the contralateral renal artery with the renal denervation catheter 18, and energy is delivered through the renal denervation catheter by the renal denervation generator 20. A suitable renal denervation system is described in U.S. Serial No. 15 / 851,68, filed December 21, 2017, the entirety of which is hereby incorporated by reference.Attorney Docket No. A0012932W001

[0036] The renal nerves or bundles may be ablated in other ways other than catheter radiofrequency ablation, as described above. For example, known systems for renal denervation include ultrasound renal denervation (e.g., high intensity focused ultrasound), cryoablation, microwave ablation, pharmaceutical denervation, among other possible method for ablating the renal nerves or bundles.

[0037] Referring to FIGS. 1 and 3, the illustrated cardiac pacing system 14 is a conduction system pacing (CSP) system configured to target or treat therapeutic targets 26 in the patient's heart. For example, the therapeutic targets 26 may be at least one of a left ventricular diastolic dysfunction, an abnormal calcium handling, and a myocardial fibrosis of the patient.

[0038] In one example, the cardiac pacing system 14 includes a pacemaker 28 to induce tachycardia (e.g., a heart rate at least 100 beats per minute) to trigger a remodeling response. For example, in a preferred embodiment, a HFpEF heart with a 75 cc can be triggered by the pacemaker 28 of the pacing system 14 to be remodeled to 100 cc. For example, but not limiting to, the pacemaker 28 operating at a 100 to 110 bpm for 10 to 12 hours can be used for remodeling. In a preferred embodiment, the pacemaker 28 operates during low activity hours, such as night. By using the pacing system 14 volume of the left ventricle of the patient is increased and heart flexibility of the patient is increased due to reducing an amount of fibrosis (e.g. collagen). After creating the tachycardia to trigger the remodeling response, the cardiac remodeling is maintained with a personalized lower rate. A suitable cardiac pacing system 14 and method for the system 10 is described in U.S. Patent Serial No. 17 / 734,958, filed May 2, 2022, the entirety of which is hereby incorporated by reference.

[0039] In an embodiment, the pacing system 14 is used to deliver cardiac pacing to a patient, cardiac pacing is delivered to the patient to stimulate normalization of a condition of the patient's heart. Short-term monitoring of one or more parameters in response to the delivered cardiac remodeling pacing is performed. Further, one or more long-term parameter indicative of a long-term effect of the delivered cardiac remodeling pacing on cardiac normalization is monitored. The long-term effect of the delivered cardiac remodeling pacing on cardiac normalization in response to the monitoring is determined. In response to one or both of the short-term monitoring and the determined long-term effect on cardiac normalization, the cardiac remodeling pacing can be adjusted.

[0040] In one embodiment, the vagus nerve stimulation system 16 is configured to modulate (e.g., stimulate) the vagus nerve (e.g., the root vagus nerve or branches thereof) toAttorney Docket No. A0012932W001 induce anti-inflammatory reflex in the heart of the patient. For example, the vagus nerve stimulation system 16 may be configured to stimulate the left vagus nerve branch that innervates the atrioventricular (AV) node of the heart. The vagus nerve stimulation system 16 within the system 10 promotes parasympathetic activation in a patient to enhance cardiac remodeling targeting and dampen overactive sympathetic tone.

[0041] Referring to FIG. 1 and 4-5, in one example the vagus nerve stimulation system 16 includes the pacemaker 28 (or another neurostimulator) configured to delivers vagal nerve stimulation (e.g., the left vagus nerve branch) to induce an anti-inflammatory reflex. In an embodiment, the vagus nerve stimulation system 16 is coupled to the patient with a standard atrial lead at the patient's posteroseptal region to deliver stimulation to the vagal nerve. The frequency stimulation system 16 may deliver a 50 Hz stimulation to the vagal branch of the atrioventricular node. To reach the posteroseptal region of the patient, an atrial lead may use to direct the stimulating energy to patient's coronary sinus (CS) ostium 30. The frequency stimulation system 16 increases R-R interval. In a preferred embodiment, the patient should result in lowered ventricular arrhythmias (Vas) incidence and an increased left ventricular function. Low-level vagus nerve stimulation (LLVNS) may be inhibited by excessive sympathetic nerve sprouting with the evidences of decreased density of TH, GAP43 and NF positive nerves. Chronic vagus nerve stimulation (VNS) ameliorates sympathetic functional remodeling following myocardial infarction and improves cardiac mechanical performance in response to simulated stress. Furthermore, chronic VNS reduces pathologic myocardial remodeling at the peri-infarct zone, potentially stabilizing resultant ventricular scar.

[0042] The vagus stimulation system 16 further reduces ventricular arrhythmias of the patient and mitigates adverse neural cardiac remodeling post-myocardial infarction. The vagus stimulation system 16 can combat withdrawal of parasympathetic tone and to counteract the reflex-mediated sympathoexcitation associated with ischemic heart disease. For example, reactive cervical vagus nerve stimulation (cVNS) delivered in a neurophysiological -guided manner, results in a substantial improvement in cardiac mechanical function and dramatic reduction in ventricular arrhythmias in myocardial infarction (MI) compared to MI alone. In a preferred embodiment, cVNS stabilizes ML induced electrical heterogeneity in the scar-border zone, reduces anisotropic electrical propagation and conduction block, and normalizes myocardial repolarization, which are key drivers of ventricular arrhythmias in vivo. Further, cVNS reduces aberrant structural remodeling of the scar-border zone and the principal sympathetic efferent and afferentAttorney Docket No. A0012932W001 ganglia (stellate and T1 dorsal root ganglia). Also, cVNS preserves sympathetic control of the heart after MI.

[0043] As will be appreciated by one skilled in the art, aspects of the embodiments disclosed herein may be embodied as a system, method, computer program product or any combination thereof. The cardiac therapy system 10 can be utilized to perform a method for re-remodeling left ventricular hypertrophy and inducing anti-inflammatory reflex, which is generally indicated at reference number 50. In general, the method 50 includes step 52 comprising ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; step 54 comprising inducing remodeling of hypertrophy of the left ventricle of the patient's heart; and step 56 comprising stimulating the vagus nerve of the patient to induce an anti-inflammatory reflex in the patient's heart. Each of these steps 52, 54, 56 may be performed simultaneously or consecutively or in any order suitable for treating MVD and / or reducing HFpEF, and in particular, for treating HFpEF with MVD.

[0044] In one embodiment, the step 52 of ablating renal sympathetic nerves includes step 58 of delivering the renal denervation catheter comprising using a rapid exchange system with the guidewire 24, step 60 of retracting the guidewire such that the renal denervation catheter conforms to the patient's renal artery, step 62 of performing a helical ablation pattern with the renal denervation catheter, and step 64 of delivering energy through the renal denervation catheter with the renal denervation generator. Further, step 52 of delivering renal denervation may include step 66 of monitoring the energy through impedance and temperature measurements of each electrodes 22 on the renal denervation catheter and step 68 of utilizing algorithms for delivering energy through the renal denervation catheter to lower blood pressure of the patient. Further, step 52 of delivering renal denervation may include step 70 of repositioning the renal denervation catheter a contralateral renal artery of the patient and preforming steps 58-70. In an embodiment, repositioning can be done after performing a helical ablation pattern or multiple iterations of performing a helical ablation pattern. In a preferred embodiment, multiple iterations of performing the helical ablation pattern of 60 seconds can be performed before repositioning. The step 52 may include other steps for ablating (e.g., denervation of) the renal sympathetic nerves.

[0045] In one embodiment, step 54 of inducing remodeling left ventricular hypertrophy includes step 72 of delivering cardiac pacing energy (e.g., via electrical stimulation using a pacemaker) to stimulate normalization of a condition of the patient's heart, step 74 of performing short-term monitoring of one or more parameters in response toAttorney Docket No. A0012932W001 the delivered cardiac remodeling pacing, step 76 of monitoring one or more long-term parameter indicative of a long-term effect of the delivered cardiac remodeling pacing on cardiac normalization, step 78 of determining the long-term effect of the delivered cardiac remodeling pacing on cardiac normalization in response to the monitoring, and step 80 of adjusting the cardiac remodeling pacing in response to one or both of the short-term monitoring and the determined long-term effect on cardiac normalization.

[0046] Referring to FIG. 9, a schematic diagram of a second exemplary cardiac therapy system that is used to impart a synergetic therapeutic effect to lower the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies (e.g., HFpEF) and promote cardiac remodeling of left ventricular hypertrophy in the patient is generally indicated at reference number 110. The cardiac therapy system 110 may be similar to the cardiac therapy system 10, with differences noted herein below. As such, like elements have been given like reference numbers plus 100. Unlike the first system 10, the cardiac therapy system 110 includes a baroreflex activation therapy system generally indicated at reference number 115 in place of the cardiac pacing system 14 and the vagus stimulation system 16. In one or more embodiments, the baroreflex activation therapy system 115 and associated method described above may be used with the first system 10, whereby a system may include the renal denervation system 12 (or 112), the cardiac pacing system 14, the vagus stimulation system 16, and the baroreflex activation therapy system 115 for performing the respectively therapies described herein.

[0047] Referring still to FIG. 9, the cardiac therapy system 110 includes a renal denervation system generally indicated at reference number 112 and a baroreflex activation therapy system generally indicated at reference number 115. The renal denervation system 112 lowers sympathetic nervous system (SNS) response to reduce afterload and inflammation in a patient similar to the renal denervation system 12 of the cardiac therapy system 10. The baroreflex activation therapy system 115 provides an autonomic reflex that is dysregulated in patients with hypertension and heart failure. Further, stimulation of baroreflex increases parasympathetic tone and decreases sympathetic tone in the patient. The disclosure and teachings of the renal denervation system 12 of the first embodiment 10 are incorporated in this embodiment.

[0048] Referring to FIG. 11, in one example, the baroreflex activation therapy system 115 includes a pulse generator 117 and an electrode 119 implanted on a patient's carotid artery and connected to the pulse generator implanted in the patient. In an embodiment, the pulse generator is placed in the patient's ipsilateral chest. The pulse generator 117 is coupledAttorney Docket No. A0012932W001 to the electrode 119 through a lead 121. The lead 121 and electrode 119 are tunneled into the patient's neck to the patient's sternocleidomastoid (FIGS. 12-13). The electrode 119 is surgically implanted on the surface of the carotid sinus (usually the right carotid), which delivers energy from the pulse generator placed in a subcutaneous chest pocket to electrically stimulate the carotid baroreceptors. This stimulation increases signaling to the patient's brain, which downregulates sympathetic tone and upregulates parasympathetic tone to improve heart failure symptoms. The baroreflex activation therapy system 115 gears toward resynchronizing the patient's autonomic nervous system by stimulating the baroreflex to decrease sympathetic tone and increase parasympathetic tone. By the pulse generator (IPG) being placed in the ipsilateral chest, and the lead and electrode being tunneled into the neck, deep to the sternocleidomastoid, the baroreflex activation therapy system 115 is placed extravascularly in the patient with no leads in the heart. The baroreflex activation therapy system 115 modulates an autonomic balance and plays a crucial role in regulating blood pressure and heart rate. For example, stimulation of carotid sinus mechanoreceptors leads to downregulation of SNS. Furthermore, downregulation of SNS is associated with suppression of Renin Angiotensin Aldosterone System (RAAS) and muscle sympathetic nerve activity, with downstream beneficial effects on hemodynamics as evident in the reduction in systemic blood pressure. Further, using the baroreflex activation therapy system 115 leads to a reduction in myocardial interstitial fibrosis and cardiac myocyte hypertrophy.

[0049] An embodiment of the baroreflex activation therapy system 115 includes an external programmer, the implantable pulse generator 117, and the single electrode 119 sutured to the surface of the patient's carotid sinus and connected to the pulse generator placed in a subcutaneous pocket in the infraclavicular space. The external programming system is used to program the implanted pulse generator 117 via radiofrequency control. In an alternative embodiment, the baroreflex activation therapy system 115 replaces the single electrode with two electrodes to have an electrode in both the patient's carotid sinuses. Referring to FIG. 13, both the baroreflex activation therapy system 115 and the pacemaker 28 can be implanted in the patient.

[0050] The cardiac therapy system 110 can be utilized to perform a method for reremodeling hypertrophy and inducing anti-inflammatory reflex, which is generally indicated at reference number 150. The method is treatment for MVD and / or for reducing HFpEF, and in particular, for treating HFpEF with MVD.

[0051] The method 150 is substantially similar to the method 50. As such, like elements have been given like reference numbers plus 100. The method 150 includes stepAttorney Docket No. A0012932W001152 of delivering renal denervation as previously described and step 155 of delivering baroreflex activation therapy. Step 155 of performing baroreflex activation therapy includes having a pulse generator and a baroreceptor implanted on a patient's carotid artery and connected to the pulse generator also implanted in the patient. Step 155 of performing baroreflex activation therapy includes electrically stimulating the electrode 119 of the baroreflex activation therapy system 115 using the pulse generator 117 of the baroreflex activation therapy system. Each of these steps 152, 154 may be performed simultaneously or consecutively or in any order suitable for treating MVD and / or reducing HFpEF, and in particular, for treating HFpEF with MVD.

[0052] The invention may be further described by reference to the following numbered paragraphs:1. A method of cardiac treatment to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient, the method comprising: ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; delivering cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart; and stimulating a vagus nerve of the patient to induce an anti-inflammatory reflex in the patient's heart.2. The method of cardiac treatment set forth in paragraph 1, wherein said ablating renal sympathetic nerves, said delivering cardiac pacing, and said stimulating a vagus nerve are performed simultaneously.3. The method of cardiac treatment set forth in paragraph 1, wherein said ablating renal sympathetic nerves, said delivering cardiac pacing, and said stimulating a vagus nerve are performed consecutively.4. The method of cardiac treatment set forth in any one of paragraphs 1 to 3, wherein said ablating renal sympathetic nerves comprises ablating the renal sympathetic nerves.5. The method of cardiac treatment set forth paragraph 4, wherein said ablating the renal sympathetic nerves is performed using an ablation catheter configured to be delivered into a renal artery of the patient.Attorney Docket No. A0012932W0016. The method of cardiac treatment set forth in paragraph 5, wherein said ablation catheter is a radiofrequency ablation catheter.7. The method of cardiac treatment set forth in any one of paragraphs 1 to 6, wherein said delivering cardiac pacing includes electrically stimulating the patient's heart.8. The method of cardiac treatment set forth in any one of paragraphs 1 to 7, wherein said cardiac pacing includes inducing tachycardia in the patient.9. The method of cardiac treatment set forth in any one of paragraphs 1 to 8, wherein said delivering cardiac pacing is performed using a pacemaker.10. The method of cardiac treatment set forth in any one of paragraphs 1 to 9, wherein said stimulating a vagus nerve comprises electrically stimulating a vagal branch of the vagus nerve innervating an AV node of the patient's heart.11. The method of cardiac treatment set forth in paragraph 10, wherein said electrically stimulating the vagal branch comprises delivering electrical energy at a frequency of about 50 Hz.12. The method of cardiac treatment set forth in any one of paragraphs 1 to 11, wherein said delivering cardiac pacing and said stimulating a vagus nerve are performed using a single pacemaker including a first electrode for said delivering cardiac pacing and a second electrode for said stimulating a vagus nerve.13. A cardiac therapy system configured to perform the method set forth in any one of paragraphs 1 to 12.14. A method of cardiac treatment to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient, the method comprising: ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; stimulating carotid baroreceptors of the patient to downregulates sympathetic tone and upregulates parasympathetic tone.15. The method of cardiac treatment set forth in paragraph 15, wherein said ablating renal sympathetic nerves and said stimulating carotid baroreceptors are performed simultaneously.16. The method of cardiac treatment set forth in paragraph 15, wherein said ablating renal sympathetic nerves and said stimulating carotid baroreceptors are performed consecutively.Attorney Docket No. A0012932W00117. The method of cardiac treatment set forth in any one of paragraphs 14 to 16, wherein said ablating renal sympathetic nerves comprises ablating the renal sympathetic nerves.18. The method of cardiac treatment set forth in paragraph 17, wherein said ablating the renal sympathetic nerves is performed using an ablation catheter figured to be delivered into a renal artery of the patient.19. The method of cardiac treatment set forth in any one of paragraphs 14 to 18, wherein said stimulating carotid baroreceptors comprises electrically stimulating the carotid baroreceptors.20. The method of cardiac treatment set forth in any one of paragraphs 14 to 19, wherein said stimulating carotid baroreceptors is performed using a device implanted in the patient.21. A cardiac therapy system to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient, the cardiac therapy system comprising: a renal ablation system arranged to ablate renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; and at least one of: a cardiac pacing system arranged to deliver cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart, and a vagus nerve stimulation system arranged to stimulate a vagus nerve of the patient to induce an anti-inflammatory reflex in the patient's heart; and a baroreflex activation therapy system arranged to stimulate carotid baroreceptors of the patient to downregulate sympathetic tone and upregulate parasympathetic tone.22. The cardiac therapy system set forth in paragraph 21, comprising the cardiac pacing system and the vagus nerve stimulation system.23. The cardiac therapy system set forth in paragraph 22, wherein the renal ablation system, the cardiac pacing system, and the vagus nerve stimulation system are arranged to simultaneously and respectively ablate the renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, deliver the cardiac pacing to induceAttorney Docket No. A0012932W001 remodeling of hypertrophy of the left ventricle of the patient's heart, stimulate the vagus nerve of the patient to induce the anti-inflammatory reflex in the patient's heart.24. The cardiac therapy system set forth in paragraph 22, wherein the renal ablation system, the cardiac pacing system, and the vagus nerve stimulation system are arranged to consecutively and respectively ablate the renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, deliver the cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart, stimulate the vagus nerve of the patient to induce the anti-inflammatory reflex in the patient's heart.25. The cardiac therapy system set forth in any one of paragraphs 21-24, wherein the cardiac pacing system is arranged to induce tachycardia in the patient to induce remodeling of hypertrophy of the left ventricle of the patient's heart.26. The cardiac therapy system set forth in any one of paragraphs 21-26, wherein the vagus nerve stimulation system is arranged to electrically stimulate a vagal branch of the vagus nerve innervating an AV node of the patient's heart to induce the anti-inflammatory reflex in the patient's heart.27. The cardiac therapy system set forth in any one of paragraphs 21 -26, comprising the baroreflex activation therapy system.28. The cardiac therapy system set forth in paragraph 27, wherein the renal ablation system and the baroreflex activation therapy system are arranged to simultaneously and respectively ablate the renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, and stimulate the carotid baroreceptors of the patient to downregulate sympathetic tone and upregulate parasympathetic tone.29. The cardiac therapy system set forth in paragraph 27, wherein the renal ablation system and the baroreflex activation therapy system are arranged to consecutively and respectively ablate the renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, and stimulate the carotid baroreceptors of the patient to downregulate sympathetic tone and upregulate parasympathetic tone.30. The cardiac therapy system set forth in any one of paragraphs 27-29, wherein the baroreflex activation therapy system includes an implant arranged to be implanted in the patient and deliver electrically stimulation to the carotid baroreceptors of the patient.

[0053] It should be understood that various aspects disclosed herein may be combined in different combinations than the combinations specifically presented in the description and accompanying drawings. It should also be understood that, depending on the example, certain acts or events of any of the processes or methods described herein may be performedAttorney Docket No. A0012932W001 in a different sequence, may be added, merged, or left out altogether (e.g., all described acts or events may not be necessary to carry out the techniques). In addition, while certain aspects of this disclosure are described as being performed by a single module or unit for purposes of clarity, it should be understood that the techniques of this disclosure may be performed by a combination of units or modules associated with, for example, a medical device.

[0054] In one or more examples, the described techniques may be implemented in hardware, software, firmware, or any combination thereof. If implemented in software, the functions may be stored as one or more instructions or code on a computer-readable medium and executed by a hardware-based processing unit. Computer-readable media may include non-transitory computer-readable media, which corresponds to a tangible medium such as data storage media (e.g., RAM, ROM, EEPROM, flash memory, or any other medium that can be used to store desired program code in the form of instructions or data structures and that can be accessed by a computer).

[0055] Instructions may be executed by one or more processors, such as one or more digital signal processors (DSPs), general purpose microprocessors, application specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated or discrete logic circuitry. Accordingly, the term “processor” as used herein may refer to any of the foregoing structure or any other physical structure suitable for implementation of the described techniques. Also, the techniques could be fully implemented in one or more circuits or logic elements.

Claims

Attorney Docket No. A0012932W001WHAT IS CLAIMED IS:

1. A method of cardiac treatment to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient, the method comprising: ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; delivering cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart; and stimulating a vagus nerve of the patient to induce an anti-inflammatory reflex in the patient's heart.

2. The method of cardiac treatment set forth in claim 1, wherein said ablating renal sympathetic nerves, said delivering cardiac pacing, and said stimulating a vagus nerve are performed simultaneously.

3. The method of cardiac treatment set forth in claim 1, wherein said ablating renal sympathetic nerves, said delivering cardiac pacing, and said stimulating a vagus nerve are performed consecutively.

4. The method of cardiac treatment set forth in any one of claims 1 to 3, wherein said ablating renal sympathetic nerves comprises ablating the renal sympathetic nerves using radiofrequency energy.

5. The method of cardiac treatment set forth claim 4, wherein said ablating the renal sympathetic nerves is performed using an ablation catheter configured to be delivered into a renal artery of the patient.

6. The method of cardiac treatment set forth in claim 5, wherein said ablation catheter is a radiofrequency ablation catheter.

7. The method of cardiac treatment set forth in any one of claims 1 to 6, wherein said delivering cardiac pacing includes electrically stimulating the patient's heart.Attorney Docket No. A0012932W0018. The method of cardiac treatment set forth in any one of claims 1 to 7, wherein said cardiac pacing includes inducing tachycardia in the patient.

9. The method of cardiac treatment set forth in any one of claims 1 to 8, wherein said delivering cardiac pacing is performed using a pacemaker.

10. The method of cardiac treatment set forth in any one of claims 1 to 9, wherein said stimulating a vagus nerve comprises electrically stimulating a vagal branch of the vagus nerve innervating an AV node of the patient's heart.

11. The method of cardiac treatment set forth in claim 10, wherein said electrically stimulating the vagal branch comprises delivering electrical energy at a frequency of about 50 Hz.

12. The method of cardiac treatment set forth in any one of claims 1 to 11, wherein said delivering cardiac pacing and said stimulating a vagus nerve are performed using a single pacemaker including a first electrode for said delivering cardiac pacing and a second electrode for said stimulating a vagus nerve.

13. A cardiac therapy system configured to perform the method set forth in any one of claims 1 to 12.

14. A method of cardiac treatment to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient, the method comprising: ablating renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; stimulating carotid baroreceptors of the patient to downregulates sympathetic tone and upregulates parasympathetic tone.

15. The method of cardiac treatment set forth in claim 15, wherein said ablating renal sympathetic nerves and said stimulating carotid baroreceptors are performed simultaneously.Attorney Docket No. A0012932W00116. The method of cardiac treatment set forth in claim 15, wherein said ablating renal sympathetic nerves and said stimulating carotid baroreceptors are performed consecutively.

17. The method of cardiac treatment set forth in any one of claims 14 to 16, wherein said ablating renal sympathetic nerves comprises ablating the renal sympathetic nerves using radiofrequency energy.

18. The method of cardiac treatment set forth in claim 17, wherein said ablating the renal sympathetic nerves is performed using an ablation catheter figured to be delivered into a renal artery of the patient.

19. The method of cardiac treatment set forth in any one of claims 14 to 18, wherein said stimulating carotid baroreceptors comprises electrically stimulating the carotid baroreceptors.

20. The method of cardiac treatment set forth in any one of claims 14 to 19, wherein said stimulating carotid baroreceptors is performed using a device implanted in the patient.

21. A cardiac therapy system to provide a synergetic therapeutic effect of lowering the hyperactive sympathetic response observed in microvascular disease (MVD) and heart failure (HF) pathologies and promoting cardiac remodeling of left ventricular hypertrophy in a patient, the cardiac therapy system comprising: a renal ablation system arranged to ablate renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, thereby reducing blood pressure; and at least one of: a cardiac pacing system arranged to deliver cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart, and a vagus nerve stimulation system arranged to stimulate a vagus nerve of the patient to induce an anti-inflammatory reflex in the patient's heart; and a baroreflex activation therapy system arranged to stimulate carotid baroreceptors of the patient to downregulate sympathetic tone and upregulate parasympathetic tone.Attorney Docket No. A0012932W00122. The cardiac therapy system set forth in claim 21, comprising the cardiac pacing system and the vagus nerve stimulation system.

23. The cardiac therapy system set forth in claim 22, wherein the renal ablation system, the cardiac pacing system, and the vagus nerve stimulation system are arranged to simultaneously and respectively ablate the renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, deliver the cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart, stimulate the vagus nerve of the patient to induce the anti-inflammatory reflex in the patient's heart.

24. The cardiac therapy system set forth in claim 22, wherein the renal ablation system, the cardiac pacing system, and the vagus nerve stimulation system are arranged to consecutively and respectively ablate the renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, deliver the cardiac pacing to induce remodeling of hypertrophy of the left ventricle of the patient's heart, stimulate the vagus nerve of the patient to induce the anti-inflammatory reflex in the patient's heart.

25. The cardiac therapy system set forth in any one of claims 21-24, wherein the cardiac pacing system is arranged to induce tachycardia in the patient to induce remodeling of hypertrophy of the left ventricle of the patient's heart.

26. The cardiac therapy system set forth in any one of claim 21 -26, wherein the vagus nerve stimulation system is arranged to electrically stimulate a vagal branch of the vagus nerve innervating an AV node of the patient's heart to induce the anti-inflammatory reflex in the patient's heart.

27. The cardiac therapy system set forth in any one of claims 21-26, comprising the baroreflex activation therapy system.

28. The cardiac therapy system set forth in claim 27, wherein the renal ablation system and the baroreflex activation therapy system are arranged to simultaneously and respectively ablate the renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, and stimulate the carotid baroreceptors of the patient to downregulate sympathetic tone and upregulate parasympathetic tone.Attorney Docket No. A0012932W00129. The cardiac therapy system set forth in claim 27, wherein the renal ablation system and the baroreflex activation therapy system are arranged to consecutively and respectively ablate the renal sympathetic nerves of the patient to reduce sympathetic afferent and efferent activity to the kidney, and stimulate the carotid baroreceptors of the patient to downregulate sympathetic tone and upregulate parasympathetic tone.

30. The cardiac therapy system set forth in any one of claims 27-29, wherein the baroreflex activation therapy system includes an implant arranged to be implanted in the patient and deliver electrically stimulation to the carotid baroreceptors of the patient.

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