System for optimizing epicardial perfusion hemodynamics

Abstract

The current invention relates to a system for optimizing epicardial perfusion hemodynamics and a method for operating the system.

Description

[0001] SYSTEM FOR OPTIMIZING EPICARDIAL PERFUSION HEMODYNAMICS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a system for optimizing epicardial perfusion hemodynamics and a method for operating said system.

[0004] BACKGROUND

[0005] Patients with angina and no evidence of obstruction in their large epicardial vessels have an increased risk of adverse clinical events. Given the lack of therapeutic options for these patients, the European Society, in 2019, labelled this condition (angina without obstructive coronary artery disease or ANOCA) as an unmet need.

[0006] Many of these patients have an impairment of their microvascular vessels, which are too small to be identified in routine coronary angiography. This condition, also called coronary microvascular dysfunction, is characterized by the inability of the heart's tiniest blood vessels to dilate properly. Coronary Microvascular Dysfunction (CMD) is a complex cardiac condition characterized by persistent angina and ischemia, despite the absence of obstructive coronary artery disease. This condition poses a substantial burden on patients, significantly impacting their quality of life due to chronic chest pain, limited physical capability, and increased psychological stress. The current therapeutic landscape for CMD is fraught with challenges, notably a lack of targeted treatments that directly address the underlying microvascular dysfunction.

[0007] CMD often leads to recurrent hospital visits and a persistent feeling of uncertainty and discomfort among patients. The condition is particularly challenging to diagnose and treat, as standard angiographic techniques used to detect coronary artery disease often fail to reveal the microvascular impairments underlying CMD. Consequently, patients with CMD frequently undergo extensive cardiac evaluations, yet many continue to experience symptoms despite standard medical therapy, including the use of conventional anti-anginal medications.

[0008] There is strong evidence that CMD is part of diffuse microvascular disease involving other organs, such as brain and kidney. In addition, impaired coronary microvascular function is strongly associated with HFpEF (heart failure with preserved ejection fraction), HFrEF (heart failure with reduced ejection fraction), diabetes, hypertensive heart disease, hypertrophic cardiomyopathy, aortic stenosis, and chronic inflammatory and autoimmune diseases. It is also present in a large number of post COVID patients.

[0009] Microvascular vessel impairment is characterized by the inability of very small coronary vessels to dilate properly. This complex cardiac condition cannot be addressed by percutaneous coronary intervention (PCI) which treats significantly larger vessels. Previous conventional systems, such as those described in WO2022214851, focus on repairing ischemic heart muscle tissue by temporarily occluding the coronary sinus (CS), causing blood to counterflow through the coronary venous system toward the ischemic tissue. However, these systems primarily rely on pressure measurements within the coronary sinus to control intermittent coronary sinus occlusion (PICSO) and do not account for the occlusion's broader impact on total heart muscle perfusion.

[0010] The CS is a large vein that collects oxygen depleted blood from the myocardium and channels it back to the right atrium. The origin of the coronary sinus is marked by the coalescence of the great cardiac vein and oblique vein of the left atrium (oblique vein of Marshall). It has a length of up to 5 cm and a variable caliber. Global myocardial perfusion improvement is the objective of coronary sinus intermittent occlusion. The positioning of the occlusion catheter in the coronary sinus is a significant factor in improving perfusion. US2004 / 0172004 uses a narrow measurement of fluid pressure inside the coronary sinus to operate and W02023 / 046501 uses a blood flow measurement constrained to the place of reperfusion therapy, thus the Coronary Sinus. These disclosures focus on the optimization of the inflation cycles of the balloon therapy, but do not describe an optimization of the position to inflate the catheter in the coronary sinus.

[0011] Gathering different epicardial hemodynamics measurements from a combination of two measures - one being the precise location of the occlusion in the CS and the other being the CS occlusion algorithm - allows the building of a patient specific response curve that will optimize his or her therapy.

[0012] The unmet need in CMD treatment arises from the unique pathology of the condition, which involves the dysfunction of the smallest coronary blood vessels, the microvasculature. These vessels are responsible for fine-tuning blood flow to the heart muscle, and their impaired function in CMD leads to inadequate blood supply, precipitating angina and ischemia. Current pharmacological interventions primarily focus on symptomatic relief, they have limited effect on symptoms and do not adequately address the microvascular dysfunction at the core of CMD.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention relates to a method according to claim 1 and a method for operating said device.

[0015] The invention is of particular importance because while the device comprises an occlusion device configured for occluding different segments of the coronary sinus it tailors its function to an epicardial monitor configured to measure a hemodynamic parameter in an epicardial vessel.

[0016] By monitoring the perfusion outside of the coronary sinus, and in particular in an epicardial vessel such as the Left Anterior Descending artery (LAD), this device and method seek to maximize the perfusion of the LAD. The LAD supplies 45-55% of the blood flow to the left ventricle, which is crucial for pumping blood throughout the body.

[0017] The modeling of this coronary sinus constriction method shows that the main impact is in the increase in the capillary transit time (CTT) and in an increase in mean capillary diameter. The CTT is the time the blood takes to transit the whole capillary network. A longer CTT allows for more nutrients to be exchanged and improves tissue oxygenation. The increase in capillary diameter implies an increase in the capillary surface area, thus beneficially aiding the diffusion of oxygen from the blood to the tissue.

[0018] It has been found that the positioning of the occlusion in the coronary sinus is an important element to optimize its impact. In particular, an occlusion at the ostium or beginning of the coronary sinus will also impact vessels connected to the right coronary artery (RCA) and will have a larger impact on the microvasculature.

[0019] Similarly, occlusion after valves or side branches along the coronary sinus will have differing impact on the resulting perfusion in the heart as measured at the LAD. In WO 2022 / 214851, for example, the catheter occlusion is happening further down from the ostium and distally to the vessels connecting to the RCA. This device thus misses occlusion at the ostium which has shown to be an important aspect for optimal LAD perfusion. The current invention provides in a preferred embodiment, a system for continuously monitoring the perfusion in the LAD. The occlusion catheter is placed in at least three positions in the coronary sinus by the operator. The positions start at the ostium of the coronary sinus (PO) and continue until they are up to 5 centimeters distally from the ostium. Each position is precisely registered by the positioning system which can be aided by an external input. At each position, the occlusion sequence in the coronary sinus is derived from a least one measurement of the perfusion in the LAD. The algorithm then guides the operator precisely to the optimal position for the occlusive catheter. Once the catheter is in that position, the algorithm will implement a preprogrammed sequence of intermittent occlusions of the coronary sinus.

[0020] The current invention will allow the building of patient specific epicardial hemodynamic responses linked to the location of the CS occlusion and the CS intermittent occlusion protocol in one setting.

[0021] The positioning of the optimal occlusion sequence along the coronary sinus will determine whether a permanent narrowing of the coronary sinus is recommended. Permanent refers to the implant of a stainless steel or nitinol or alloy structure into the coronary sinus. If the perfusion effect weakens immediately after the occlusion sequence ends, a permanent implant can be recommended. If the perfusion is sustained after the optimal occlusion sequence an intermittent occlusion sequence can be recommended. If there is no perfusion improvement then no coronary sinus narrowing therapy will be recommended. The invention will guide the therapy from permanent implant, intermittent or none.

[0022] The device of the present invention offers several advantages. Firstly, it allows to predict the response of the patient to a permanent implant by observing the effects on perfusion or related measure of flow of the intermittent narrowing of the coronary sinus. Secondly, it allows the physician to tailor therapy from no therapy, only intermittent, intermittent and permanent, providing a highly flexible and personalized approach to the treatment of CMD and medical conditions associated with CMD.

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

[0025] As used herein, the following terms have the following meanings:

[0026] In the context of the provided patent application, "predetermined" refers to a set pattern or sequence that is established in advance. It is used in the description of how the occlusion device, particularly a balloon catheter, operates within the coronary sinus. The device is described to intermittently narrow the coronary sinus in a "predetermined sequence," indicating that the narrowing of the coronary sinus, in a specific embodiment caused by the inflation and deflation of the balloon catheter, follows a specific sequence or pattern that is established before the treatment occurs. This "predetermined" manner may be programmable or set based on clinical criteria, tailored to optimize the therapeutic impact on coronary microvascular dysfunction by intermittently altering the dynamics of coronary blood flow.

[0027] The expression "intermittent narrowing of the coronary sinus" is synonym to "intermittent occlusion of the coronary sinus" and describes a process where the diameter of the passageway for the blood flow in the coronary sinus is periodically reduced in a predetermined way.

[0028] The expression "coronary sinus" refers to a large vein located on the posterior aspect of the heart, responsible for collecting deoxygenated blood from the myocardium and delivering it to the right atrium. It plays a significant role in the heart's circulatory system.

[0029] The expression "occlusion device" refers to a device used to obstruct or reduce the flow of blood through the coronary sinus. This occlusion device can be mechanically or electronically controlled to adjust the degree and duration of the narrowing, tailored to the patient's specific medical needs.

[0030] The expression "ostium of the coronary sinus" refers to the anatomical opening or entry point of the coronary sinus, where it empties its blood into the right atrium of the heart. This area is critical in cardiovascular procedures involving the coronary sinus. The expression "overdilation" refers to the process of expanding or enlarging the coronary sinus beyond its normal diameter. In the medical device's context, overdilation is controlled and used therapeutically to alter the flow dynamics within the coronary sinus, impacting the blood distribution in the heart's microvascular system.

[0031] The expression "guidewire" describes a thin, flexible wire used in medical procedures as a guide for positioning larger instruments like catheters within blood vessels. In this device, the guidewire is crucial for navigating through the vascular system to accurately place the occlusion device in the coronary sinus.

[0032] The expression "controller device" is synonym to "console" and "indeflator" and serves as the operational control unit of the occlusion device. It may be a manual device, requiring physical manipulation, or a software-controlled console using electronic commands for operation. This device is key to regulating the degree and timing of the narrowing action. A specific example of a controller device is an inflation device.

[0033] The expression "perfusion" in a medical context refers to the process of delivering blood to the capillary bed in biological tissue. Perfusion measurement is used for assessing how well blood flows through the coronary arteries and microvascular vessels to the heart muscle, especially important in CMD where perfusion is often compromised.

[0034] The expressions "IMR", "CFR", "Absolute Flow", and "FFR" denote various diagnostic techniques used to measure heart perfusion or blood flow. IMR (Index of Microvascular Resistance) assesses resistance in the heart's smallest vessels. Absolute Flow quantifies the actual blood flow volume, and FFR (Fractional Flow Reserve) measures the pressure differences across a coronary artery lesion to determine its severity. CFR (Coronary Flow Reserve) measures how much blood flow to coronary arteries can increase under stress or exertion.

[0035] The expression "balloon catheter" refers to a type of catheter equipped with an inflatable balloon at its tip, used in medical procedures to dilate or occlude blood vessels. In these claims, the balloon catheter plays a central role in the narrowing mechanism of the coronary sinus. The expression "hourglass-shaped balloon" describes a specific design of a balloon with a narrowed middle section and wider ends, resembling the shape of an hourglass. This design is used in the balloon catheter and contributes to the effectiveness of the coronary sinus narrowing process.

[0036] "A", "an", and "the" as used herein refers to both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compartment" refers to one or more than one compartment.

[0037] "About" as used herein referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of + / - 20% or less, preferably + / -10% or less, more preferably + / -5% or less, even more preferably + / -1% or less, and still more preferably + / -0.1% or less of and from the specified value, in so far such variations are appropriate to perform in the disclosed invention. However, it is to be understood that the value to which the modifier "about" refers is itself also specifically disclosed.

[0038] "Comprise", "comprising", and "comprises" and "comprised of" as used herein are synonymous with "include", "including", "includes" or "contain", "containing", "contains" and are inclusive or open-ended terms that specifies the presence of what follows e.g. component and do not exclude or preclude the presence of additional, non-recited components, features, element, members, steps, known in the art or disclosed therein.

[0039] Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order, unless specified. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

[0040] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints.

[0041] The expression "% by weight", "weight percent", "%wt" or "wt%", here and throughout the description unless otherwise defined, refers to the relative weight of the respective component based on the overall weight of the formulation. Whereas the terms "one or more" or "at least one", such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members.

[0042] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, definitions for the terms used in the description are included to better appreciate the teaching of the present invention. The terms or definitions used herein are provided solely to aid in the understanding of the invention.

[0043] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

[0044] System for optimizing epicardial perfusion hemodynamics

[0045] The invention relates to a system for optimizing epicardial perfusion hemodynamics. The system is suitable for determining the course of treatment of CMD.

[0046] In a preferred embodiment, the system comprises an occlusion device configured for placement in the coronary sinus.

[0047] The system preferably comprises an occlusion device configured for placement in the coronary sinus, wherein the occlusion device comprises at least one expandable member. Preferably, the occlusion device comprises two or more expandable members. In a preferred embodiment the occlusion device comprises three or more expandable members.

[0048] The system further comprises an epicardial perfusion monitor configured for measuring the perfusion in an epicardial vessel. The epicardial perfusion monitor can measure at least one hemodynamic parameter of an epicardial vessel. The epicardial vessel can be the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx), and is preferably the LAD.

[0049] The system further comprises a processing unit configured to receive signal input from said occlusion device and said epicardial perfusion monitor.

[0050] In a particular embodiment, the system comprises: an epicardial perfusion monitor configured for measuring the perfusion in an epicardial vessel, an occlusion device configured for placement in the coronary sinus, wherein the occlusion device comprises two or more expandable members, and wherein the occlusion device further comprises at least one sensor, a processing unit configured to receive signal input from said epicardial perfusion monitor, comprising a controller device configured to increase and decrease the dimensions of the expandable members in response to the signal input from said epicardial perfusion monitor.

[0051] In an embodiment, each expandable member comprises one or more sensors. Preferably, the sensors are hemodynamic sensors configured to measure a change in hemodynamics in the coronary sinus.

[0052] In a preferred embodiment, said epicardial perfusion monitor is configured for measuring at least one hemodynamic parameter in an epicardial vessel. The hemodynamic parameter can be chosen from IMR, CFR, wedge pressure, RRR absolute flow, FFR, or a combination thereof. Preferably the said epicardial perfusion monitor is configured for measuring at least the CFR in an epicardial vessel, for example with a threshold value of 2-2.5.

[0053] The epicardial perfusion monitor can measure the hemodynamic parameter by catheter or radiofrequency RF via sensor data indicative of hemodynamic parameters. The epicardial perfusion monitor can comprise a physiology catheter for placement in the epicardial vessel.

[0054] The processing unit preferably has a memory for storing the measurements of the epicardial perfusion monitor and measurements and positions the occlusion device. The memory can be searched and organized into relevant analyses.

[0055] In an embodiment, the system is configured to create a narrowing of the coronary sinus in different segments between 0 and 10 centimeters behind the ostium of the coronary sinus. This range is not restrictive and can be adjusted based on individual patient needs and physician assessment. In a further embodiment, the occlusion device is adjustable to be positioned between 0 and 7 centimeters behind the ostium of the coronary sinus. In preferred embodiments, the occlusion device can be positioned at any point between 0 and 7 centimeters behind the ostium of the coronary sinus. This includes, but is not limited to, positions at 0, 1, 2, 3, 4, 5, or 6 centimeters behind the ostium. The ability to precisely adjust the position of the occlusion device to these intermediate points provides additional flexibility and allows for even more precise tailoring of the treatment to the patient's specific needs. This can potentially lead to improved patient outcomes and a reduced risk of complications.

[0056] In a particular embodiment, one of the expandable members is configured for placement in the ostium. An occlusion at the ostium or beginning of the coronary sinus will also impact vessels connected to the right coronary artery (RCA) and will have a larger impact on the microvasculature.

[0057] The occlusion device can be adjusted to various positions within the specified range. For instance, in one embodiment, the occlusion device can be positioned at 0 centimeters behind the ostium of the coronary sinus, which may be beneficial in cases where the coronary sinus is particularly narrow or obstructed. In another embodiment, the occlusion device can be positioned at 7 centimeters behind the ostium of the coronary sinus, which may be suitable for patients with a wider or less obstructed coronary sinus. The ability to adjust the position of the occlusion device within this range allows for a high degree of customization, taking into account the unique characteristics of each patient's coronary sinus.

[0058] In a particular embodiment, said occlusion device is configured for placement in the full length of the coronary sinus. In a further or another embodiment, the system is configured to create a narrowing of the coronary sinus at least two, preferably at least three, positions between 0 and 10 centimeters behind the ostium of the coronary sinus. To this end, the occlusion device comprises at least two, preferably at least three, expandable members, which are each configured for placement at a different position in the coronary sinus.

[0059] In an embodiment, the occlusion device can further comprise additional balloons or dilatable components. In an embodiment, the occlusion device can further comprise balloons or dilatable components with different diameters and characteristics can be added to adapt to different anatomies.

[0060] In an alternative embodiment, the two or more expandable members can be replaced by one expandable member that can be sequentially repositioned in the coronary sinus and of which precise positioning can be recorded.

[0061] The occlusion device can be made from various materials and can take various forms, such as a balloon catheter. In a preferred embodiment, said occlusion device is a balloon catheter. In this embodiment, the expandable members are balloons, such that said occlusion device is a balloon catheter comprising two or more balloons, preferably three or more balloons.

[0062] Firstly, the balloon catheter allows for precise control over the degree of constriction in the coronary sinus. The degree of constriction needs to be carefully calibrated to achieve the desired increase in coronary flow without causing undue stress to the heart and vessels. The balloon catheter can be inflated to a specific diameter, thereby constricting the coronary sinus to a specific degree. This allows the physician to tailor the therapy to the individual patient's needs and coronary sinus diameter and length, also taking into account factors such as the patient's overall health, the severity of their condition, and their response to previous treatments. The balloon catheter can be deflated and re-inflated as needed, allowing for adjustments to be made during the procedure. This mode of operation and precision are not performed with other types of occlusion devices.

[0063] Secondly, the use of a balloon catheter in the present invention aids in the easy adaptation of this new therapeutic method. Balloon catheters are widely used in medical practices, and physicians are familiar with their operation. This means that the learning curve for adopting this new therapy is relatively low, and it can be quickly and easily integrated into existing treatment protocols. Additionally, the widespread availability of balloon catheters means that this therapy can be implemented without the need for significant investment in new equipment.

[0064] Furthermore, the balloon catheter used in the present invention can be introduced into the coronary sinus via a minimally invasive procedure. The accesses can be jugular, femoral, subclavian and basilic. This reduces the risk of complications and shortens the recovery time for the patient, making the therapy more tolerable and increasing the likelihood of its acceptance and adoption.

[0065] Thus, the use of a balloon catheter as the occlusion device in the present invention provides several significant advantages. It allows for precise control over the degree of constriction in the coronary sinus, facilitating the tailoring of the therapy to the individual patient's needs. It is a familiar and widely available device, aiding in the easy adaptation of the new therapy. And it can be introduced via a minimally invasive procedure, reducing the risk of complications and making the therapy more tolerable for the patient.

[0066] In an embodiment, the occlusion device comprises two or more lumens, wherein said lumens include sensor lines and fluid pressure lines. In a further embodiment, the lumens are configured for deployment.

[0067] The occlusion device further comprises preferably at least one sensor. The at least one sensor can be present in or on the expandable members or in the lumens.

[0068] In an embodiment, the occlusion device is provided with one or more outer electrodes, preferably the expandable members are provided with one or more outer electrodes. The outer electrode, which can be in the shape of a ring, has multiple electrodes around its diameter that can both sense electrical signals and stimulate the vessel before, during and after the programmed occlusion sequence. This allows for electrical stimulation concomitantly to the occlusion therapy.

[0069] In a preferred embodiment of the invention, the processing unit comprises a controller device. The controller device is preferably configured to modify the dimensions of the occlusion device in a predetermined manner, thereby intermittently narrowing specific segments of the coronary sinus. The ability of the controller device to increase and decrease the dimensions of the occlusion device in a predetermined manner allows for a tailored therapy approach, which can be customized to each patient's individual needs and condition. This could potentially lead to improved patient outcomes, as the therapy can be adjusted and optimized according to the patient's response and progress.

[0070] The occlusion device is configured to be positioned within the coronary sinus, and its dimensions can be adjusted by the controller device. The controller device basing itself on epicardial hemodynamic measures can increase the size of the occlusion device to restrict the blood flow within specific segments of the coronary sinus, thereby increasing and controlling the pressure within the coronary microvasculature. This increased pressure can lead to the dilation of the arterioles, which can improve the blood flow within the microvasculature. On the other hand, the controller device can decrease the size of the occlusion device to allow a normal blood flow within the coronary sinus, thereby giving the microvasculature a chance to rest and recover. This intermittent narrowing of the coronary sinus improves the epicardial hemodynamic measures.

[0071] In a preferred embodiment, the system comprises a balloon catheter as occlusion device and a controller device that is an inflation device. This inflation device is specifically configured and configured to inflate and deflate the balloon catheter in a pulsating manner. The predetermined pulsating action of the inflation device operated by a physician allows for an intermittent narrowing of the coronary sinus. This intermittent narrowing is achieved through the cyclical inflation and deflation of the balloon catheter, which is precisely controlled by the inflation device. The predetermined inflation can be as short as 1 inflation or have a more elaborate sequence of inflations and deflations. The inflation device may be manually operated by a medical professional, or it may be automated with pre-set inflation and deflation cycles.

[0072] The controller device can be programmed to adjust the dimensions of the occlusion device in a pulsating manner at predetermined intervals. For example, the controller device can increase the size of the occlusion device for a certain period of time (e.g., 30 seconds, 1 minute, 5 minutes, 10 minutes, 15 minutes, etc.), and then decrease the size of the occlusion device for another period of time (e.g., 30 seconds, 1 minute, 5 minutes, 10 minutes, 15 minutes, etc.). This pulsating pattern can be repeated for a certain duration (e.g., 30 minutes, 1 hour, 2 hours, etc.), or until the therapy session is completed. The specific parameters of the pulsating pattern (e.g., the duration of the narrowing and widening phases, the size of the occlusion device during each phase, the total duration of the therapy session, etc.) can be customized based on the patient's epicardial hemodynamic response, coronary sinus length, coronary sinus diameter, coronary sinus pressure, the patient's condition and response to the therapy.

[0073] In another embodiment, said controller device is configured to increase and decrease the dimensions of the occlusion device through an electrode connected to an implanted stimulator. In a specific embodiment, the controller device, preferably an inflation device, and the occlusion device, preferably a balloon catheter, are connected through an implanted electrode connected to a stimulator.

[0074] In an alternative embodiment, the controller device can be configured to adjust the dimensions of the occlusion device in a pulsating manner based on real-time feedback from the patient's body, epicardial perfusion hemodynamics or pain. For example, the controller device can be connected to a sensor that measures the epicardial perfusion hemodynamics, and the controller device can adjust the timing and size of the occlusion device based on the measured blood flow. This real-time feedback system can potentially provide a more responsive and effective treatment for coronary microvascular dysfunction.

[0075] In a preferred embodiment, the present invention provides a system that comprises an occlusion device and a controller device. The controller device is configured to adjust the dimensions of the occlusion device in a pulsating manner, thereby intermittently narrowing in a programmed sequence specific segments of the coronary sinus. This unique feature of the system allows for a tailored therapy approach, which can be customized to each patient's individual needs and condition. This could potentially lead to improved patient outcomes, as the therapy can be adjusted and optimized based on the patient's response and progress.

[0076] The controller device is capable of both increasing and decreasing the dimensions of the occlusion device, allowing for precise control over the degree of narrowing. This precise control can be particularly beneficial in medical applications where the degree of narrowing may need to be adjusted based on the individual patient's condition and response to treatment. In some embodiments, the controller device may be configured to automatically adjust the dimensions of the occlusion device based on feedback from a sensor or other monitoring device.

[0077] The intermittent narrowing of the coronary sinus is a significantly advantageous aspect of this invention. This is because the intermittent narrowing leads to a reduction in vascular resistance in the subendocardium. The subendocardium is the innermost layer of the heart wall and is composed of a network of tiny blood vessels. These vessels are responsible for supplying oxygen and nutrients to the heart muscle. In patients with coronary microvascular dysfunction, these vessels are unable to dilate properly, leading to decreased blood flow and the symptoms of angina.

[0078] By intermittently narrowing the coronary sinus, the device according to this embodiment is able to increase epicardial perfusion by reducing the vascular resistance in the subendocardium. This resistance is the main cause of the reduced flow through the tiny vessels in the subendocardium. This increased flow improves the supply of oxygen and nutrients to the heart muscle, relieving the symptoms of angina and improving the overall health of the patient.

[0079] The system of the invention provides several advantages. For example, by intermittently narrowing the coronary sinus, the device allows for a prediction of the patient's response to a permanent coronary sinus device implant. This prediction can help guide the medical professional in determining the most effective treatment strategy for the patient. The device allows the physician to tailor the therapy from no therapy, only intermittent, intermittent and permanent implant of a coronary sinus reducer, providing a personalized treatment strategy for each patient.

[0080] In one embodiment of the invention, the system is configured such that the occlusion device is capable of inducing an overdilation of the coronary sinus by 1 to 50%, preferably 1 to 40%, more preferably 1 to 30%, even more preferably 5 to 30%. The overdilation of the coronary sinus has several significant effects. Most notably, it leads to improved perfusion in the heart. This is a key benefit for patients suffering from coronary microvascular dysfunction, a condition characterized by the inability of the heart's tiniest blood vessels to dilate properly. By inducing a slight overdilation of the coronary sinus, the backward pressure in the coronary venous system is elevated. This, in turn, results in a dilation of the diameter of the arterioles, leading to a significant reduction in vascular resistance in the subendocardium. This reduction in vascular resistance drives an increase in epicardial coronary flow, which improves perfusion in the heart. As a result, patients suffering from coronary microvascular dysfunction experience relief from their symptoms. The system can also be configured to induce overdilation within narrower or broader ranges, providing flexibility to tailor the therapy to the specific needs of the patient. For example, in some embodiments, the device may be configured to induce overdilation of the coronary sinus by 1 to 15%, 1 to 20%, 1 to 25%, 5 to 30%, 10 to 30%, or 15 to 30%. In other embodiments, the device may be configured to induce overdilation of the coronary sinus by less than 1% or more than 30%. The specific range of overdilation used will depend on a variety of factors, including the patient's specific condition, the diameter and length of the coronary sinus, the severity of their symptoms, and their overall health status.

[0081] The occlusion device can be inserted into the coronary sinus through various access points, including the jugular or femoral access. A guidewire may be first inserted into the coronary sinus, followed by the placement of an occlusion device, such as a balloon catheter, at or after the ostium. The guidewire is a useful component of the device, providing the necessary navigational aid to reach the coronary sinus. Given the delicate nature of the procedure, the guidewire is configured to be flexible yet sturdy, providing the necessary support to navigate the complex vascular system without causing damage or unnecessary discomfort to the patient. The guidewire's design and material selection are optimized to ensure it can smoothly traverse the chosen access route, be it the jugular or femoral, and reach the coronary sinus with precision.

[0082] Access to the coronary sinus through the jugular or femoral routes offers distinct advantages. The choice of access route can be tailored to the patient's specific condition and the physician's preference, providing a level of customization to the procedure. Access via the jugular route can be advantageous in certain cases due to its direct path to the heart. On the other hand, the femoral route might be preferred in other instances due to its larger diameter and straighter path to the coronary sinus.

[0083] The guidewire's role in facilitating access to the coronary sinus is not merely mechanical. It also contributes to the safety and efficiency of the procedure. By providing a clear path to the coronary sinus, the guidewire reduces the risk of misdirection and potential damage to the surrounding tissue. This, in turn, can lead to fewer complications during the procedure and a quicker recovery time for the patient. The guidewire also allows for a more controlled and precise placement of the balloon dilation catheter or occlusion device, enhancing the effectiveness of the device. In addition to the safety and efficiency benefits, the use of a guidewire can also contribute to the predictability of the procedure. By providing a clear path to the coronary sinus, the guidewire can help the physician anticipate potential challenges and plan the procedure accordingly. This can lead to a more effective and efficient procedure, further enhancing patient outcomes.

[0084] The processing unit is preferably configured to provide an automatic quantification of a patient specific optimization curve based on one or more parameters comprised of the location of the occlusion within the coronary sinus and varying occlusion sequences. In this embodiment, a patient specific optimization curve is built based on epicardial hemodynamics measurements relative to the location of the occlusion in the CS and relative to the CS occlusion algorithm.

[0085] Thus, in a preferred embodiment, the processing unit is configured to receive signal input from said epicardial perfusion monitor and signal input from said occlusion device, wherein the signal input from said epicardial perfusion monitor relates to epicardial hemodynamics measurements, and the signal input from said occlusion device relates to the position of the occlusion in the coronary sinus and the occlusion algorithm at that position. The processing unit is further configured to build a patient specific optimization curve based on these signal inputs.

[0086] In a specifically preferred embodiment, the system is suitable for use in the treatment of coronary microvascular dysfunction (CMD).

[0087] In a further preferred embodiment, the system comprises further a temperature or pressure sensor continuously measuring the epicardial perfusion in the LAD, a memory for storing the perfusion curve as a function of time and an evaluation circuit for the determination of the pressure increase and / or pressure decrease per time unit each occurring at a heartbeat.

[0088] In an even further embodiment, the evaluation circuit cooperates with the balloon catheter to trigger and / or release the occlusion of the coronary sinus depending on said perfusion increase and / or perfusion decrease per time unit.

[0089] In an aspect, the invention relates to a kit suitable for use in the treatment of CMD comprising the device as described above and a composition of antianginal agents comprising beta-blockers. In an embodiment, the system can further be used to deliver antianginal agents, preferably comprising beta-blockers, directly to the affected area, thereby maximizing their therapeutic effects while minimizing potential side effects. The device can be configured to release the antianginal agents in a controlled manner, ensuring a consistent level of the drug is maintained in the patient's system. This can help to improve the patient's quality of life and reduce the need for additional treatments or interventions.

[0090] In some embodiments, the system can be configured to deliver a combination of different antianginal agents. This can be antianginal agents of different categories, such as nitrates and beta-blockers, or different antianginal agents from the same category, such as one or more beta-blockers. This can provide a synergistic effect, with each antianginal agent enhancing the effects of the others.

[0091] In other embodiments, the system can be configured to deliver a single antianginal agent, preferably a single beta-blocker. This can be particularly useful in situations where the patient has a specific sensitivity or intolerance to certain antianginal agents. The system can be tailored to deliver the specific antianginal agent that is most effective for that particular patient, providing a personalized approach to treatment.

[0092] The system can also be configured to adjust the dosage of the antianginal agents, preferably beta-blockers, based on the patient's needs. This can be particularly useful in situations where the patient has a specific sensitivity or intolerance to certain beta-blockers. The system can be tailored to deliver the specific beta-blocker that is most effective for that particular patient, providing a personalized approach to treatment. The device can also be configured to adjust the dosage of the betablockers based on the patient's needs. This can be done manually, or the system can be equipped with sensors that monitor the patient's condition and automatically adjust the dosage as needed. This can help to ensure the patient receives the optimal level of treatment at all times.

[0093] In conclusion, the system of the present invention, when used in conjunction with one or more antianginal agents, preferably one or more beta-blockers, provides a highly effective treatment option for patients with coronary microvascular dysfunction. By delivering antianginal agents comprising beta-blockers directly to the affected area, the system can significantly alleviate the symptoms of angina and prevent future cardiac events. This can greatly improve the patient's quality of life and reduce the need for additional treatments or interventions.

[0094] Method for operating a system

[0095] In an aspect, the invention relates to a method for operating a system as described herein. Measures of perfusion in the LAD are used to inflate segments of an occlusion device. The occlusion device has preferably been inserted in a subject, preferably a subject that was previously diagnosed with coronary microvascular dysfunction (CMD). The system allows multiple sequences of occlusion spanning one or more dedicated expandable members designed to optimize LAD perfusion.

[0096] For the placement of the occlusion device, signals may be obtained from intravascular ultrasound (IVUS), optical coherence tomography (OCT), noninvasive angiography or computed tomography (CT) based systems that can be used as external inputs to optimize the placement of the dilatable components. These systems can map the whole or portions of the coronary sinus.

[0097] Preferably the method is for treating perfusion measured at the LAD with the system as described herein operated in a manner to identify an optimal position to intermittently occlude the coronary sinus according to a preprogrammed sequence.

[0098] In another aspect, the invention relates to a method for operating a system as described herein. The occlusion device has preferably been inserted in a subject, preferably a subject that was previously diagnosed with a medical conditions associated with coronary microvascular dysfunction (CMD).

[0099] The medical condition associated with coronary microvascular dysfunction (CMD) is preferably chosen from the list of hypertrophic cardiomyopathy, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, diabetes, hypertensive heart disease, post-covid complications, chronic inflammatory and autoimmune diseases, aortic valve stenosis, or a combination thereof.

[0100] The method comprises the step of increasing and decreasing the dimensions of separate segments of the occlusion device in a predetermined sequence by said controller device, thereby intermittently narrowing the coronary sinus. The intermittent narrowing of the coronary sinus can be carried out in a predetermined sequence, which can include pulsating patterns, wave-like patterns or programmable sequences.

[0101] In a preferred embodiment, the method comprises the steps of: i. inserting the occlusion device in the coronary sinus wherein each expandable member is positioned at a different position in the coronary sinus, ii. expanding each of the expandable members consecutively in a preprogramed occlusion sequence and measuring each time the perfusion in an epicardial vessel, preferably the LAD, iii. determining the optimal position of the occlusion device and carrying out a predetermined occlusion protocol to the expandable member at this optimal position, iv. measuring the duration of the hemodynamic response in the epicardial vessel subsiding after the end of the predetermined occlusion protocol.

[0102] The method is advantageous because the occlusion device does not need to be repositioned to inflate at the different positions in the coronary sinus.

[0103] The shorter periods of this time period will indicate the need for a permanent coronary sinus reducer implant. The longer periods of this time will indicate the need for an intermittent occlusion therapy. An absence of improvement in hemodynamic values during the programmed obstruction sequences at each site will identify patients who will not benefit from treatment.

[0104] The ability of the system to increase and decrease the dimensions of the occlusion device in a predetermined manner allows for a tailored therapy approach, which can be customized to each patient's individual needs and condition. At each site, a preprogramed occlusion sequence is performed.

[0105] The method and system optimize the flow rate in a coronary artery of a patient or a rate of change of the flow rate in the coronary artery of the patient by executing position specific and sequence specific occlusions in the coronary sinus.

[0106] The method and system optimize the quantitative flow ratio of microcirculation or a rate of change of the quantitative flow ratio by executing position specific and sequence specific occlusions in the coronary sinus. The method and system optimize the microvascular resistance or a rate of change of the microvascular resistance by executing position specific and sequence specific occlusions in the coronary sinus.

[0107] In another or a further embodiment, the method comprises the steps of: a. measuring the perfusion Pl in an epicardial vessel, such as the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx); b. inflating the occlusion device, thereby overdilating the coronary sinus; c. measuring the perfusion P2 in said epicardial vessel, such as the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx); d. deflating the occlusion device; e. measuring the perfusion P3 in said epicardial vessel, such as the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx).

[0108] Based on the perfusion values it can be determined whether a permanent narrowing of the coronary sinus is recommended.

[0109] In a further embodiment, the method comprises the step of permanently narrowing the coronary sinus if P2 is greater than Pl and P3 is at a similar value to Pl, or intermittently inflating and deflating the occlusion device if P2 is greater than Pl and P3 is greater than Pl.

[0110] In this embodiment, the method comprises the step of inserting a permanent implant if P2 is greater than Pl and P3 is at a similar value to Pl, or providing an intermittent treatment if P2 is greater than Pl and P3 is greater than Pl.

[0111] In a preferred embodiment, said epicardial vessel is chosen from: the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx).

[0112] CMD is a condition characterized by the inability of the heart's smallest blood vessels to dilate properly. This condition is often associated with significant symptoms of angina, even after the patient has exhausted all available therapies. The invention addresses this unmet need by offering an effective therapeutic option for patients who fail to respond to existing treatments. In an embodiment, the subject has previously been diagnosed with one of the diseases chosen from diabetes, hypertensive heart disease, hypertrophic cardiomyopathy, aortic valve stenosis, chronic inflammatory and autoimmune diseases, heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction (HFrEF), and post-covid complications. In a specific embodiment, the subject has previously been diagnosed with heart failure with preserved ejection fraction.

[0113] Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome associated with poor quality of life, substantial health-care resource utilization, and premature mortality. There is a high prevalence of CMD in HFpEF in the absence of un-revascularized macrovascular coronary artery disease.

[0114] Coronary Microvascular Dysfunction (CMD), a structural and functional remodeling of the coronary microcirculation, is a catalyst for the development of a range of cardiovascular diseases.

[0115] Other diseases beside HFpEF, currently undertreated and included in this application are CMD in Post Covid patients, CMD in HF, CMD in HFrEF, CMD in diabetes, CMD in Hypertensive Heart Disease, CMD in Hypertrophic Cardiomyopathy (HCM), CMD in Aortic Valve Stenosis, CMD in Chronic Kidney Disease (CKD) and CMD in Chronic inflammatory and autoimmune diseases.

[0116] The system is suitable for use in patients with a variety of underlying conditions. For instance, in patients with diabetes, the device can help counteract the detrimental effects of high blood glucose levels on the coronary microvasculature. Similarly, in patients with hypertensive heart disease, the device can help mitigate the impact of high blood pressure on the heart's microvascular vessels. In patients with hypertrophic cardiomyopathy, a condition characterized by thickened heart muscle and often associated with impaired dilation of the coronary microvascular vessels, the device can help enhance coronary flow, improve symptoms and slow the development of the disease. The device can also be beneficial in patients with aortic valve stenosis, a condition that can lead to reduced coronary flow reserve. In patients with chronic inflammatory and autoimmune diseases, the device can help counteract the negative effects of systemic inflammation on the coronary microvasculature. In patients with heart failure with preserved ejection fraction, a condition often associated with CMD, the device can help improve coronary flow and alleviate symptoms. Lastly, in patients with post-covid complications, the device can help address CMD that may result from the virus's impact on the cardiovascular system.

[0117] The system is advantageous to address the unmet need in the treatment of CMD. It maximizes epicardial coronary flow by the intermittent pre-programmed narrowing of multiple segments of the coronary sinus. This mechanism increases the backward pressure in the coronary venous system and triggers a dilation of the diameter of the arterioles. The specifics of the improved epicardial flow are calculated for each patient taking into consideration both the best position of the inflation sequence and the specific pre-programmed occlusion sequence that produces the best impact on epicardial perfusion. This patient specific optimization curve enhances perfusion in the heart, relieves myocardial ischaemia, and alleviates symptoms in a tailored way for patients suffering from CMD.

[0118] It is believed that intermittently narrowing the coronary sinus might induce a "memory" in the arterioles, leading to a durable effect on global cardiac hemodynamics and a cure of CMD.

[0119] In an embodiment, the subject has previously been administered antianginal agents, preferably antianginal agents comprising beta-blockers. The expression "antianginal agent" refers to compounds used to alleviate angina, which is chest pain or discomfort resulting from a (coronary) heart disease.

[0120] The antianginal agents can be chosen from: nitrates, beta-blockers or calcium channel blockers. Nitrates can be nitroglycerin isosorbide dinitrate and isosorbide mononitrate. Calcium channel blockers can be amlodipine, diltiazem and verapamil. Beta-blockers can be metoprolol, atenolol, bisoprolol, carvedilol, nebivolol, and propranolol.

[0121] In a further embodiment, the subject has previously been administered one or more beta-blockers, preferably selected from a list comprising metoprolol, atenolol, bisoprolol, carvedilol, nebivolol, propranolol, or a combination thereof. The betablockers are known to have beneficial effects on the cardiovascular system and are suitable for use in the treatment of various heart conditions. These beta-blockers, when used in conjunction with the device, can effectively enhance the overall therapeutic effect. The invention further relates to a method of evaluating the effectiveness of a possible treatment with a device that was previously inserted in the coronary sinus of a subject.

[0122] The method may further comprise the step of performing a baseline measurement of perfusion at the point of the occlusion device. Various known methods can be used such as IMR, CFR (Coronary Flow Reserve), Absolute Flow, FFR, or other measures that can derive similar conclusions of improvement such as a reduction in vascular resistance in the sub endocardium. The steps required to measure perfusion and resistance are well described in literature and can be easily implemented in the use of this device.

[0123] Once the baseline measurement is established, the coronary sinus can be narrowed, for example by inflating the balloon catheter via a manually operated indeflator or predetermined sequence of the console, following a set protocol to induce a slight overdilation of the coronary sinus (0 to 30%). At this point, a measure of perfusion can be performed and compared to the baseline measure. An improvement of the measure within defined parameters will determine the benefit of the therapy. An additional measure after the removal of the dilation system can be performed to determine lasting effects of the inflation and help in assessing the therapy needed.

[0124] The method may comprise the steps of: a. measuring the perfusion Pl in an epicardial vessel, such as the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx); b. positioning the occlusion device in the coronary sinus, and inflating the occlusion device, thereby overdilating the coronary sinus; c. measuring the perfusion P2 in an epicardial vessel, such as the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx); d. deflating the occlusion device and removing the occlusion device from the coronary sinus; e. measuring the perfusion P3 in an epicardial vessel, such as the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx).

[0125] In one embodiment, the method comprises further the step of permanently narrowing the coronary sinus if P2 is greater than Pl and P3 is at a similar value to Pl, or intermittently inflating and deflating the occlusion device during the procedure if P2 is greater than Pl and P3 is greater than Pl.

[0126] In this embodiment, the method comprises the step of implanting a permanent coronary sinus reducer if P2 is greater than Pl and P3 is at a similar value to Pl, or intermittently inflating and deflating the occlusion device according to a predetermined sequence during the procedure if P2 is greater than Pl and P3 is greater than Pl.

[0127] In one embodiment, the method comprises further the step of not treating the subject if P2 is lower than Pl and P3 is lower than Pl.

[0128] In a further embodiment, the fluid pressure in the coronary sinus is continuously measured and stored, a fluid pressure curve is determined as a function of time, and the occlusion of the coronary sinus is triggered and / or released as a function of at least one characteristic value derived from the measured pressure values.

[0129] In an even further embodiment, wherein a pressure increase and / or pressure decrease per time unit each occurring at a heartbeat is used as said characteristic value.

[0130] The invention can be used to adjust dosage of antianginals such as beta blockers, ranolazine, nitrates, statins, calcium channel blockers and Trimetazidine. The invention can be used to adjust microvascular pharmaceutical compounds, including Autologous CD 34+ stem cells and Zibotentan.

[0131] DESCRIPTION OF FIGURES

[0132] Figure 1 shows an occlusion device according to an embodiment of the invention.

[0133] Figure 2A and 2B show a zoomed view of an expandable member according to an embodiment of the invention.

[0134] Figure 3 shows a cross-sectional view of a catheter according to an embodiment of the invention.

[0135] Figure 4 shows a schematic overview of the working of the system for optimizing epicardial perfusion hemodynamics according to an embodiment of the invention. Figure 5 shows an example of the increase over time of the LAD perfusion resulting from the occlusion of position P0, Pl and P2 of the balloon catheter in the coronary sinus and a specific programmable sequence is displayed on the monitor.

[0136] Figure 6 shows a patient specific example of measured and predicted values of a hemodynamic parameter derived from multiple programed occlusion sequences delivered at the different positions PO, Pl and P2 in the coronary sinus. This is referred to as a patient specific optimization curve.

[0137] Figure 7 shows a schematic overview of an algorithm for identifying an optimal position and performing a final coronary sinus occlusion treatment.

[0138] Figure 8 shows a schematic overview of a device for optimizing epicardial perfusion hemodynamics according to an embodiment of the invention.

[0139] Figure 9A and 9B illustrates possible combinations of pre-determined occlusion sequences which include periods of occlusion and periods of deflation of specific segments of the occlusion device.

[0140] The occlusion device (100) of figure 1 is a balloon occlusion device configured for placement in the coronary sinus. The occlusion device (100) comprises a catheter (4) with three expandable members (1) (2) (3) which can be expanded independently and intermittently. The expansion of the expandable members (1) (2) (3) can be carried out according to programmable sequences.

[0141] The expandable members (1) (2) (3) are present on the occluding portion (17) of the occlusion device (100). The occluding portion (17), which is also the distal portion of the occlusion device (100) will be inserted in the coronary sinus. The catheter (4) is a multi-lumen catheter, which is shown in figure 3, wherein the lumens (9) (10) (11) (12) (14) can be used for one or more sensor lines to measure one or more parameters to generate data signal and / or one or more fluid lines.

[0142] A guidewire can be used to advance the multi-lumen coronary sinus occlusion device as it fits through the center (13) of the catheter (4). The guidewire's role in facilitating access to the coronary sinus is not merely mechanical. It also contributes to the safety and efficiency of the procedure.

[0143] The sensor and fluid lines placed on the occlusion device (100) connect to the control system via the line (5) and (8). The sensor line (7) is connected using a Luer lock (6) to maintain the fluid path from the central lumen (13). Radiopaque marker bands can be placed at each expandable member (1) (2) (3).

[0144] The expandable members (1) (2) (3) of the multi-lumen coronary sinus occlusion device (15) can be timed with a ECG sensor signal that can be obtained by an intra coronary ECG from an arterial vessel. Figures 2A and 2B show an expandable member. In figure 2B an outer electrode (16) is placed on the expandable member which can electrically stimulate different locations around the diameter of the coronary vessel to improve the perfusion of the epicardial vessels. This electrode can be placed on one or all expandable members of the multi-lumen coronary sinus occlusion device. The outer electrode (16), which can be in the shape of a ring, has multiple electrodes around its diameter that can both sense electrical signals and stimulate the vessel before, during and after the programmed occlusion sequence. This allows for electrical stimulation concomitantly to the occlusion therapy.

[0145] Figures 4 and 8 show the working of a system as described herein. The system uses an epicardial perfusion monitor comprising a hemodynamic sensor of the LAD. The sensor uses a hemodynamic parameter, preferably the Coronary Flow Reserve (CFR). The system is configured to operate the coronary sinus occlusion device as shown in figures 1, 2A, 2B and 3 and can, in particular, operate each expandable member of the coronary sinus balloon catheter to intermittently occlude the coronary sinus according to programmable sequences.

[0146] The hemodynamic value resulting from the position and programmed obstruction sequences of each individual obstruction site is recorded consecutively. In Figure 5 the increase over time of the LAD perfusion resulting from the occlusion of position PO of the balloon catheter in the coronary sinus and a specific programmable sequence is displayed on the monitor. The resulting perfusion from the LAD is then sequentially measured when the balloon catheter is obstructed in positions Pl and P2.

[0147] The most proximal position PO is positioned at the ostium or entrance of the coronary sinus. The occlusion of this position will impact vessels connected to the Right Coronary Artery (RCA). These vessels will be missed by more distal occlusive positions. Occlusion at the ostium is an important aspect for optimal LAD perfusion. The occlusion will increase the capillary transit time (CTT) and increase the mean capillary diameter of a larger portion of the microvascular vessels. The longer CTT will allow for more nutrients to be exchanged and improves tissue oxygenation. The increase in capillary diameter implies an increase in the capillary surface area, thus beneficially aiding the diffusion of oxygen from the blood to the tissue.

[0148] Each position and programable sequence allows the creation of a patient specific optimization curve Figure 6. The processing unit will analyze and process the data to determine the optimal position for coronary sinus occlusion therapy. A predetermined occlusion protocol will then be applied to the identified optimal position in the coronary sinus. Figure 9A shows an example of programable sequence, wherein the sequence may be repeated 10 times. Figure 9B also shows an example of programable sequence, wherein the sequence may be repeated 5 times, and wherein the occlusion is kept for 10 seconds each time, with 5 seconds in between.

[0149] The hemodynamic response subsiding after the end of the predetermined occlusion protocol will determine if a permanent implant sometimes called a coronary sinus reducer is recommended. An algorithm (the processing unit) can evaluate length in time of the hemodynamic response after the end of the predetermined protocol. The shorter periods of this time period will indicate the need for a permanent coronary sinus reducer implant. The longer periods of this time will indicate the need for an intermittent occlusion therapy. An absence of improvement in hemodynamic values during the programmed obstruction sequences at each site will identify patients who will not benefit from treatment.

[0150] The hemodynamic value resulting from the position and programmed obstruction sequences of each individual obstruction site is recorded consecutively, according to an algorithm such as shown in figure 7. The programmed sequences are represented in figure 6 by "the pressure algorithm" axis and will have varying diameter and timed cycles of inflations and deflations.

[0151] The ability of the system to increase and decrease the dimensions of the occlusion device in a predetermined manner allows for a tailored therapy approach, which can be customized to each patient's individual needs and condition. At each site, a preprogramed occlusion sequence is performed.

Claims

CLAIMS1. A system for optimizing epicardial perfusion hemodynamics, the device comprising: an epicardial perfusion monitor configured for measuring the perfusion in an epicardial vessel, an occlusion device configured for placement in the coronary sinus, wherein the occlusion device comprises two or more expandable members, and wherein the occlusion device further comprises at least one sensor, a processing unit configured to receive signal input from said epicardial perfusion monitor, comprising a controller device configured to increase and decrease the dimensions of the two or more expandable members.

2. System according to claim 1, wherein the controller device in the processing unit is configured to increase and decrease the dimensions of at least two expandable members in response to the signal input from said epicardial perfusion monitor.

3. System according to any of the previous claims, wherein said occlusion device is a balloon catheter comprising two or more balloons.

4. System according to any of the previous claims, wherein each expandable member comprises one or more sensors.

5. System according to claim 4, wherein said sensor is a hemodynamic sensor configured to measure a change in hemodynamics in the coronary sinus.

6. System according to claim 4 or 5, wherein the processing unit is configured to receive signal input from said sensor.

7. System according to any of the previous claims, wherein said occlusion device configured for placement in the full length of the coronary sinus.

8. System according to any of the previous claims, wherein one of the expandable members is configured for placement in the ostium.

9. System according to any of the previous claims, wherein said occlusion device comprises at least three expandable members.

10. System according to any of the previous claims, wherein said epicardial perfusion monitor is configured for measuring the coronary flow reserve in an epicardial vessel.

11. System according to any of the previous claims, wherein said epicardial perfusion monitor is configured for measuring the perfusion in an epicardialvessel by catheter or radiofrequency RF via sensor data indicative of hemodynamic parameters.

12. System according to any of the previous claims, wherein said epicardial perfusion monitor is configured for measuring IMR, wedge pressure, and / or RRR absolute flow in an epicardial vessel.

13. System according to any of the previous claims, wherein said occlusion device comprises two or more lumens, wherein said lumens include sensor lines and fluid pressure lines14. System according to claim 13, wherein said lumens are configured for deployment.

15. System according to any of the previous claims, wherein said occlusion device is provided with one or more outer electrodes, preferably the expandable members are provided with one or more outer electrodes.

16. System according to any of the previous claims, wherein the processing unit is configured to receive electrical signals and deliver electrical stimulation pulses in at least two expandable members while measuring the perfusion in an epicardial vessel.

17. System according to any of the previous claims, wherein the processing unit is configured to provide an automatic quantification of a patient specific optimization curve based on epicardial flow and one or more parameters comprised of the location of the occlusion within the coronary sinus and varying occlusion sequences.

18. A method for operating a system according to any of the previous claims 1- 17, wherein said occlusion device and said epicardial perfusion monitor have been inserted in a subject, wherein operating includes increasing and decreasing the dimensions of the occlusion device in a predetermined sequence by said controller device, thereby intermittently narrowing the coronary sinus, and further measuring the perfusion in an epicardial vessel.

19. Method according to claim 18, wherein the subject was previously diagnosed with coronary microvascular dysfunction (CMD).

20. Method according to claim 18 that permits the identification of the best patient specific therapy between a permanent coronary sinus implant, intermittent occlusion therapy or no coronary sinus therapy.

21. Method according to claim 18 that allows the quantification of a patient specific optimization curve taking into account epicardial flow and one or two parameters comprised of the location of the occlusion within the coronary sinus and varying occlusion sequences.

22. Method according to claim 16 that allows the automatic quantification of a patient specific optimization curve taking into account epicardial flow and one or more parameters comprised of the location of the occlusion within the coronary sinus and varying occlusion sequences.

23. Method according to claim 18, comprising the steps of: measuring the perfusion Pl in an epicardial vessel; inflating the occlusion device, thereby overdilating the coronary sinus; measuring the perfusion P2 in said epicardial vessel; deflating the occlusion device; measuring the perfusion P3 in said epicardial vessel.

24. Method according to claim 23, further comprising the step of permanently narrowing the coronary sinus if P2 is greater than Pl and P3 is at a similar value to Pl, or intermittently inflating and deflating the occlusion device during the procedure if P2 is greater than Pl and P3 is greater than Pl.

25. Method according to claim 23 or 24, wherein said epicardial vessel is chosen from: the left coronary artery (LCA), the right coronary artery (RCA), the left anterior descending artery (LAD) and the circumflex artery (LCx).

26. Method according to any of claims 18-25, wherein the subject does not have an occluded coronary sinus.

27. Method according to any of claims 18-26, wherein the subject has been administered one or more beta-blockers.

28. Method according to claim 27, wherein the one or more beta-blockers chosen from the list of: metoprolol, atenolol, bisoprolol, carvedilol, nebivolol, propranolol, or a combination thereof.

29. Method according to any of claims 18-28, wherein the occlusion device is positioned between 0 and 7 centimeters behind the ostium of the coronary sinus.

30. Method according to any of claims 18-29, wherein at least one expandable member is positioned at the ostium of the coronary sinus.

31. A kit suitable for use in the treatment of coronary microvascular dysfunction (CMD) comprising a system according to any of claims 1-17, and a composition comprising one or more beta-blockers.

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