Calcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes

Abstract

Ca2+ enters both normal and failing cardiac myocytes during the late portion of the AP plateau via reverse mode NCX. In (normal) myocytes with good SR function, this Ca(2+) influx helps maintain and regulate SR Ca2+ load. In (failing) human myocytes with poor SR function this Ca2+ influx directly contributes to contraction. These studies suggest that the Ca2+ transient of the failing human ventricular myocytes has a higher than normal reliance on Ca2+ influx via the reverse mode of the NCX during the terminal phases of the AP.

Na+/Ca2+Exchanger is a Determinant of Excitation–Contraction Coupling in Human Embryonic Stem Cell–Derived Ventricular Cardiomyocytes

“…Under physiological conditions (high external Na + ), the Ca 2+ outward mode of NCX plays a crucial role in maintaining a low resting cytosolic Ca 2+ after systole [26]; when intracellular Na + ions start to accumulate (eg, during AP when Na + channels open), the NCX can operate in the reverse mode to transport Ca 2+ from the outside to the inside while exporting Na + . This reverse mode NCX has been thought to synergize I Ca-L to trigger SR Ca 2+ release in adult myocytes [23,24], and contribute to the slow Ca 2+ transient decay observed in failing heart cells [27,28]. A similar mechanism has also been reported to trigger the Ca 2+ release from intracellular Ca 2+ stores in cultured cortical neurons [29].…”

Excitation-contraction coupling and mitochondrial energetics

“…During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212]. In this context, the elevation of [Na + ] i in cardiac failure and hypertrophy may be regarded as a beneficial and compensatory mechanism [94].…”

“…Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212] Are defects in EC coupling linked to energy starvation in heart failure?Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”

Impaired angiotensin II–extracellular signal-regulated kinase signaling in failing human ventricular myocytes

“…Unlike JNK, the ERK1/2 response to Ang II was indeed reported to be influenced by the release of calcium from inositol 1,4,5-trisphosphate (IP3)-sensitive intracellular stores (sarcoplasmic reticulum) both in vascular smooth muscle cells [35,36] and in cardiomyocytes isolated from neonatal rats [37]. However, although a reduced calcium release from intracellular stores was consistently observed in human failing ventricular myocytes [38][39][40][41], we did not specifically investigate Ca mobilization in our study, so the possible participation of this mechanism can only be hypothesized. Therefore, these experiments, although not clarifying in detail the mechanisms involved in the reduced ERK response in failing myocytes, provide evidence in support of a direct link between the impairment of an important intracellular pathway and reduced growth factor formation in human failing myocytes.…”