Talking Tall Rounds®: Left Ventricular Reconstruction

Podcast Transcript

Announcer:

Welcome to the Talking Tall Rounds series, brought to you by the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic.

Chonyang Albert, MD:

It's my pleasure to kick off with our case presentation this morning. I will present a male in his seventh decade of life who developed a delayed presentation of an anterior anterolateral ST-elevation myocardial infarction. He underwent a percutaneous intervention. Unfortunately, this was complicated by severe no-reflow phenomenon and persistent ST-elevations, despite our best efforts. His past medical history include type 2 diabetes, hypertension, chronic kidney disease Stage 3, dyslipidemia and chronic pain syndrome with reflex sympathetic dystrophy. Representative images from his acute coronary intervention reveal the culprit lesion was the left anterior descending, it was a delayed presentation. Despite our best efforts, at the conclusion of the case, there was restoration of flow, however, the flow was very slow down the anterior descending, as you can see, with significant residual disease.

Chonyang Albert, MD:

On his EKG, one can appreciate persistently elevated ST-segments in the antero/anterolateral leads. Unfortunately, only one month later after his initial PCI, he self-discontinued his ticagrelor due to perceived intolerance and because of this, he sustained a recurrent ST-elevation MI due to acute instant thrombosis at the distal edge of his previous LAD stent, for which he received another drug eluting stent to the left anterior descending. At the conclusion of these PCI events, this gentleman was unfortunately left with ischemic cardiomyopathy with an ejection fraction that was severely reduced at 25%. Additionally, he developed New York Heart Association Class 3 symptoms of dyspnea, despite optimal medical management with guideline-directed medical therapies. He also sustained a heart failure hospitalization approximately three months after his initial PCI.

Chonyang Albert, MD:

As one can appreciate, this is his heart failure medication list. He's optimized on maximally tolerated doses of guideline-directed medical therapy, which in this day and age would include a beta blocker, an ARNI, an MRA, and an SGLT2 inhibitor. Representative images from his echocardiogram demonstrates a dilated left ventricle with reduced ejection fraction. Most importantly, on his apical four imaging here on the right, one can appreciate a distal left ventricular aneurysm with akinesis and potentially dyskinesis, as well. On his read of the echocardiogram, we can appreciate that his ejection fraction is 24%, his left ventricle is severely dilated, and the apical segment is an akinetic. Again, on the string imaging one can appreciate that, as well. With multi-modality imaging, which Dr. Harb will go over, one can further ascertain the geometric changes in this ischemic substrate. Here, on the cardiac MRI, again, the LV aneurysm is demonstrated. On a CT analysis, again, one can appreciate the enlarged ventricle with enlarged and diastolic and systolic volumes and a reduced ejection fraction of 28% on the CT measurement.

Chonyang Albert, MD:

So, because of these reasons, this patient met multiple inclusion criteria in the LV reconstruction trial, or the ALIVE trial, with BioVentrix Revivent, which you will hear a lot more about during this talk. Specifically, this gentleman had an ejection fraction less than 45%, evidence of left ventricular scar, or akinesis, dyskinesis. His LV end-systolic index was greater than 50 milliliters per meter squared. He continued to have New York Heart Association Class 3 symptoms, despite being optimized on excellent heart failure guideline-directed medical therapies. I will pause my case presentation at this point to make way for our speakers, and I will circle back at the end of the presentation for patient updates in this case. Thank you very much.

Rishi Puri, MD, PhD:

It's a great pleasure to be here to talk about some of the future of LV restoration. I'm a coronary structural interventionist and naturally, I'm inclined to want to fiddle with devices and to do fancy things to people's ventricles, so it's been amazing to learn from Dr. Starling and colleagues about how some of these theories have evolved over time. Here in my disclosures. Now, we're at the stage where we have a new subspecialty called interventional heart failure, which is really the merging of interventional cardiology based on cardiac surgical principles with key involvement with of heart failure imaging, and even sometimes electrophysiology, and so this is how we are evolving. Dr. Starling highlighted the important point of Laplace's law, which is a foundation for not only the pathophysiology of HFrEF, or heart failure with reduced ejection fraction, which is a self-propagating vicious cycle of ongoing elevated intraventricular pressures, ongoing ventricular dilation and wall thinning, and also, it highlights the goals of reverse remodeling, or reversing the adverse remodeling, where we have a range of biological and physical therapies.

Rishi Puri, MD, PhD:

We all know that the foundational backbone for HFrEF are a range of medical therapies that are started in different order, depending upon the patient's phenotype, we have CRT, we have some valve therapies, if you believe in the valve-first hypothesis for functional mitral regurgitation, MitraClip has been shown to be effective in at least half of the patients and there are some flow contractility devices. But in parallel, we've learned lessons from surgery about physical means of remodeling. Doctors Starling and Soltesz have introduced to you the surgical Batista procedures, the door procedure, aneurysmectomies. Dr. Estep went through the evolving hybrid transcatheter BioVentrix Revivent procedure, which we are very excited to be a part of. I'm going to highlight two or three devices that are also happening in parallel, one of which is the AccuCinch device, which we've consented three patients and have randomized one patient to placebo, where we're looking very closely for our first treatment patient. We're happy to get any referrals for patients that fit the phenotype, which I'll discuss with you in a minute.

Rishi Puri, MD, PhD:

But this is really the first true fully transcatheter therapy that is designed to restore support and strengthen the enlarged dilated left ventricle. It's a completely percutaneous procedure, transfemoral access with a 20 French femoral arterial sheath, so just like TAVI. They're retrograde aortic access, there are especially designed catheters that are designed to navigate around the cordal apparatus and around the cords at the base of the left ventricle. That gives you the road map to position a guidewire, and therefore an implant, which is used using anchors, multiple anchors depending upon the size, the perimeter of the left ventricle, to stitch in these anchors and then ultimately cinch. These are procedures that take between 90 minutes to three hours, depending on the complexity and how the patient goes.

Rishi Puri, MD, PhD:

You can see here that there's early echo guidance, in terms of taking the catheter around the papillary muscles. But once you've actually successfully and confirmed your position at the base of the left ventricle using a predefined, preshaped track catheter or nav catheter, it really is a fluoroscopic procedure. Those of us who have performed transcatheter mitral annularplasty procedures such as Cardioband and Millipede, it is a fairly similar workflow, working under the mitral annulus, coming around towards the other side. Once you've actually implanted your anchors, you then are able to cinch, simply by turning a knob that clicks over a course of a few minutes, and you are able to significantly reduce the diameter at the base of the ventricle between the septum and the lateral wall. Typically, you can achieve around a 26% reduction based on the actual difference in the distance between the pre- and post-cinch. Here is a fluoroscopic example of one of my colleagues in New York who performed the first procedure in this particular trial.

Rishi Puri, MD, PhD:

So, here is a quick trial overview. It's the CORCINCH-HF trial. It's a prospective randomized multicenter study, patients who randomized 1:1 to treatment with the AccuCinch device, with background established guideline-directed medical therapy, similar to COAP. It's a fairly strict medical eligibility committee criteria that you have to get the patient through that they're on their maximally tolerated HFrEF GDMT and/or CRT and/or ICD, if relevant. And then the patients, if they still have NYHA 3 or have had a heart failure hospitalization within the 12 months and they have a dilated ventricle, as defined by an internal diameter in diastole for at least 55 millimeters and their ejection fraction is between 20 and 40%, then they are candidates. These are the kind of patients that we'd love for you to send our way. You can email any one of us and we'd do all the work and screen the patient for you.

Rishi Puri, MD, PhD:

Now, this device has been used in Europe in an early feasibility study in the mitral regurgitation cohort. So, this device was initially designed to treat functional mitral regurgitation, and as the company and the implanters looked at what this device was actually achieving, it became readily apparent that this was a device keyed into actually treating HFrEF patients and the functional mitral regurgitation could be treated in parallel. So, when they pulled all of their early feasibility studies, that were performed both here and in the US, they identified 41 patients who matched the criteria for the current ORCINCH-HF trial. It turns out that they have 12-month data on these patients. Here are some of the summary findings based on the quality of life outcomes on the top right, the KCCQ questionnaire. You can see here that out to 12 months, there's 20-point improvement in the KCCQ score. Now, just to put that into perspective, a delta of 10 or an improvement of 10 in the KCCQ has been validated as a moderate to large improvement in the quality of life of these patients.

Rishi Puri, MD, PhD:

There is an emerging data pool that shows, across different procedures, both TAVI, MitraClip, that when you have at least a 10 point improvement in your KCCQ score, that does tend to correlate with improved outcomes, including mortality, and so the KCCQ score is really the foundation of the endpoints that we use in some of these interventional heart failure device trials. You can see here the impressive, sustained improvements in the end systolic and end diastolic volumes.

Rishi Puri, MD, PhD:

Moving on to a new device that's really exciting, it's called the V-sling. It's a company based in Israel called Cardiac Success. This is really based around the premise that when you have HFrEF and you have ongoing dilation of the left ventricle, the papillary muscles are displaced as the ejection fraction reduces. This causes leaflet tethering and 20% of these patients have functional mitral regurgitation. Really, most of their efforts so far have been on trying to repair the valve, namely MitraClip. However, we need to always go back and learn some lessons from our surgeons. There is a procedure called the sling procedure, which is a placement of a PTFE GORE-TEX tube around the pap muscles. Usually, it's combined with ring annuloplasty to treat mitral regurgitation. So, as it stands, there was a randomized trial using, essentially, surrogate outcomes, a small trial by investigators in Italy that looked at surgical patients who underwent mitral valve annuloplasty with or without the sling. You can see here that there was some significant improvements towards the patients who had the combined procedure, in terms of their ejection fraction, the size of the LV reduction, and also the tenting reduction. Unsurprisingly, when we look at medical device companies, we look back on what our surgical colleagues have learned and we try and mimic some of these maneuvers to see whether we can achieve this in a fully transcatheter technique. This company are developing the V-sling device, which, essentially, is at the stage where they are close to starting their first-in-man trial planned in Europe and Israel in the next few months.

Rishi Puri, MD, PhD:

Standard inclusion criteria, very similar to CORCINCH. You really need to have a dilated left ventricle and an end systolic interpapillary muscle distance of at least 20 millimeters. This really will be, we'll see if it works, an adjunct therapy to AccuCinch and BioVentrix, in restoring the shape of the ventricle, and hopefully, achieving some of the similar outcomes that we see with other therapies that physically aim to reduce the size of the left ventricle. Dr. Starling showed you the PARACHUTE device, which was really a scaffold sitting at the apex of the left ventricle designed to reduce volume, but it was a static scaffold, not a dynamic scaffold, and that particular device didn't work. Eucardia is an Italian-based company that are designing the Heart Damper device that looks very much like PARACHUTE, but actually, is a dynamic device that moves in systole and distally. So, it gives you a systolic kick and is designed really to try and augment and reduce left ventricular structure and function. This is in very early preclinical development, so we will see how this device emerges and whether it can improve on the lessons we learned from PARACHUTE.

Rishi Puri, MD, PhD:

You can see here, there's no need for an external power source, it's a dynamic functional device. Myocardial restoration is an established therapy. It really has been left in the research realm after the AUGMENT heart failure trial was published in the European Heart Journal about seven years ago. Alginate, or alginate hydrogels, are stable, inert, biocompatible compounds that are naturally occurring and stem from seaweed and brown algae. They have mechanical properties that are compatible with healthy myocardium, they tend not to degrade, and they are able to scaffold and restore structures over time. One of the structures that it may be able to restore, if injected into, is the left ventricle. This has been a surgical procedure in the past, whereby a thoracotomy-based approach was taken and hydrogel injections were placed in various locations in the left ventricular wall.

Rishi Puri, MD, PhD:

If you go back to Laplace's law and you look at one of the factors that contribute towards wall stress and that self-propagating remodeling process, one of the factors is wall thickness. So, if you can scaffold and enhance the left ventricular wall, you can actually improve wall thickness, and that contributes to reduction in wall dimensions, diameter and radius, and then can subsequently reduce wall stress. The AUGMENT heart failure certainly wasn't a perfect trial. There were issues with some of the major adverse cardiovascular events, but when you look at some of the functional parameters, certainly, the data looks intriguing. There were some significant improvements in peak oxygen consumption, 6-minute walk testing, and quality of life scores, and you look here, at some of the comparisons from established therapies, so certainly, it is intriguing.

Rishi Puri, MD, PhD:

There is now a system that is completely transcatheter-based and this is now becoming a very competitive space, with some recent business acquisitions that have occurred in the device industry that you'll hear about in the coming weeks. This particular Chinese trial, which was a first-in-man trial presented at DHF, the device and heart failure meeting, a few months ago, shows you the early safety and feasibility results of the Xdrop system. Those of you who are interventional cardiologists and do structural interventions, you can see that this looks very much like a MitraClip device or transcatheter devices we use for mitral or tricuspid therapies. It really is a simple retrograde aortic system that is designed to sit in the LV, and using echocardiographic guidance, you can navigate in various regions of the left ventricle and you can inject hydrogels based on your pre-procedural imaging. This is 10 patients with HFrEF, the standard kind of patients that we have seen in most of these device trials. This has yet to be peer-reviewed and published, this is really just data that was presented at the D-HF meeting recently. There were no serious adverse device effects. You can see here, in those patients that had 90-day follow-up, you can see some intriguing improvements in their KCCQ scores. Some of the volume changes you can see on the bottom right also are very intriguing. So, this sort of space, in terms of LV restoration, is really going to expand in the coming years. It's exciting to be a part of this venture and there's a lot of work to be done collectively between heart failure imaging and intervention, as well as cardiac surgery. We certainly look forward to playing a key role in this space. Thanks.

Chonyang Albert, MD:

So, recall our gentleman with ischemic cardiomyopathy who developed an LV apical aneurysm. These are pictures that recapitulates what Dr. Soltesz demonstrated earlier with a series of anchors. The LV apical aneurysm was successfully excluded. Again, on representative imaging on cardiac MRI, one can appreciate the reduction in end diastolic and systolic volumes and improvement in ejection fraction, again with a 39% reduction in end systolic volume index, which is important in improvement in ejection fraction after his procedure. The NT-proBNP level in this patient, again, an important biomarker we use in heart failure, correlates with response to the BioVentrix LV reconstruction surgery. As you can see, during his initial presentation after his myocardial infarction, his NT-proBNP levels maxed out at greater than 6,000. He did have acute decompensated heart failure requiring admission after his BioVentrix Revivent was implanted. The overall trajectory of his BNP level is downward, correlating with an improvement in symptomology.

Chonyang Albert, MD:

So, in conclusion, this gentleman underwent LV reconstruction, there was a subsequent reduction in LV size, as previously mentioned, but also importantly, an improvement in heart failure severity. He is now NYHA Class 2 by symptomology and he remains optimized on guideline-directed medical therapies. So, in the appropriate patient population, LV reconstruction therapies coupled with well-established guideline-directed medical therapies for heart failure offers intriguing therapeutic potential. Thank you.

Announcer:

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