Abstract 12082: 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, mutations of sarcomeric proteins and collagen accumulation. 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, 50 patients with obstructive HCM undergoing septal myectomy were studied, and 14 sex- and age-matched septa, collected from patients who died from non-cardiovascular causes were used as controls. Mutations of genes coding for contractile proteins were present in 34 cases of HCM. The majority of patients, 67%, were in NYHA class III and mean LV outflow tract gradient was 81 mmHg. Arrhythmic events consisting of atrial fibrillation and ventricular tachycardia were seen in 15 patients. In 11 cases, HCM was diagnosed in relatives as well. In comparison with control hearts, septal thickness increased 2-fold in HCM, from 12 to 25 mm. This difference in HCM was dictated by 38% increase in cell diameter, from 16 to 22 μm, and, most importantly, by 1.8-fold higher number of myocytes across the septum, from 520 to 939. The occurrence of myocyte regeneration was documented by the expression of the cell cycle proteins Ki67 and MCM5. With respect to controls, HCM hearts showed a 6.2-fold and 26-fold increase in the number of Ki67-positive and MCM5-positive myocytes, respectively. In contrast, apoptotic myocytes did not differ in HCM and non-diseased hearts. Fibrosis, measured as volume fraction of collagen type I and III, increased ~1.8-fold, while the volume fraction of cardiomyocytes decreased only by 5% in HCM septa. In the adult human heart, cardiomyogenesis is regulated by activation and commitment of c-kit-positive cardiac stem cells (CSCs). Consistently with the enhanced formation of myocytes detected in HCM hearts, the pool of CSCs was 3.3-fold larger in these patients. In conclusion, myocyte hyperplasia and hypertrophy contribute to septal thickening in HCM, indicating that the traditional view of the pathophysiology of this disease should be reconsidered.
- © 2012 by American Heart Association, Inc.