My name is Perry Elliott. I'm a professor of cardiovascular medicine at University College in London and St. Bartholomew's Hospital. It's a great pleasure to talk to you today about hypertrophic cardiomyopathy, and in particular, how we understand this condition.
At one level, this is relatively straightforward. I think most cardiologists would recognize this kind of image showing disproportionate thickening of the interventricular septum, the hallmark of this condition. Indeed, left ventricular hypertrophy has been recognized as an entity for hundreds of years, going back to William Harvey through Laënnec, who actually used the term hypertrophy for the first time, clinicians in the 19th century such as Vulpian in Paris. Then the first pathological description of the disease in the 1950s by Donald Teare, who described the characteristic hypertrophy, disarray of the myocytes, fibrosis, and mitral valve abnormalities. His description really remains our pathological paradigm of hypertrophy, disordered myocyte arrangement with areas of increased connective tissue and fibrosis, and also small vessel disease, where we see thickening of the small vessels within the myocardium. Our contemporary diagnostic criteria are really quite simple. When we see thickening of the myocardium in an adult 1.5 centimeters or more, which is not explained by abnormal loading conditions, which in everyday clinical practice translates into either aortic valve disease or hypertension, that is sufficient to make the diagnosis of hypertrophic cardiomyopathy. Since Donald Teare's first description, we obviously now have sophisticated cardiac imaging, which shows us, as you can see here, the typical asymmetric pattern. We've also recognized that really any pattern of hypertrophy is consistent with this diagnosis. Here you see a pattern that we see maybe in about 10% of patients showing hypertrophy confined to the left ventricular apex. Here on these still images, you see other patterns where we see hypertrophy in the mid ventricle causing obstruction. We see hypertrophy of both ventricles and we see the consequences of disease progression into the so-called burnt out phase, where we see loss of hypertrophy and progressive myocardial fibrosis. Another key feature that you will hear about in the treatment section of this presentation is left ventricular outflow tract obstruction. Here, if you look at the echo in the top left, you see this curious characteristic movement of the mitral valve moving anteriorly and systole and making contact with the interventricular septum and causing obstruction to the left ventricular outflow. This is something that we see in maybe 75% of symptomatic patients, either present at rest or only when we perform provocation maneuvers such as the Valsalva maneuver. It was recognized for decades that hypertrophic cardiomyopathy can be a familial disease. The real breakthrough in understanding the pathophysiology of this disease happened in the late 1980s with the discovery of a mutation in a gene called myosin-7 or myosin heavy chain. This is one of the key components of the cardiac sarcomere and accounts for maybe about 20% of disease. Since that first description, mutations have been described in all of the major genes that encode the protein complexes that make up the sarcomere of the thick, the thin filament, and its associated proteins. Despite those discoveries, however, we only identify such a genetic variant in maybe about 40% or 50% of individuals. What you see in this cartoon, taken from the 2014 Hypertrophic Cardiomyopathy Guidelines is a broad description of the other diseases that may present to clinicians as apparently unexplained hypertrophy. Some of these conditions are genuinely very rare and affect particular age groups. Some of them are actually relatively common if we look for them, for example, cardiac amyloidosis in older patients. This paradigm of hypertrophic cardiomyopathy as being a description for which there are many etiologies, is a core component of the latest ESC guidelines for cardiomyopathy published at the European Society of Cardiology Congress. The basic definition of any cardiomyopathy remains the same. It's a myocardial abnormality, which is not explained by abnormal loading conditions or coronary disease. Then the clinical approach should move beyond that initial description and integrate the context, particularly in relation to family history, other key signs and symptoms which may point you towards a particular etiology of either a disease confined to the myocardium or systemic disease. We also recognize that the genetics of this disease can be complex. We see patients who have a variant in a gene which expresses itself consistently within a family in a classic Mendelian autosomal dominant fashion. More typically, we see a genetic predisposition and increasingly recognize that genetic predisposition may be complex and relate to multiple variants that are relatively common in the population. The future is very much driven by the etiology of hypertrophic cardiomyopathy because we're now entering an era in which we can actually target specific etiologies, whether that be through small molecules, nucleic acid therapies, or potentially even genetic therapy. Thank you very much for your attention.
