Cardiac pacemaker cell failure with preserved If, ICaL, and IKr: A lesson about pacemaker function learned from ischemia-induced bradycardia

Abstract

Cardiac ischemia is an important global health problem. It leads to contraction failure, arrhythmias, and cardiac cell death. Sinus bradycardia characterized by a slow heart rate (<60 bpm) is a prominent ischemia-related arrhythmia directly caused by a deficiency of heart beat initiation within the sinoatrial node (SAN), due to a failure of the heart's primary pacemaker cells (SANC). The study presented by Yi-Mei Du and Richard Nathan in this issue of Journal of Molecular and Cellular Cardiology [1] deals with the ionic basis of ischemia-induced bradycardia in isolated SANC. The results of their study not only contribute to understanding of ischemia-induced bradycardia, but also help to delineate the fundamental mechanisms of cardiac pacemaker cell function. Study design and hypothesisIn their studies, Du and Nathan simulated ischemia by superfusing SANC with a solution without glucose, at pH 6.6 that contained either 5.4 or 10 mM KCl. This lead, to a 13% or 43% reduction, respectively, in the spontaneous beating rate of freshly isolated SANC. This simulated ischemia is not true ischemia, e.g. there is no associated hypoxia or flow deficiency effects other than elevated [K + ]. Nonetheless simulated ischemia of this sort is often applied in studies like the present one. And, in their careful approach to the problem, the authors first demonstrated that their "ischemic" solutions produced bradycardia in the intact rabbit heart. Then, in isolated SANC they measured the effects of this simulated ischemia on membrane potential and ion currents under voltage clamp. Such an approach is not surprising, because it has been believed for almost half a century that the heart rhythm originates on the surface membrane of the cardiac pacemaker cells. This dogma stems from the Nobel prize triumph of the Hodgkin-Huxley neuron membrane excitability theory [2] and subsequent modification of this theory and extrapolation to the heart cells by Noble (1960) [3]. According to this theory, generation of spontaneous action potentials (APs) by cardiac pacemaker cells is portrayed as a membrane delimited process, i.e. by a pure interplay of time-and voltage-dependent ion currents. Pacemaker field researchers have focused mainly on the identification of multiple ion current components in pacemaker cells, and their respective roles in the spontaneous diastolic depolarization of these cells (DD, Fig.1A) that brings the membrane to the excitation threshold (reviews [4,5]). Du and Nathan thus tested an hypothesis that bradycardia induced by their

Synergism of coupled subsarcolemmal Ca2+clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model

“…Thus the difference in the models is in their late DD mechanisms, which are: "LCR-induced I NCX ϩ I CaL " in the present model; "I Na ϩ I CaT ϩ I CaL " in the Demir et al (9) model; and "I st ϩ I CaL " in the Kyoto model (16,57). If we exclude I Na , I CaT , and I st as major regulation players in primary SANC, then the regulation only via I f and/or I CaL seems to be insufficient to explain the high balance of robustness and flexibility of SANC function (40) so that our LCR-induced I NCX mechanism may be suggested as the missing link in the mystery of cardiac automaticity (see recent review in Ref. 32).…”

“…The model requires a single, straight-forward assumption: the existence of submembrane Ca 2ϩ clock in SANC, an assumption based on solid experimental evidence of the emergence and critical functional importance of spontaneous rhythmic subsarcolemmal releases in rabbit SANC under normal physiological conditions [original studies (4,5,37,38,42,65,67,68,70), editorials (2,7,34,40), and recent reviews (31,32,41,43,45)]. By varying rates of SR Ca 2ϩ pumping and release, we determined the parametric space of the oscillatory SR behavior and then explored how this modeled Ca 2ϩ oscillator integrates with classic membrane voltage oscillator of SANC to insure robust and flexible spontaneous AP firing.…”

Functional Expression and Regulation of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (HCN) in Mouse iPS Cell-derived Cardiomyocytes afterUTF1-Neo Selection

“…6). In fact, the efflux of Ca 2+ from intracellular storage via Inositoltriphosphate (IP3), the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) or the ryanodine receptor (RyR) may contribute to the beating activity of CMs that do not possess functional and measurable I f currents [4,44] because a block of L-type Ca 2+ channels has been shown to abolish the beating activity in iPS-CMs [2,22]. Most CMs recorded in the late stage of differentiation possess detectable I f currents and beat faster with regular rhythm.…”

Normal Heart Rhythm is Initiated and Regulated by an Intracellular Calcium Clock Within Pacemaker Cells

“…Under conditions simulating ischemia in rabbit SANC, pacemaker function fails when I CaL and I f increase, I Kr is unchanged, and I CaT and I NCX decrease [27,37]. The failure of normal automaticity in this case is associated with the elimination of the late exponential phase of the DD.…”