Functional Imbalance Among Individual Cardiomyocytes Caused By Cell-To-Cell Variation In Mutant Mrna Expression. A Possible Trigger For Hypertrophic Cardiomyopathy

Familial hypertrophic cardiomyopathy (HCM) has been related to many different mutations in at least 20 different sarcomeric and some non-sarcomeric proteins. While development of the HCM phenotype is thought to be triggered by the respective mutation, a common mechanism has not yet been identified.We hypothesized that functional imbalance among individual cardiomyocytes, seen in our previous work on M. soleus fibers of patients with different β-MyHC missense mutations, may be due to cell-to-cell variation in expression of mutated myosin and may trigger development of the HCM-phenotype.We tested this hypothesis by recording force-pCa relations of individual cardiomyocytes and quantified expression of mutant β-MyHC mRNA in individual cardiomyocytes of myocardium of two HCM-patients with β-MyHC mutations R723G and A200V. For both mutations, cardiomyocytes showed a large cell-to-cell variation in Ca++-sensitivity with some cells being essentially indistinguishable from controls as if they had not expressed mutant β-MyHC while other cells had highly reduced Ca++-sensitivity suggesting substantial levels of mutant β-MyHC. Quantification of the fraction of mutant β-MyHC-mRNA in individual cardiomyocytes of both patients showed a wide spectrum from cardiomyocytes with essentially pure mutant β-MyHC-mRNA to cells with essentially pure wildtype β-MyHC-mRNA.This behavior could be modelled on the basis of random, independent, burst-like transcription of the mutant and wildtype alleles using known turnover rates of the β-MyHC-protein and β-MyHC-mRNA. We therefore propose that random, independent, burst-like transcription of mutant and wildtype alleles, via large cell-to-cell variation in mutant mRNA and related cell-to-cell functional variation, results in structural distortions (cellular/myofibrillar disarray). This may trigger altered cell signaling leading to interstitial fibrosis, another hallmark of the HCM phenotype. Such a mechanism may well act for other mutations in other proteins as well.