My task is to talk about novel approaches in managing patients with hypertrophic cardiomyopathy. Over decades, we have shifted our attention from focusing almost exclusively on sudden death prevention and arrhythmic risk to the most common complications of the disease, which are in fact, heart failure-related complications. The most common cause of hospitalization and mortality in this disease, as you can see from the SHaRe registry, is actually heart failure-related and atrial fibrillation-related.

Heart failure in HCM occurs in two different contexts. There's an initial hyper-contractual phase of the disease. It is associated with, as you can see here, systolic anterior motion of the mitral valve and left ventricular outflow obstruction. Whereas in the later phase of disease, the most unfortunate patient is associated with progressive fibrosis and refractory heart failure due to systolic and diastolic dysfunction, as you can see here on the right.

The real novelty, as you know by now, comes from the recent acquisition of a novel class of drugs that can be usefully employed, as for now, in obstructive hypertrophic cardiomyopathy. Studies are ongoing to understand whether we can also use it in non-obstructive disease. In the meantime, the new ESC guidelines on cardiomyopathies have been released containing for the first time an indication, a class IIa indication for mavacamten, which is the first-in-class myosin inhibitor to be used and considered in patients with symptomatic obstructive hypertrophic cardiomyopathy as a second line indication in patients who have failed to respond or cannot tolerate beta blockers, diltiazem or verapamil.

There are two, and as you can see here, recommendations here, both are IIa with a level of evidence A and B, which are respectively for the use of, again, mavacamten in association with first-line therapy with beta-blockers of calcium antagonists or even to be considered as monotherapy.

This is really quite a major advancement, particularly because the development of mavacamten is a real success story, starting from very good basic science highlighting the core mechanism of the myosin mutations and also of other genetic substrates, which ultimately lead to a hypercontractile phenotype and hyperpresentation of the active state of myosin, which is leading to excess contractivity, excess energy propagation, and a number of downstream consequences leading to anything from diastolic dysfunction to fibrosis. A specific molecular mechanism was adopted to, which is a small molecule in this case, mavacamten first-in-class binding to the myosin head, reducing the affinity of myosin for actin, and therefore, reverting the core mechanism of disease. This has been then shown to have very nice effects in animal models, so very strong preclinical evidence of disease modification, and even disease prevention in transgenic mice. This has finally translated in phase three clinical trials, which as for now, are limited to obstructive disease including EXPLORER and VALOR, which has both shown clear benefit in terms of symptomatic improvement, gradient reduction, and quality of life improvement. There's also studies ongoing on non-obstructive disease, hopefully soon to be released. What the drug does, what mavacamten does in patients with obstructive disease, as you can see summarized here, not only improvement in symptoms, but also clear signs of initial positive remodeling, left atrial reduction, improvement in diastolic function, and reduction in the main biomarkers, including NT-proBNP and troponin I release. Based on this evidence, the drug has been approved by the FDA in April 2022. This is a landmark date for HCM patients, the first ever approved drug specifically developed for this disease and followed by approval in many countries, including the European Commission in June 2023. '

The drug is a first-in-class so there is some justified caution in the implementation, which will require a scheme of serial evaluation of left ventricular function and titration along the way and serial checks, echocardiographic checks, which are necessary to make sure we ensure safety. However, the drug has shown excellent safety profile in the studies so far.

There's already an next-in-class, which is aficamten, is the drug that is very similar in concept, binds to a different site, but otherwise very similar in concept, shorter half-life, shallower dose response curve, and maybe less drug-drug interaction. This could be appealing as a runner up. There's very nice phase two studies already completed and phase three studies are ongoing. SEQUOIA study is actually ongoing on obstructive symptomatic obstructive HCM.

Let's look at the drug in action. This is a patient from EXPLORER, from Florence. You can see here the baseline evaluation. You can see the SAM, the hypercontractual left ventricle, the typical shape of the ventricle, of the outflow obstruction and the marked ECG abnormalities.

After 30 weeks of treatment, the heart doesn't look the same. You can see the SAM has vanished. You see the gradient is not there. Even the ECG has almost normalized. This is really quite intriguing to see, and the patients, of course, accordingly feel a lot better.

That the question arose during these studies, can we actually in fact have such a good result with these drugs that we may avoid or even delay? Or even avoid, sorry, the need for invasive septal reduction therapies including myectomy and alcohol ablation.

The EXPLORER trial says, it probably is the case because in patients who presented in the trial with clear indication a listing for myectomy, you can see that 82% of these patients were actually not eligible for the procedure at the end of the study, and 63% had improved at least an NYHA class at the end of the study. Very encouraging result.

This does not mean that we are not doing the surgery anymore. In fact, very recently, this report has shown that very promising approach with transapical myectomy that can be performed with minimal invasiveness in a beating heart. This could definitely lead to expanding our indications here.

There always will be problems with surgery and alcohol ablation, and many of the challenges are well known, including operational dependency and the lack of widespread expertise. However, the main mutation is that we are not addressing the pathophysiology of myocardial diseases because surgery obviously does not address the myocardial level of things, the molecular level of things such as myosin inhibitors does.

This leaves us with the last part of my brief presentation is what do we do with a patient with non-obstructive disease that undergo the other kind of heart failure in this patient? That is progressive heart failure associated with fibrosis. Of course, do we treat these patients with what we would normally use in a heart failure patient? There is promise from recent advances. For example, the use of SGLT2 inhibitors and ARNI may definitely help in case where there's clear systolic dysfunctional or in case where there's clear signs or evidence of congestion and heart failure. That is generally not completely sufficient in patients with hypertrophic cardiomyopathy, particularly in terms of progression of disease prevention. Whereas, again, myosin inhibitors there can make a difference.

There are a number of mechanism by which myosin inhibition by reducing calcium sensitivity and calcium overload and other mechanisms may actually improve diastolic function. I don't have time to go into details here, but suffice it to say that in the animal model, for example, fibrotic pathways associated with hypertrophic cardiomyopathy are very powerfully suppressed by mavacamten. I think that there is hope, even for patients who have the non-obstructive physiology, and if studies ongoing will prove successful, then we will keep climbing in this steep ladder that we have started climbing many years ago now and that has been so successful so far.

As you can see, what we know now about myosin inhibitors is that they can definitely reduce obstruction, they can definitely avoid or postpone the need for surgery in obstructive patients, promote advantageous cardiac remodeling. There are many things we still don't know about these drugs, including the very long-term safety, including whether we can use it in non-obstructive disease, including whether we can use it to improve outcomes because we don't have outcome studies. They are really challenging to do and will take time and whether we can reduce arrhythmic risk with it and maybe even prevent disease progression, produce development in individuals who are gene carriers. Last but not least, whether we can use the experience and the knowledge from gain from HCM to benefit other patients with other conditions, including certain slices, certain portions of patients with hypercontractile HFpEF. With this, I thank you for your attention.

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