Congestive heart failure: role of cross-bridge cycle kinetics.

The fundamental role of the heart in the circulatory the animal studies that have shown depressed calcium system is to pump an amount of blood that is precisely responsiveness in experimental heart failure (7-10). matched to the requirements of the body's tissues for However, the ability to maintain contractile force at a adequate perfusion. This task must be accomplished with- given cytosolic calcium concentration is but one aspect of out interruption and under all conditions. Because of this, cardiac contractile function. In order to pump a volume of and under normal conditions, cardiac output is tightly blood under pressure, a total amount of energy equivalent controlled via a multitude of regulatory feedback systems to stroke work must be generated by the cardiac myofila- that operate with different time constants that range from ments in a process termed 'chemo-mechanical transduc- virtually instantaneous (heart rate, contractile state, venous tion', in which ATP hydrolysis by active cycling cross- capacitance), intermediate (fluid and salt retention) and bridges is converted into mechanical energy. The rate at long term (cardiac remodeling). Under pathological con- which energy is converted is reflected in the power- ditions when myocardial function is depressed, cardiac generating capacity of the heart (11). Both of these output is maintained by an increase in the regulatory parameters are fundamental properties of the sarcomere feedback signals. However, if myocardial function con- that are directly linked to the force-velocity relationship, tinues to decline, a point is ultimately reached at which as was demonstrated early in this century by the seminal cardiac output no longer increases upon an increase in the work of A.V. Hill (12). Although there is some debate as to feedback signals. At this point, all regulatory cardiovascu- the exact nature of the mechanical-energetic link in lar feedback control systems have been exhausted and the cardiac muscle (13), there is no doubt that cross-bridge clinical syndrome of heart failure ensues (1). cycling plays an integral role in determining the dynamic The symptoms of heart failure are due to the responses properties of the heart. of the peripheral cardiovascular system to reduced cardiac To date, however, only one study has been reported in pump function, yet the underlying cause of the syndrome which the dynamic mechanical properties of failing iso- lies in the depression of intrinsic myocardial function (2). lated human myocardium is compared to non-failing There have been numerous studies in the last decade aimed tissue. In work on skinned myocardium, Hajjar and at elucidating the mechanisms that underlie the cellular Gwathmey (14) found 40% reductions in the maximum contractile dysfunction that is seen in human heart failure unloaded shortening velocity and minimum dynamic stiff- (3). Collectively, these studies have shown, rather conclu- ness frequency. Both of these parameters are reflections of sively, that calcium homeostasis is altered in end-stage the intrinsic cross-bridge cycling rate. The report by Ruf et human heart failure. To determine whether myofilament al. (15) from the group of Holubarsch in Freiburg, in this function is affected, investigators have measured the issue of Cardiovascular Research , both confirms and relationship between isometric contractile force generation extends these observations to intact isolated myocardium and calcium concentration in intact or skinned isolated during a barium contracture. As in the work of Hajjar and human myocardium (4-6). Unfortunately, the results of Gwathmey (14), these investigators find a 40% reduction these studies have been inconsistent, showing either no in the cross-bridge cycling rate in failing human myocar- change or an increase in the myofibrillar calcium respon- dium, which suggests that alterations in the dynamic siveness. In addition, these studies contrast with some of properties of the cardiac sarcomere may play an important role in the development of human heart failure. *