The role of Na dysregulation in cardiac disease and how it impacts electrophysiology

Abstract

Ca 2+ is well known as the central player in cardiac cell physiology, mediating Ca 2+ activation of myosin ATPase and contraction, the stimulation of Ca 2+ -activated signaling pathways and modulation of mitochondrial energy production. Abnormalities of Ca 2+ handling are a well-studied mechanism of decompensation in heart failure. Less appreciated is the role of cytosolic Na + (Na i + ), which can dramatically influence the transfer rates and distribution of Ca 2+ among the intracellular compartments of the myocyte. Since Na i + can vary widely under different physiological and pathological conditions, and its effects depend on multiple ion gradients and membrane electrical potentials, unraveling the global influence of Na i + on cell function is complex, requiring an integrative view of cardiomyocyte physiology. Here, we discuss how abnormal Na i + regulation not only influences the cytosolic Ca 2+ transient and the cellular action potential but also alters mitochondrial Ca 2+ uptake and the balance of energy supply and demand of the cardiomyocyte, which may contribute to oxidative stress and cardiac decompensation. The implications for sudden cardiac death and the potential for novel therapeutic interventions are discussed. Na i + balance: the playersNa i + balance in the heart cell is maintained by a variety of ion channels, pumps and exchangers whose function is strongly influenced by the transmembrane gradients of various ions, and in some cases, by the electrical potential across the sarcolemmal or organelle membranes ( Fig. 1; see [1] for a review). At the sarcolemma, two well-known processes contribute to unidirectional Na + fluxes during the cardiac cycle; voltage-dependent Na + channels mediate the rapid inward Na + current (I Na ) during the upstroke of the cellular action potential and may also contribute to persistent Na + influx, while the Na + /K + ATPase (NKA) utilizes the energy released by ATP hydrolysis to pump Na + out of the cell against a concentration gradient in exchange for K + in an electrogenic process (3Na + :2K + ). A variety of electroneutral exchangers also influence Na i + when ion homeostasis is disturbed under pathological conditions; these include the Na + /H + exchanger (NHE), the Na + /HCO 3 -cotransporter (NBC), the Na + /K + / 2Cl -cotransporter (NKCC) and the Na + /Mg 2+ exchanger (NMgX). Influx of Na + through these pathways is generally well compensated by NKA action. Uniquely, under physiological conditions, the sarcolemmal Na + /Ca 2+ exchanger (NCX) operates in both the forward-mode (Ca 2+ extrusion/Na + entry) and reverse-mode (Ca 2+ entry/Na + extrusion) during different phases of the cardiac cycle, depending on the dynamically changing membrane potential and gradients of Na + and Ca 2+ across the sarcolemma. Its sensitivity to membrane voltage is

Mitochondrial Ca2+ uniporter and CaMKII in heart

“…1b). Our data support the observation that elevated Na + may regulate heart mitochondrial [Ca 2+ ] 11,12 . Importantly, the whole-mitoplast I MCU was about two orders of magnitude lower than the current reported by Joiner et al (∼2 pA at -160 mV in 0.2 mM Ca 2+ vs. ∼180 pA) and did not exhibit high fluctuations as expected for a small-conductance channel.…”

Inhibiting Mitochondrial Na + /Ca 2+ Exchange Prevents Sudden Death in a Guinea Pig Model of Heart Failure

“…The pathway of contractile and electrical dysfunction involves a vicious cycle whereby increased cytoplasmic Na + ([Na + ] c ), along with impaired SR Ca 2+ release, leads to blunted Ca 2+ signaling to the mitochondria during increased work 17-20 . Consequently, the failure to stimulate Ca 2+ -dependent dehydrogenases of Krebs cycle 21-25 results in the net oxidation of the matrix NADH pool.…”

“…Consequently, the failure to stimulate Ca 2+ -dependent dehydrogenases of Krebs cycle 21-25 results in the net oxidation of the matrix NADH pool. The decreased NADH/NAD + redox potential, on the one hand, results in a deficiency of reducing equivalents that drive oxidative phosphorylation (OXPHOS) and ATP production, and, on the other hand, compromises the ability to scavenge ROS, owing to the interdependence of the NADH and NADPH redox pools 20 (see schema in Online Figure I). Mitochondrial NADPH is crucial because it provides the reducing power to maintain the reduced glutathione (GSH), thioredoxin (Trx(SH)2) and glutaredoxin pools, all of which are vital for ROS scavenging and the prevention of protein thiol oxidative damage 26 .…”

Reducing the Late Sodium Current Improves Cardiac Function during Sodium Pump Inhibition by Ouabain

“…This effect was transient and was followed by mechanical, electrical, and metabolic dysfunction, including a rise of LVEDP, a decrease in left ventricular systolic function, episodes of car- diac standstill (contracture, inexcitability), and a pronounced loss of approximately 50% of ATP and PCr. Sodium-induced Ca 2ϩ overload is known to lead to a mismatch of energy demand and supply in the heart (Hotta et al, 1998;O'Rourke and Maack, 2007). Energy demand increases caused by activation of myosin ATPase, sarcoplasmatic reticulum Ca 2ϩ ATPase, the sarcolemmal Ca 2ϩ ATPase, and the sodium pump.…”

“…Energy demand increases caused by activation of myosin ATPase, sarcoplasmatic reticulum Ca 2ϩ ATPase, the sarcolemmal Ca 2ϩ ATPase, and the sodium pump. ATP synthesis may be reduced because of Na ϩ and Ca 2ϩ overload (Balaban, 2002;O'Rourke and Maack, 2007) as the activity of Ca 2ϩ -dependent Krebs cycle dehydrogenases (pyruvate, isocitrate, and ␣-ketoglutarate) is reduced when the mitochondrial Ca 2ϩ level falls in response to increased mitochondrial NCX driven by elevation of intracellular Na ϩ (Maack et al, 2006;Kohlhaas et al, 2010). The mismatch of energy demand and supply results in decreases in [ATP] and [PCr], increases in [ADP], [P i ], and cellular acidosis, and ultimately in a decrease of the free energy available from hydrolysis of ATP.…”