Increased Functional Importance of the Na,Ca-Exchanger in Contracting Failing Human Myocardium but Unchanged Activity in Isolated Vesicles

Abstract

SUMMARYThe present study aimed to investigate the hypothesis that the function of the Na,Caexchanger (NCX) is of higher importance for contractility and Ca 2+-homeostasis in left ventricle from terminally failing than from nonfailing human hearts.The effect of decreasing extracellular [Na] e (140 to 25 mmol/L) on force of contraction in isolated left ventricular papillary muscle strips was studied as a reflection of NCX function in multicellular preparations (terminally failing, DCM, dilated cardiomyopathy, NYHA IV, n = 13; nonfailing, NF, donor hearts, n = 10). Decreasing [Na] e has previously been shown to increase contractility in vitro secondary to a decreased Ca 2+ -extrusion by the NCX. In addition, the NCX activity was measured as Na + -dependent 45 Ca 2+ -uptake into isolated myocardial vesicles as a function of time and Ca 2+ -concentration (DCM n = 8, NF n = 8). Decreasing [Na] e enhanced the contractility of papillary muscle strips in both DCM and NF, but the contractility of DCM was increased at smaller reductions of [Na] e than NF. The NCX activity in isolated myocardial vesicles was unchanged as a function of time (T 1/2 : DCM 2.4 ± 0.3 s versus NF 2.5 ± 0.3 s) and as a function of Ca These results demonstrate a higher sensitivity of the failing human myocardium towards Na,Ca-exchanger mediated positive inotropic effects, suggesting a higher significance of the Na,Ca-exchanger for the extrusion of Ca 2+ -ions in intact failing versus nonfailing human myocardium. Since the activity and the Ca 2+ -affinity of the Na,Caexchanger in isolated vesicles was unchanged, we propose that alterations in Ca 2+ -and Na + -homeostasis (due to impaired function of the sarcoplasmic reticulum and the Na + , K + -ATPase) or the prolonged action potential are the reason for this observation. (Int Heart J 2007; 48: 755-766)

Temporal and mutation-specific alterations in Ca2+ homeostasis differentially determine the progression of cTnT-related cardiomyopathies in murine models

“…However, we can begin to speculate that the observed flexibility, alterations of cTnT-FHC mutations, such as R92L (16), may lead to abnormal thin-and thick-filament interactions sufficient to directly impair systolic and diastolic perfor- http://ajpheart.physiology.org/ mance at the whole heart level. R92W pathogenesis, on the other hand, exhibits a temporal disease progression characteristic of a classic heart failure response, with its impairments in SERCA2a-to-PLB ratio and SR Ca 2ϩ uptake and the increased NCX protein levels (9,17,38,43). Nonetheless, the agedependent improvements observed in R92W contractility, Ca 2ϩ kinetics, and Ca 2ϩ homeostasis uncover a novel underlying mechanism via the initial, presumably compensatory actions of PLB phosphorylation and CaMKII-mediated Thr17 phosphorylation in particular.…”

Functional Effects of Hyperthyroidism on Cardiac Papillary Muscle in Rats

“…Decreases in the electrochemical gradient of sodium reduce or even revert the NCX function, leading to increased intracellular concentration of calcium and, consequently, increased force. 28,32,33 …”

“…Diedrichs et al 33 have shown that the cardiac muscle in patients with heart failure is more sensitive to a reduction in extracellular sodium, exhibiting a greater increase in contractile force when compared with the muscle in normal individuals. According to the authors, this is due to intracellular calcium accumulation via NCX, whose expression and function is increased in heart failure.…”

Electrophysiological remodeling in heart failure

“…Similar to animal models, increased NCX mRNA and protein abundances in failing human heart have been reported[162, 169]. The functional role of the NCX in failing human myocardium is of greater importance to Ca 2+ -homeostasis than in non-failing myocardium due to the altered function of SR[170]. However, the alterations of NCX in HF are controversial; unchanged levels of NCX protein in human heart failure have been reported[171, 172], and some have reported a HF-related decrease in NCX expression[173] [174].…”