Sarcomeric cardiomyopathies: from bedside to bench and back

Sarcomeric cardiomyopathies represent a perfect example of the power of translation and clinic/research interactions: The question arises from the clinical phenotype of the patient (signs and symptoms), basic laboratory research identifies molecular and cellular aspects of the phenotype and develops diagnostics and treatment strategies for the patient. In clinical terms, 25 years ago patients with unexplained left ventricular hypertrophy suffering from dyspnoea and potentially life-threatening arrhythmias were observed, since then underlying genetic mutations and molecular mechanisms have been identified, which already have helped to understand the disease and diagnose the patients, and nowadays molecular treatment options are on the way. The cycle from bedside to bench and back is ongoing. What are sarcomeric cardiomyopathies? As implied by the name, these cardiomyopathies are caused by mutations in a number of sarcomeric genes. The prototype is hypertrophic cardiomyopathy (HCM), which is clinically defined by the presence of increased left ventricular wall thickness that is not solely explained by abnormal loading conditions.1 The frequency of unexplained left ventricular thickness ranges from 0.02 to 0.23% in adults or up to 1:500.2 Patterns of hypertrophy show great variations from patient to patient including hypertrophic obstruction of the left ventricular outflow tract. In fact, outflow tract obstruction occurs in one-third of patients with hypertrophic cardiomyopathy (HOCM; hypertrophic obstructive cardiomyopathy).3 Early stages of the disease show normal left ventricular ejection fraction with diastolic dysfunction. In later stages, ejection fraction may decline and both diastolic and systolic dysfunction may occur. Many patients are clinically asymptomatic. If symptoms occur, they may include dyspnoea, a reduced exercise capacity, chest pain, arrhythmias, and syncope. The most severe form of arrhythmias is sudden cardiac death. In fact, hypertrophic cardiomyopathy is the most frequent cause of sudden cardiac death in young athletes. The first gene identified to be linked to hypertrophic cardiomyopathy was β-cardiac myosin heavy chain gene mutation.4,5 According to current knowledge, in up to 60% of patients with HCM, the disease is an autosomal-dominant trait caused by mutations in cardiac sarcomeric protein genes.1 Therefore, the terms sarcomeric cardiomyopathy and hypertrophic cardiomyopathy have been used synonymously. However, this is inaccurate and superficial because, on the one hand, in hypertrophic cardiomyopathy 10% of mutations are located in genes of non-sarcomeric proteins, and in 25–30% disease cause is unknown. On the other hand, mutation in sarcomeric genes can also cause dilated cardiomyopathy, restrictive cardiomyopathy, and ventricular non-compaction.1 In a number of cases, a sporadic mutation without family history is identified. The present technical revolution in genetic and epigenetic analysis continuously and rapidly increases our understanding of the disease and enables the development of new therapeutic strategies. These most recent scientific progress triggered the generation of the present exciting spotlight of ‘Sarcomeric cardiomyopathies: from bedside to bench and back’. As is pointed out by Olivotto et al.6 despite tremendous progress in genetic analyses, dedicated studies have so far failed to establish clear relationships between specific sarcomeric genes, phenotype and outcome. Therefore, in current guidelines genetic analysis is mainly recommended for genotype-directed family evaluation. Ho et al.7 addresses molecular mechanisms underlying the important question, why penetrance varies considerably from patient to patient, including multiple gene mutations in sarcomeric genes, epigenetic and environmental factors. They speculate how next-generation sequencing and a multidisciplinary approach of cardiologist, geneticists, and bio-mathematicians will dramatically influence diagnostics and treatment of sarcomeric cardiomyopathy within the near future. This may be supported by computational, quantitative biology based on the development of comprehensive, biologically complex models which incorporate structural and functional information across multiple experimental levels. This in silico approach is discussed by Duncker et al.8 Significant potential for a better understanding for sarcomeric cardiomyopathies, and genetic diseases in general, is also expected from research in patient-derived induced pluripotent stem cells (hiPSCs). Cardiomyocytes generated from hiPSCs carry the genotype of the donor. Comparison of affected and non-affected family members carrying the mutation with mutation-negative family members and ideally with cells after correction of the putative mutation with gene-editing approaches holds great promise to study pathophysiology in great detail. Eschenhagen et al.9 review these fascinating possibilities. They explained generation of these cells, potential for disease modelling, risk prediction, drug testing, and prediction of cardiac toxicity. They define promises, quality control measures, and discuss limitations. By reviewing previous studies on hiPSCs models of sarcomeric cardiomyopathies and other experimental data, they emphasize that energetic and calcium cycling disturbances may be main pathophysiological mechanism underlying hypertrophic cardiomyopathies due to sarcomeric mutations. In this direction, Tardiff et al.10 discuss experimental evidence that increased Ca2+ sensitivity may be a common factor in HCM due to sarcomeric gene mutations. Therefore, Ca2+ desensitizers may reflect a more causal type of therapy. Ca2+ desensitation would deactivate contractile proteins during diastole and thereby improve diastolic dysfunction which is an important mechanism for symptoms in patients with HCM. This approach seems of particular interest, because increased Ca2+ sensitivity by increasing contractile force and energy consumption without increasing Ca2+-dependent mitochondrial respiration may be a major mechanism for energetic disturbance in HCM. Ca2+ desensitation would therefore improve both diastolic dysfunction and energy lack.11 Another interesting finding is increased late sodium current activity, which results in sodium overload, and through reversed sodium–calcium exchange results in myocyte calcium overload. The latter would activate calcium-calmodulin-dependent kinase (CaMK). Since CaMK phosphorylates and activates late sodium current, this may result in a vicious cycle. Accordingly, the late sodium-channel blocker drug, ranolazine, which is approved for the treatment of coronary heart disease, is under clinical investigation in patients with HCM. Application of ranolazine during cardiac catheterization has recently been shown to improve diastolic function in patients with heart failure with normal ejection fraction.12 These novel therapeutic strategies are discussed by Tardiff et al.10 Finally, potential new research priorities are discussed by van der Velden et al.13 These include innovative clinical trials as well as experimental studies from gene expression analysis to posttranslational modification.