Cell-to-Cell Imbalance in Gene Expression and Contraction Force as Trigger for Disease Phenotype Development
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- allelic imbalance
- contractile protein
- heart failure
- myosin heavy chains
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease with an incidence of about 1 in 500 individuals.1 It is characterized by asymmetrical hypertrophy of the left ventricle in the absence of other causes for hypertrophy. HCM can vary from essentially asymptomatic to highly malignant up to end-stage heart failure or cause life-threatening arrhythmias with sudden cardiac death particularly in young adults. In most familial HCM cases, heterozygous mutations in sarcomeric proteins have been identified as underlying cause. About one third of the patients are heterozygous for mutations in the β-cardiac myosin heavy chain gene MYH7, another third in cardiac myosin-binding protein C (cMyBPC).2 Few mutations were found in nonsarcomeric proteins. Cardiomyocyte and myofibrillar disarray with interstitial fibrosis and hypertrophy are hallmarks of HCM.3 The degree of myocardial disarray correlates with risk factors for sudden cardiac death,4 and it was suggested that myocyte disarray directly results from functional changes induced by the HCM-related mutations at the sarcomeric level.5
From studies mostly based on animal models or recombinant contractile proteins, it was postulated that HCM-associated mutations generally enhance contractility of the myocardium, whereas mutations with reduced contractility would lead to dilated cardiomyopathy.6–8 Accordingly, the different HCM mutations are thought to lead to the HCM phenotype by increasing calcium sensitivity, contractility, and ATPase activity of the cardiomyocytes.5 Results from our group and others, however, were inconsistent with this hypothesis. Instead, contractility and calcium sensitivity can be enhanced or decreased in HCM.6,9–12 Thus, it is still unclear what triggers development of HCM. On the other hand, trials with new therapeutic approaches for HCM would greatly benefit from detailed knowledge of the disease-causing mechanisms.
Here, we propose an entirely new concept of how different mutations in sarcomeric proteins may lead …