 Without further ado, I would like to introduce the first speaker for the session, and that is Dr. Sankap Sehgal. Sankap is a colleague of mine at the Beth Israel Deaconess Medical Center, where he is an attending cardiac anesthesiologist and a member of the team who delivers image guidance to structured heart disease interventions. Sankap will be talking to us this morning about current trans-catheter mitral valve interventions, the current evidence, and best practice. Sankap, take it away. Hello, everyone, and welcome to the 2023 Toronto Symposium. My name is Sankap Sehgal. I'm a cardiac anesthesiologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts. And today, we will be talking about trans-catheter mitral valve interventions, current evidence, and best practice. I have no disclosures. The objectives of our talk today are going to be understanding the need for trans-catheter interventions of the mitral valve, review trans-catheter edge-to-edge repair techniques for the mitral valve, and trans-catheter mitral valve replacement therapies for the mitral valve as well by analyzing landmark clinical trials, current evidence, and guidelines, and review some outcome predictors, compare trans-catheter edge-to-edge repair to valve replacement therapies and a certain optimal patient selection, and finally discuss the future perspectives. Now, the need and challenges of trans-catheter mitral valve interventions. Population-based analysis have revealed that the prevalence of moderate to severe mitral valve disease in the elderly population is very high, about 9% to 10%. Mitral valve prolapse is the most common organic mitral valve pathology, with a prevalence of roughly 2.5% in all adults. Advanced cases of mitral regurgitation, particularly symptomatic mitral regurgitation, are attributable to progressive left-integrated dysfunction, heart failure, and can have an annual mortality rate of up to 35%. There remains a very high prevalence of untreated mitral regurgitation, mainly primary mitral regurgitation, as only 29% of these patients undergo surgery, and the operative mortality risk of mitral valve surgery still remains high. It's somewhere between 1.5% and 4.5% for repair and replacement. The five-year survival after mitral valve surgery is somewhere between 70% and 80%, and the outcomes are worse for patients with advanced age, female gender, low ejection fraction, presence of diabetes, and obesity. It is estimated that approximately half of all patients with symptomatic severe mitral regurgitation do not receive surgery because of this perceived elevated operative risk, so there remains a big population at large that needs a trans-gatherer intervention for the mitral valve. The Kaplan-Meier curves here show the life expectancy for up to 10 years after mitral valve repair and replacement. You can see it's worse with valve replacement than the valve repair, and it's somewhere between 70% to 80% at five years. Now, the challenges for trans-gatherer mitral valve intervention arise from the fact that no big randomized study or studies have really compared the trans-gatherer interventions to either optimal medical therapy or surgical interventions. So despite increasing scientific data in the last decade, there remains only a small number of patients enrolled in structural heart disease studies that really limits the ability to verify the real clinical impact of these procedures on clinical outcomes. So let us first discuss trans-gatherer edge-to-edge repair strategies for the mitral valve. There are two main devices currently available for commercial use, Abbott's MitroClip and Edwards Pascal device. Abbott's MitroClip is the first trans-gatherer technology with CE mark and FD approval for the treatment of both primary and secondary mitral regurgitation. Since its first implantation in about 2003, over 100,000 procedures have been performed worldwide. The MitroClip system is now widely adopted for mitral edge-to-edge therapy for primary mitral regurgitation at high surgical risk on the basis of Everest. Everest 1, that is Everest 2, and Everest 2 realism studies. And in patients with secondary mitral regurgitation who remain symptomatic, despite guideline-directed medical therapy with non-accessible f-intruder enlargement, absence of right f-intruder dysfunction overwhelming hypertension, on the basis of the co-op trial results. The co-op study randomized patients of about 600 patients with heart failure and moderate to severe or severe functional mitral regurgitation who remain symptomatic despite guideline-directed medical therapy. It showed sustained three-year improvements in mitral regurgitation severity, quality of life, and functional capacity with the MitroClip compared to guideline-directed medical therapy alone with reduced analyzed rates of heart failure, hospitalization, and mortality. Also, subsequent composite rate of mortality or heart failure hospitalizations was reduced even for the patients that were assigned to guideline-directed medical therapy alone who crossed over and were treated with a MitroClip edge-to-edge repair when compared to those who continued on guideline-directed medical therapy alone. So re-emphasizing the advantage of MitroClip in this patient population. Now, the MitroFR trial in 2018 enrolled about 300 patients and showed no difference between the two groups in composite outcome of death from any cause or unplanned hospitalization for heart failure at 12 months between edge-to-edge repair with guideline-directed medical therapy or medical therapy alone. Now, this was surprising that there was no reduction in the primary endpoint for all-cause mortality or heart failure hospitalizations in this trial, whereas a significant benefit was shown in the co-op trial. Now, this trial actually gave us two lessons. The first lesson we learned is that functional mitral regurgitation should be considered as a leading cause in cardiomyopathy progression rather than a mere marker of disease severity. The second lesson we learned from these two big trials, the co-op and the MitroFR, which resulted in basically diametrically opposite results, is a subclassification of patients with functional mitral regurgitation into those with proportionate and disproportionate mitral regurgitation. And it has proven very useful in understanding the response to different therapeutic interventions. In proportionate mitral regurgitation, the principal source of MR is the dilation and symmetric tethering of the mitral valve leaflets. This is primarily because of left interpreter enlargement, which produces a classic secondary MR jet. So basically the global LV disease drives some mitral regurgitation. These patients with proportioned mitral regurgitation have a very high favorable response, both clinical and hemodynamic response to medical therapy. In market contrast, disproportionate functional mitral regurgitation typically is associated with a focal left ventricle of all motion abnormality, an asymmetric regurgitation jet in a classic rather primary mitral regurgitation pattern. You see those asymmetric jets, eccentric jets, and the degree of mitral regurgitation that cannot be ascribed to global left ventricle dilation. So these ventricles are not severely dilated. These patients have a significant benefit from treatments that are directed towards the valve apparatus itself, that is a mitral valve repair or replacement. And they have a poor response to drugs or devices that are intended to make the left ventricle smaller. The relationship of effective regurgitation orifice area to the left ventricle or endisolic volume helps define proportionate versus disproportionate mitral regurgitation. So if you have a small EROA with a large endisolic volume for the left ventricle, that becomes a proportionate mitral regurgitation. If you have a larger EROA with a smaller ventricular size, that becomes a disproportionate mitral regurgitation. Now, most patients in the mitral FR trial have proportionate mitral regurgitation with large dilated ventricles and does reduced benefit from edge-to-edge repair, which helps explain the disparity between the results of the trial for mitral FR versus a co-app trial. So how we should approach severe mitral regurgitation patients is by classifying these patients into proportionate versus disproportionate mitral regurgitation after medical optimization and then considering for transcatheter therapies with the repair or replacement versus advanced heart failure therapies based on imaging findings. Moving further with the trials, the X-Band MitraClip X-Band trial is the largest contemporary real-world study of MitraClip NTR and XTR devices that also shows effectiveness with almost 90% reduction in mitral regurgitation at one year and about 65% reduction in hospitalizations from heart failure at one year with really good safety profile and minimum complications, which reinforces the need and the use of this device. From other studies, we have also learned about MitraClip outcome predictors. Patients younger than age 75, lower cerium creatinine, lower left ventricular endostatic volume, stable hemodynamics, lack of atrial fibrillation, RCOPD, and low cancer quality scoring, patients usually have good outcomes with the MitraClip procedure. Other sub-studies of the co-op trial have shown that if there's a residual mitral regurgitation following the procedure, anything that is greater than grade three at 30 days is a predictor of mortality, a higher mortality at two years of follow-up. Now, regarding gender-specific impact of transcatheter edge-to-edge repair of MitraClip in heart failure hospitalization treatment, the benefit was less pronounced in women compared with men beyond the first year of treatment, which is not very well understood. Finally, edge-to-edge repair in comparison to surgical MitraVal repair in post-MI patients in retrospective analysis of roughly 500 patients who had at least moderate to severe mitral regurgitation following MI showed lower in-hospital and one-year mortality rates in the patients that were in the transcatheter group. However, the immediate post-procedural success did not differ between the two groups. Now, unfortunately, if the MitraClip fails, the patients need surgery and there is dismal outlook. In the cutting edge registry of over 300 patients, MitraVal surgery after failed edge-to-edge repair revealed approximately 24% mortality at one year and 32% after three years of surgery. Now, this is primarily driven by the fact that these patients are high surgical risk to begin with and only less than 10% of patients who had failed edge-to-edge repair underwent a surgical MitraVal repair. Most of them, which is 90% and greater, needed a valve replacement, which inherently has a higher mortality risk. Now, the reasons for surgical reintervention amongst these failed tier or edge-to-edge repair group was mainly, which is check-on for 40%, was recurrent or residual mitral regurgitation. Single leaflet device attachment accounted for about another 25% of these re-operations. A partial leaflet detachment occurred in about 20% and MitraVal stenosis in another 10 to 15%. Two retrospective studies also suggest that transcatheter edge-to-edge repair can be safely performed with moderate conscious sedation using intracardiac echo with same-day discharge, which shows that there's a promising evolution in these transcatheter therapies. Now, the second device to discuss for MitraVal edge-to-edge repair, or the tier technique, is a PASCAL device from Edwards. It gained the CE mark in February 2019 for the treatment of both primary and secondary MR and is also now FDA-approved for using secondary mitral regurgitation as of 2022. Under the Class 2 study, we have two-year outcomes of over 100 patients which reveal favorable results in both primary and functional mitral regurgitation. The results showed a high rate of survival, over 70% in functional mitral regurgitation and over 90% in primary MR and high rates of freedom from heart failure hospitalizations of over 80 and 95% in these patients. Transcatheter edge-to-edge repair now is the standard of care for patients with symptomatic functional mitral regurgitation despite guideline-directed medical therapy without an alternative indication for cardiac surgery. That is their high surgical risk patients. The 2020 ACCH guidelines upgraded its use to Class 2A recommendation for select primary mitral regurgitation while the 2021 European guidelines have given a Class 2B recommendation for its use in primary mitral regurgitation. A new Class 2A recommendation for select use in functional mitral regurgitation patients has been given by both the ACCH and the European guidelines. Tens of thousands of patients have now undergone transcatheter edge-to-edge repair for mitral valve disease with continuously improving 30-day mortality which averages about 4.5% now and an average length of stay-off about one day in the hospital post-procedure. Compared to tier or transcatheter edge-to-edge repair, the field of valve replacement using transcatheter techniques, which is TMDR, is still in its infancy, mainly limited by high rates of screening failure due to unsuitable anatomy. The two-year outcomes after the implantation of the 10-line valve which is one of the prominent TMDR valves used showed a high all-cause mortality of about 39%. However, over 90% of surviving patients had no mitral regurgitation with a decrease in heart failure hospitalization, hence it showed great feasibility, but with high mortality. Now I wanted to point out that there are numerous transcatheter mitral valve replacement devices that have previously come on market which are not currently available and also are in progression and in the pivotal trial phase now. So we'll just be discussing two or three of these 10-line being the more commonly seen one. Another device, the interpret TMDR valve system with the metronic has shown favorable 30-day results in a pivotal study. The 15 patients enrolled had 100% corrected mitral regurgitation, trace or no parababular leak from the mitral regurgitation and excellent valve function, no mortality or stroke with significant improvement in functional class. And this shows great promise and we're waiting for more patients to be enrolled and to see long-term durability of this valve. Next, the one-year outcomes were reported from the mitral trial which is evaluating the transcephal mitral valve and valve with the sapient three trans-catheter heart valve at high risk patients with failed surgical mitral bioproceses. Transcephal mitral valve and valve is associated with 100% technical success rate, low procedure complication rates and very low mortality just between three and 4% at one month and about 17% at one year. Now, sapient three is the only approved valve currently in use for failed rings bioproceses or for use in valve and valve in severe MAC cases. In another large study, looking at the sapient valve and TMVR use of over and over 500 patients, there was a high adverse event rate in these patients. The all cause mortality was between 20 and 23% at one year which was highest in valve and MAC followed by valve and ring followed by valve and valve. As you can see, 30 to mortality was highest in valve and MAC and also the one-year mortality was highest in the valve and MAC group. Now, when it comes to clinical practice and deciding candidacy for trans-catheter repair or replacement, the complex pathophysiology of mitral valve disease plays a huge role. Functional mitral regurgitation may pose a heterogeneous anatomical spectrum that may be difficult to treat with current trans-catheter repair devices. This is exemplified from the fact that proportionate mitral regurgitation with severely dilated left ventricles as we discussed, severely increased LDEDV may not benefit much from edge-to-edge repair strategies as compared to medical therapy. And in these cases, if a trans-catheter intervention is needed, then a TMVR device may be able to negate this heterogenicity and target numerous anatomical variations. Now, other cases where TMVR may be beneficial compared to tier or repair strategies are in patients that are at risk for resulting mitral valve stenosis from an edge-to-edge repair or in patients in whom there is a risk for inadequate reduction of mitral regurgitation expected or in patients who have anatomic or imaging challenges for an edge-to-edge repair and also in patients for whom a tier would be futile because of cardiac or non-cardiac complications. Further, the long-term durability of trans-catheter repair remains unknown. Now, the TMVR may be the only option available in patients for use as valve and ring, valve and valve or valve and mac use, which is a sapien trans-catheter heart valve. Some of the advantages, the disadvantages of TMVR includes its large-profile delivery system, a near-complete obliteration of mitral regurgitation, which can cause increased afterload to an already compromised left ventricle, and also anatomic challenges such as left-integral outflow tract obstruction or appearance of an extremely large mitral annular diameter. Now, in a large recent prospective multi-center single-arm observational study called the X-Band study, they looked at suitability of patients who have been previously deemed a tier unsuitable based on some of these factors that we discussed, which is expected a minimal reduction in MR or anatomic challenges or risk of mitral valve stenosis. And they evaluated the use of mitral clip for severe mitral regurgitation in these rather tier-unsuitable patients. The primary effectiveness endpoint in these patients was MR reduction to less than two plus at 30 days. And the study revealed very significant findings that there was a high implantation success 96 to 99% and a significant 30-day reduction in functional class one or two at 30 days. Also, there was significant improvement in quality of life scores in these patients, thus concluding that transcatheter edge-to-edge repair can be successfully used even in complex anatomies and borderline unsuitable patients, but only when performed by experienced operators and high volume centers as a caveat. Overall, both edge-to-edge repair and replacement strategies continue to be growing. The median age for patients in both of these groups is somewhere between 75 and 80, and there's increasing incidence of frailty in these patients. The 30-day mortality rates overall in these patients are between 4.5% for edge-to-edge repair with a one-year mortality for TMVR dropping somewhere to about 20 to 22%. The minority representation in a lot of these trials and in the large-scale commercial youth studies is actually pretty good. For both, there's roughly about 80% white population, 9% to 11% black population and 5% to 7% Hispanic population representing a nationwide population pretty well. So the 30-day mortality rates as they are reducing over time, you see that there's decrease in complication and all-cause mortality from these devices. So in the near future, we're going to see continuous increased use of these devices. Now, tier versus surgery, we have a little evidence from two main studies as a large meta-analysis of about 21 edge-to-edge repair and 27 surgical mitral valve repair studies comparing over 3,000 patients in each group. The in-hospital mortality when you do a head-to-head comparison was significantly lower in the peer group at 3% compared to the surgical group at 5%, but the one-year mortality did not differ significantly between the two groups. The New York Heart Association reduction and the mitral regurgitation reduction both were comparable between the two cohorts. Now, this remains a meta-analysis. We don't have a big prospective randomized study. Interestingly, at a late-breaking session during the 2023 European Society of Cardiology Congress meeting last month in August 23 on Valver Heart Disease, they presented from France a nationwide analysis comparing the outcomes following mitral trans-catheter edge-to-edge repair with mitral valve surgery for patients with severe mitral regurgitation. Now, there were over 57,000 patients who underwent either a tier, isolated tier or isolated valve surgery and then their propensity matched, score matched these patients and post-matching there were roughly 2,000 patients in each group with a mean follow-up of about one year. Interestingly, both the two groups had similar incidents of all-cause mortality. However, cardiovascular deaths were significantly lower in the tier group. It was also interesting that when they looked at the analysis with patients who had a high Euro score of two, greater than four or advanced age, greater than 75 years, there was a lower all-cause mortality in the tier group concluding that perhaps tier may have benefit over surgical repair in patients who have more comorbidities, higher STS or Euro two scores or advanced age greater than 75 years. Now, there are some ongoing clinical trials. The most important one is a repair, mitral regurgitation trial is an openly able randomized study comparing a microclip and surgical repair for primary mitral regurgitation in older or moderate surgical risk patients. Now, the summit trial is also another ongoing trial with instances of three arms, examining treatment with 10-9 TMVR versus mitral clip in a one-to-one ratio, a non-randomized cohort with moderate or severe MR treated with the 10-9 TMVR valve and the third arm being the mitral end of calcification treated with the 10-9 TMVR. They are aiming to enroll about 1,000 patients with a one-year follow-up and the completion due date of 2026. So to summarize everything we just talked about, there is increasing prevalence of mitral regurgitation and untreated MR with increasing morbidity and mortality and there's a growing need for trans-catheter therapies, especially in advanced age and high surgical risk patients. In functional mitral regurgitation, there's complex and dynamic aspects which represent an interplay of the mitral valve apparatus in the left ventricle. Understanding this would help in clinical practice and deciding optimal therapy for our patients. Both edge-to-edge repair and trans-catheter valve replacement offer high procedural success and low complication rates in rather high surgical risk population with improving end points such as heart failure, readmissions, and quality of life. Also, the head-to-head comparison of repair versus replacement is still lacking. So the long-term durability data of both these devices is something that we will be looking forward to. Finally, patient selection for both repair and replacement strategies is critical. So what we understand is that the good quality imaging, the timing of intervention, and appropriate device selection are really important. Again, large-scale studies would be required to compare these different modalities in different patient cohorts. I hope you all learned from this talk. Thank you so much for giving me the opportunity.