HCM is a genetic disease which results in severe thickness of the walls of the heart. It has markedly variable clinical presentations, often disabling symptoms and is the most common cause of sudden death in otherwise healthy young individuals such as athletes. Only half of the genetic abnormalities have been identified and the natural history of most of these is not determined. We have characterized the clinical features of several large families in which HCM is caused by known disease mutations and by as yet unidentified genetic abnormalities. Missense mutations of the essential and regulatory light chains of the myosin have been associated with a distinct and rare cardiac morphology: excessive thickening of the heart muscle results in obstruction to blood flow in the mid portion of the left ventricle (LV). This mid-cavity obstructive HCM is associated with a high incidence of sudden death from arrhythmias. Skeletal biopsies have a shown that the is also skeletal muscle abnormality (red-ragged fibers). Cardiac hypertrophy varies significantly in HCM, even in affected individuals with an identical disease mutation. We determined the relation between ACE gene polymorphisms, plasma ACE levels and LV wall thickness in three large families in which HCM is caused by two benign beta-MHC gene mutations. The DD polymorphism was associated with significantly higher ACE levels and LV hypertrophy. This finding suggests that ACE inhibitors may play an important role in causing regression of the LV hypertrophy in HCM. A study is ongoing to examine the ability of DDD pacemakers to relieve LV outflow obstruction and to prevent obstruction and hypertrophy from developing in HCM children. At a 1-year follow up evaluation, this therapy has resulted in significant reductions obstruction to LV outflow in most of the children. We have also examined the long term (>4 years) results of DDD pacing in 15 adults. The patients continue to benefit symptomatically and hemodynamically. This novel therapy may obviate the need for cardiac surgery in most patients with obstructive HCM.
