Welcome to this symposium on hypertrophic cardiomyopathy, and we will try to unhide all hidden aspects of this disease.

Let's start from the basics. Hypertrophic cardiomyopathy is a thick heart, hypertrophied heart. According to the scientific definition, what is hypertrophied in this heart, what is thick is the myocytes, the cells. We expect to see hypertrophied cells, and we also expect to see scar tissue between the cells, fibrosis, and we also expect to see loss of the myocyte architecture, which we call disarray. This is when the cells are not aligned anymore, and they lose their normal structure. On top of these, and additionally, we sometimes see microvascular ischemia, which has a number of different mechanisms. Although these are common markers, common features of hypertrophic cardiomyopathy, we don't always see them together, and we don't see them in the whole heart, they can affect different areas of the heart, and therefore we may not be able to identify them in certain parts of the heart.

Since hypertrophic cardiomyopathy is associated with hypertrophied cells, it is important that we discriminate it from other conditions that appear with a thick heart, but the cells are not hypertrophied, and the thickness and the appearance of the thick heart is because of deposits. Deposits can be lipids, such as in Fabry disease, or amyloid, such as in amyloidosis. It's important that we diagnose and discriminate those conditions early because they have different prognosis, different pattern of inheritance in the family, but also, they have different treatment. Nowadays, these conditions can be treated, can be stabilized, and sometimes reversed if we diagnose them early, so it's very important that the diagnosis happens timely. Hypertension is followed by question marks because hypertension has historically been one of the conditions that we need to eliminate from the diagnostic list before we diagnose hypertrophic cardiomyopathy. In hypertensive patients, we do see a degree of hypertrophy. Nowadays, although hypertrophic cardiomyopathy is a separate disease, we believe that hypertension sometimes can play a role in the development of hypertrophic cardiomyopathy, and therefore the two are studied very carefully together, although they're separate diseases.

The etiology of hypertrophic cardiomyopathy at a genetic level is usually associated with the sarcomeric genes, the genes that encode information for the sarcomeric proteins, and follows an autosomal dominant pattern of inheritance. The commonest genes which are affected in hypertrophic cardiomyopathy are the myosin heavy chain and the myosin-binding protein C gene. The genetic testing has a number of challenges. Patients often present with mutations, DNA changes, which have not been observed elsewhere. We call them private mutations. These are difficult to study because we don't have data on how they will behave in the future, what clinical conditions they will produce. When we send a DNA sample to the lab, we expect the lab to identify a pathogenic change in the DNA. This means that the change in the DNA can be safely associated with the clinical condition, and is expected to cause the same condition in all people who carry it. However, we often get from the lab, the result which is a VUS, which means Variant of Unknown Significance, and it's self-explanatory. It means that the DNA change cannot safely be associated with the clinical condition. Although it may not be benign, equally, it cannot be confirmed that it is pathogenic. When we are in this situation, we need to study both the genetic change and the family in more depth and possibly follow both in the future because sometimes the classification of the VUS changes and they become either benign or pathogenic. Until we have a new classification, the VUS is a result from the lab that is not actionable. We cannot do anything with that. Another complex issue is that the changes in the DNA in hypertrophic cardiomyopathy have incomplete penetrance, so they don't give the full phenotype in all patients, and this variability can exist also within the same family. Therefore the study of both the genetic change in the family and the clinical expression in the same family, as well as in other families who have similar genetic change is both challenging and very helpful, and we have to do it when we are uncertain about the genetic result. When there is history of hypertrophic cardiomyopathy in the family, then the possibility of getting back a positive genetic result, a genetic result which is pathogenic, is higher, which means that we are in the right direction. When we confirm pathogenicity in one genetic change, in one mutation, then it does affect and cause the condition in more people in the same family.

How does the genetic change translate to the clinical condition? Obviously, it's a very long pathway. Since there are multiple genes involved and multiple mutations, it's not a straight line. The starting points can be different, but what happens, in a very short summary, is that the protein produced is either not good quality or it is produced at low levels. This is not only because it is not translated, the DNA change, but it's also because the body itself rejects the proteins which are not of good quality, and therefore the overall volume of them is reduced. In the cell, in the myocardial cell, what happens is that the actin and the myosin are bound together more firmly than what they should, and sometimes the unbinding is problematic and doesn't happen. The metabolism of the calcium is affected and this complicates this binding of actin and myosin even more, and at the end, the metabolism of the cell is more demanding. This triggers a number of pathways, some of them are gene-specific, others are nonspecific to the gene, which at the end cause hypertrophy.Many other factors play a role in this long journey, epigenetic factors, post-translational protein modifications, factors from the environment, and we are looking also into modifier genes which means that some other genes may play a role in the expression of the responsible gene and they can either enhance or reduce the expression of the main gene, causing more or less severe clinical condition.

When the patient comes to our clinic, though, all this information is in the background. What the patient is expecting from us to look at is three main domains. One is the risk of complications, and usually what is in people's mind is the risk of sudden death. It's a real risk, it does happen in some patients with hypertrophic cardiomyopathy, but fortunately, it's a low risk. The second question that the patients have is their symptoms. This is an interesting question because there are patients who don't experience any symptoms despite the diagnosis, there are patients who experience mild symptoms, and there are patients who experience quite significant symptoms which can be debilitating. The challenges here are quite few. The two main challenges are that these symptoms are quite dynamic and the patients typically describe good and bad days, good and bad periods, and therefore to get a full and holistic understanding of their symptoms needs a lot of work. The other challenge is that patients suffer from this chronic disease, and over the time they adapt their physical activities and their lifestyle to the symptoms in order to prevent them. Of course, that's the right thing to do. However, this gives us possibly a false impression of mild symptoms or sometimes nonexistent symptoms because the patients are not doing many physical activities and they have given up a number of hobbies and other activities that would have caused symptoms. Finally, we need to look at the family and consider the genetic testing, which we have discussed, but also the screening of the family members in order to diagnose them early and to make sure that they don't have risks.

Assessing the heart with hypertrophic cardiomyopathy is not very different than assessing any other heart at the beginning. However, the individual morphology and anatomy of this heart poses a number of challenges here as well. When assessing the systolic function, we usually look at the ejection fraction, which is sometimes incorrect because of the hypertrophy and the small end-diastolic volumes and overestimates the systolic function. End-diastolic function is always difficult to assess in these patients because it's multiparametric, and in probably 70% of these patients, we can detect left ventricular outflow tract obstruction which is responsible for their symptoms. This is the obstruction of the outflow of the left ventricle during systole. It's a very dynamic event, and to this, contribute the hypertrophied interventricular septum, the abnormalities of the mitral valve, the position in the left ventricle of the papillary muscles, the angulation of the interventricular septum, the contractility of the heart, the loading conditions, and many other factors which are not listed here. Essentially, this is a pathology of the whole left ventricle and not of the left ventricular outflow tract, or of the hypertrophied septum. The very detailed study of this can assist, can help us make the correct diagnosis and treat it in an appropriate way. Some patients, though, do not have obstruction in the left ventricle. When this is our impression, we need to confirm it with a number of tests and provocation tests, and if all these tests suggest that there is no obstruction, then we need to start looking at the heart muscle and how the heart muscle's stiffness contributes to the symptoms of these patients. For both obstructive and non-obstructive hypertrophic cardiomyopathy, in an ideal situation, we would like to use specific treatment and specific drugs. However, we don't have those. For many years, we have been using nonspecific treatment, treatment that has been developed for other cardiac conditions and has been used in hypertrophic cardiomyopathy, hoping that it will help these patients. The commonest medication used here is the beta blocker which have a negative inotropic effect. A small number of these patients will end up with heart failure and reduced systolic function, and then maybe invasive and advanced options and escalation of the management are necessary, such as transplantation.

From this presentation, I think a number of points can be identified as action points, and one of them is the early and accurate diagnosis of the hypertrophic cardiomyopathy and the discrimination from other causes of a thick heart. The recertification is an ongoing challenge, which will be massively helped by big data and artificial intelligence. In terms of assessing the patient's clinical condition, we need to focus on the real life symptoms and try to evaluate them in a way that will give us useful information about who needs treatment, when, and what type of treatment. This treatment needs to be more efficient, needs to be disease-specific, it needs to address the problems which cause symptoms in hypertrophic cardiomyopathy in obstructive and non-obstructive. In an ideal situation, again, knowing now the root cause of this condition, we should be able to modify the condition or even prevent it from expressing altogether.

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