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Advances in DNA sequencing technology have exposed the immense genetical diversity that underlies hypertrophic cardiomyopathy (HCM), with >1000 individual mutations in sarcomeric and sarcomere-related genes being implicated as causal, often specific (or ‘private’) to individual families. And while each of these mutations leads to the common phenotype of LV hypertrophy, the effect of these mutations on cardiac performance, at the myocyte (eg, actin-myosin crossbridge kinetics and calcium sensitivity) and myocardial (eg, mechanical properties of the extracellular matrix) levels, is quite varied.
Exercise limitation in patients with HCM is frequent, but the mechanisms responsible for this limitation in individual patients are often multifactorial and clinically opaque. The presence of LV outflow tract obstruction (LVOTO), either at rest or during exercise, is a principle cause of symptoms that is present in up to 70% of patients with HCM, and the reduction of LVOTO through pharmacological or procedural means has become the mainstay of HCM therapy.1 However, the relationship between the severity of LVOTO and the symptoms is complex and some patients with severe obstruction remain curiously asymptomatic.
As a converse, patients with non-obstructive HCM often have severe symptoms despite apparently ‘normal’ systolic function, and it has been challenging to identify the exact mechanisms responsible for this limitation. HCM results in LV hypertrophy, small LV end-diastolic volumes, altered intracellular calcium dynamics, increased extracellular collagen deposition and replacement fibrosis, and decreased LV compliance. Each of these processes occurs to varying degrees in patients with HCM, and likely contributes to varying degrees to exercise limitation.
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