Revealing the Cellular Basis of Heart Failure

It is a sobering fact that 25 centuries after the first recorded description of heart failure we are just beginning to understand the cellular and biophysical changes that underlie this condition. Clearly, physiology does not reveal herself easily. Roughly 2500 years ago Hippocrates was able to give a detailed account of the signs and symptoms of heart failure (HF) including the peripheral edema that accompanies this pathology (1). Currently physiologists and clinicians rely on a definition of heart failure of the type proposed by Eugene Braunwald (2) as ‘‘a pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues’’. What therefore are the cellular mechanisms that lead to this condition? Different types of heart failure have been described and these depend onwhich portion of the contraction-relaxation cycle (duty cycle) is affected. Systolic HF is often accompanied by a permanent reduction in sarcoplasmic reticular (SR) Ca content. How and why this decline takes place is extremely important as it underlies the loss in contractility and therefore cardiac pump function that defines HF. Using a pacing-induced canine model of HF, Belevych et al. (3) report some results in this edition of the Biophysical Journal that go far toward answering these questions. It is particularly notable that these authors are able to provide data that suggest that decreased SR Ca content in HF is due to a single cause: an increased SR Ca leak. This is a significant departure from other explanations, which, for example, suggest that it is due to impaired SERCA 2 activity or increased Na-Ca exchanger (NCX) activity, e.g., Schwinger et al. (4) and Hasenfuss et al. (5). In addition, the authors suggest that the leak could contribute to the slowed kinetics of the cytosolic Ca transients in HF myocytes. This is usually explained by reduced SERCA or increased NCX activity. Before discussing their data, a brief mention of some key aspects of cardiac excitationcontraction coupling may be helpful. The SR is an intracellular store of Ca that is periodically released to activate contraction. Release takes place through clusters of large Ca channels or Ryanodine receptors (RyRs) in the SR membrane. Release is activated when small quantities of Ca pass through voltage-gated Ca channels in the sarcolemma, which in turn gate the RyRs to which they are closely apposed. When RyRs are gated they release much larger quantities of Ca from the SR. Ca that initially entered the cell and gated the RyRs during each duty cycle is extruded by the NCX. Released Ca is resequestered by an SR membrane bound Ca pump. It is important to appreciate that during steady-state contractions two conditions must hold. The first is that during each duty cycle the total SR Ca released must equal the subsequent Ca uptake by the SR. Second, total Ca efflux must balance total Ca influx across the cell membrane within the duty cycle. The difficulty in explaining why SR Ca content is reduced in heart failure is partly due to the difficulty of explaining mechanisms that can overcome powerful homeostatic processes proposed by Eisner et al. (6) that maintain a stable SR content, but nevertheless leave some regulatory capacity. However, we shall see that the proposals of Eisner et al. (6) are consistent with a new setpoint for the SR content. Moreover, because excitation-contraction coupling is complex, difficult measurements are required to dissect the cellular mechanisms that underlie HF. To appreciate how SR Ca content can be reduced it is helpful to consider the following equations together with some assumptions that, as we shall see, Belevych et al. (3) completely justify with their findings. Here we derive simple equations that relate release flux to parameters associated with SR functions that are likely to control it. The Ca release flux through unit area of the SR is given by the equation JSR 1⁄4 nPoPRyR1⁄2Ca SR: (1) JSR is the flux through unit area of the SR membrane, n is the number of RyRs, Po is the open probability of a single RyR, PRyR is the permeability coefficient for the flux through a single RyR, and [Ca]SR is the SR Ca concentration. The term PRyR [Ca]SR is the unitary flux through a single RyR and it produces a unitary current iRyR. We assume that no voltage exists across the SR membrane. A straightforward extension of Eq. 1 is