Abstract 50: Cardiomyogenesis in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most prevalent heritable cardiovascular disease and the leading cause of sudden death in young adults. HCM is characterized by regional ventricular hypertrophy in the absence of cavitary dilation. Myofibrillar disarray associated with mutations of sarcomeric proteins and collagen accumulation are considered major determinants of the disease phenotype. Septal hypertrophy has been viewed as the result of an increase in size of preexisting myocytes, but whether myocyte formation contributes to septal thickening has never been determined. Thus, 29 patients with HCM undergoing septal myectomy were studied, and 10 sex-, age-matched septa, collected from patients who died from causes other than cardiovascular diseases, were used as controls. Mutations of genes coding for contractile proteins were present in all cases of HCM; 79% of patients were in NYHA class III, 17% in class II, and 4% in class IV. Arrhythmic events consisting of atrial fibrillation and ventricular tachycardia were found in 11 patients. In 8 cases, HCM was diagnosed in family members as well. Septal thickness is the product of myocyte diameter and the number of myocyte across the septum. The thickness of the septum increased 2.3-fold in HCM (Controls: 11±1 mm; HCM: 25±8 mm, p<0.001). Septal thickening in HCM was mediated by a 69% increase in myocyte number (Controls: 722±120; HCM: 1,217±375, p<0.001) and a 31% increase in cell diameter (Controls: 16±3 λm; HCM: 21±4 λm, p<0.001). Myocyte regeneration was confirmed by the expression of the cell cycle protein, Ki67. The number of Ki67-positive myocyte nuclei increased 15-fold in HCM (Controls: 400 myocytes/106 cells; HCM: 6,000 myocytes/106 cells, p<0.001). In humans, myocyte formation is regulated by commitment of resident c-kit-positive cardiac stem cells (CSCs). In comparison with control hearts, the number of CSCs increased 2.7-fold in patients with HCM (Controls: 11±5 cells/mm3; HCM: 30±17 cells/mm3, p<0.01). Additionally, the expression of contractile proteins was detected in differentiating CSCs. In conclusion, myocyte regeneration and hypertrophy contribute to septal thickening in HCM and newly formed myocytes originate from growth activation and lineage specification of resident CSCs.