Chaotic Behavior of Myocardial Cells: Possible Implications Regarding the Pathophysiology of Heart Failure

CHAOTIC BEHAVIOR OF MYOCARDIAL CELLS: POSSIBLE IMPLICATIONS REGARDING THE PATHOPHYSIOLOGY OF HEART FAILURE EDWARD G. LAKATTA* Efficient Cardiac Pump Function Requires an Ordered Response of Individual Myocytes The heart is a machine designed to pump blood; its duty cycle is the heartbeat. At the cellular level, the essence of a heartbeat is a Ca2+ oscillation (fig. IA): sarcolemmal membrane depolarization (action potential ) leads to a transient increase (oscillation) of cytosolic [Ca2+] that causes a transient stiffening and displacement of the contractile filaments leading to cell shortening; subsequent reduction of the cytosolic [Ca2+] permits relaxation of the myofilaments and cell relengthening . A fair degree of order among cells is required for normal pump function, that is, effective ejection of blood by the pump and its efficient filling between cycles require that the Ca2+ oscillations that underlie the heartbeat occur and subside uniformly within each cell and relatively synchronously among cells. Recent experimental results and their interpretation have led to a hypothesis of how a single type of disorder among myocardial cells can produce the trilogy of common manifestations of heart failure that results from a variety ofetiologies, that is, abnormal diastolic tonus, limited systolic function, and a high probability that arrythmias will occur. This disorder is a spontaneous Ca2+ oscillation that occurs locally within and asynchronously among cells constituting the myocardium. Cardiac "CaOs" The rapid increase in cytosolic [Ca2+] triggered by an action potential (fig. IA) is due to the rapid release ofCa2+ from an intracellular storage ?Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224. Copyright is not claimed for this article. Perspectives in Biology and Medicine, 32, 3 ¦ Spring 1989 \ 42 1 DEPOLARIZATION INDUCED Ca** RELEASE»MYOFILAMENTS SAHCOPUSMIC RETICULUM *n Y IPUSMIC¦ CULUM¦ SPONTANEOUS Ca" RELEASE FORCE \ DISPLACEMENT^ *SARC0LEMMA /V0LTAGE\ ^CURRENT^ 0.5 s« SARCOPLASMIC RETICULUM I FORCE \ MYOFILAMENTS^,¡¡PLACEMENT,) sarcolemma(™|¡^) s h Fig. 1.—A, The normal heartbeat at the cellular level. Simultaneous recordings of cytosolic [Ca2+ ] measured by Indo 1 fluorescence 410/490 nm (top trace), cell length measured via a photodiode array (middle trace), and transmembrane action potential, measured via a patch pipette (lower trace) in a single isolated rat ventricular myocyte in response to field stimulation [I]. B, Top, Action potential induces Ca2+ release from the SR via Ca2+-induced Ca8+ release. Ca2+ interacts with myofilaments binding sites to cause a contraction and with sarcolemmal binding sites to produce inward current (see text for details). SR is both a source and sink for the cytosolic [Ca2 +], i.e., it is a "Ca2+ oscillator." (In addition to triggering the release OfCa2+ from SR, the Ca2+ current activated during the action potential places a Ca2+ load on the cell and SR). In the steady state, this Ca2+ loading is balanced by other sarcolemmal Ca2+ extrusion mechanisms (not shown). Lower, Spontaneous SR Ca2+ oscillations (CaOs) can occur in the absence of an action potential. The increase in cytosolic [Ca2 +] from CaOs has the same sequelae as those induced by an action potential. These sequelae, which occur heterogeneously within and among cells during the distole interval, resemble the common manifestations of heart failure from a variety of causes and are the focus of this essay. site, the sarcoplasmic reticulum (SR). A second function of SR is to pump the Ca2+ it releases into the cytosol back into itself, resulting in a fall in cytosolic [Ca2+] to the diastolic level. Thus, at closer inspection, the heartbeat is an organized cycling of Ca2+ from SR into the cytosol and back into the SR (fig. IB, top). In a machine of this design, the potential for spontaneous Ca2+ recycling or oscillations (CaOs) to occur between organized heartbeats is ever-present (fig. Iß, bottom). A substantial body of evidence gleaned from a variety of mammalian cardiac preparations indicates that such CaOs can indeed occur [2-10]. The probability of CaOs occurrence varies with the extent to which the SR becomes Ca2+ loaded. The Ca2+ load present within the cell determines the Ca2+ load available for pumping by SR; thus, a regulation ofthe cell Ca2+ content by sarcolemmal ion pumps and carriers is a major determinant of whether CaOs will occur. For example, catecholamines and...