The failing human heart

Heart failure remains a significant public health problem with an unacceptably high morbidity and mortality affecting about three persons per thousand per year [1]. The percent survival following diagnosis decreases significantly as a function of the severity of the disease with survival rates for NYHA (New York Heart Association) I–II being 65% at the end of 4 years, for NYHA III it is 50% at the 4-year period and for NYHA IV it is 50% after only 1 year [2,3],1. In the patients with heart failure, there is a significant correlation between survivability and ejection fraction [4]. The deficits in ventricular function in failing human hearts led us to examine the contributions of the contractile (acto–myosin interaction) and excitation–contraction–coupling (EC) (calcium cycling) systems to that insufficiency. ### 2.1 Myofibrillar ATPase activity and velocity of shortening The first demonstration of a molecular alteration in the contractile system of human failing hearts was found in studies carried out on myofibrils from failing hearts (secondary to hypertensive heart disease) and non failing hearts (accident victims) [5]. The myofibrillar ATPase activity in the failing human hearts was reduced from non failing values (mean±S.D.)2 of 0.99±0.05 to 0.69±0.04 μmole Pi/mg myofibrillar protein/15 min ( P <0.001). The functional consequences of the depressed ATPase activity were not completely clear at the time these experiments were carried out although we believed the depressed activity was associated with a decrease in contractility of the heart muscle. This view was supported by a decrease in the contractility of actomyosin strands [6] and glycerinated fibers [7] from failing heart muscle. From the perspective of ventricular function, the decreased contractility involves contractile force, velocity of shortening or a combination of the two. The relationship between force and velocity of shortening was thoroughly described by Hill [8] where the hyperbolic relationship was believed to be … * Corresponding author. Fax: +1-807-656-747