Cellular Mechanisms of Altered Contractility in the Hypertrophied Heart

Abstract

Abstract-To investigate the cellular mechanisms for altered Ca 2ϩ homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca 2ϩ currents (I Ca,L ), whole-cell Ca 2ϩ transients ([Ca 2ϩ ] i ), and Ca 2ϩ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age-and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. C ardiac hypertrophy is associated with marked changes in myocardial contractility. Peak active tension increases, 1-4 and the rates of both contraction and relaxation are slowed. 3,[5][6][7][8] These contractile abnormalities are associated with alterations in the whole-cell calcium transient ([Ca 2ϩ ] i ). In the hypertrophied myocardium, the amplitude of [Ca 2ϩ ] i increases, 9 whereas in failing myocardium, the amplitude of [Ca 2ϩ ] i decreases. 10 -13 In most animal models of hypertrophy 8,10,11,[13][14][15] and in failing human hearts, 12,16 the duration of the whole-cell [Ca 2ϩ ] i is also prolonged. However, the precise cellular mechanisms that are responsible for changes in contractility and alterations in [Ca 2ϩ ] i are largely unknown. Identification of the cellular mechanisms that underlie altered excitation-contraction coupling in cardiac hypertrophy and heart failure is complicated by several issues, including differences in experimental animal models and disease progression. In addition, it has only recently proved possible using confocal microscopy to measure local nonpropagating elevations of Ca 2ϩ (Ca 2ϩ sparks) at the level of individual sarcomeres. [17][18][19][20][21][22] The ability to measure Ca 2ϩ sparks provides an opportunity to evaluate directly the role of sarcoplasmic reticulum (SR) Ca 2ϩ release in muscle cells from animal models associated with cardiac hypertrophy.In this study, we used laser scanning confocal microscopy and Ca 2ϩ -sensitive fluorescent indicators to detect Ca 2ϩ sparks evoked by electrical field stimulation in ventricular cells from normal rats and from spontaneously hypertensive rats (SHRs) with cardiac hypertrophy. By quantitative analysis of the kinetic characteristics of Ca 2ϩ sparks, we identify enhanced SR Ca 2ϩ release from hypertrophied SHR cells. In

Myocardial infarction in rat eliminates regional heterogeneity of AP profiles,ItoK+currents, and [Ca2+]itransients

“…Prolongation of APD, reductions in I to density, decreased expression of Kv4.2 and increases in [Ca 2ϩ ] i transient amplitudes have been reported previously in the rat myocardium for a number of models of cardiac hypertrophy (6,9,10,30,50). Although alterations in any number of currents could explain the changes in APD after infarction, only reductions in I to without changes in I Ca,L , I sus , or I K1 were observed in the two regions studied.…”

“…As was the case with high Ca 2ϩ -buffering conditions (i.e., 5 mM EGTA), there were significant differences in APD 50 and APD 90 between RVW and SEP myocytes. After MI, APD 50 It is important to note that the APD 50 and especially the APD 90 were generally prolonged in all groups when recorded in the presence of Ca 2ϩ transients when low intracellular Ca 2ϩ buffering was used compared to high Ca 2ϩ -buffering conditions. Associated with the observed differences in APD, the mean peak systolic [Ca 2ϩ ] i was higher (P Ͻ 0.01) in the SEP (687.4 Ϯ 84.9 nmol/l, n ϭ 15) compared with the RVW (381.8 Ϯ 44.7 nmol/l, n ϭ 17).…”

“…For sham-operated hearts, 50% and 90% APD (APD 50 and APD 90 , respectively) in RVW myocytes (APD 50 ϭ 4.8 Ϯ 0.6 ms, n ϭ 31, and APD 90 ϭ 28.9 Ϯ 2.7 ms, n ϭ 31) were shorter (P Ͻ 0.01) in duration than in SEP myocytes (APD 50 ϭ 9.7 Ϯ 1.1 ms, n ϭ 26, and APD 90 ϭ 49.4 Ϯ 4.5 ms, n ϭ 26). In SEP myocytes, APD 50 was unchanged (12.2 Ϯ 1.3 ms, n ϭ 25, P ϭ 0.1), whereas APD 90 was slightly increased (71.2 Ϯ 7.0 ms, n ϭ 25, P Ͻ 0.05) after MI. In RVW myocytes both APD 50 (13.2 Ϯ 1.6 ms, n ϭ 26, P Ͻ 0.05) and APD 90 (70.9 Ϯ 7.0, n ϭ 26, P Ͻ 0.05) were increased by MI.…”

Increased InsP 3 Rs in the junctional sarcoplasmic reticulum augment Ca 2+ transients and arrhythmias associated with cardiac hypertrophy

“…As previously described, at 6 months, cardiomyocytes from SHRs are hypertrophic (20 2 To whom correspondence should be addressed. E-mail: llewelyn.roderick@bbsrc.ac.uk.…”

Cardiac Basal Metabolism.

“…This same species-difference (ratϾguinea pig) was suggested by a series of papers from the laboratory of Lakatta [156][157][158][159][160][161] in which the occurrence of spontaneous light intensity and mechanical fluctuations were attributed to spontaneous release of Ca 2ϩ from the SR under resting conditions. More recently, the discovery of Ca 2ϩ -sparks, using techniques of laser-scanning confocal microscopy, has further legitimized the phenomenon of spontaneous Ca 2ϩ release from the sarcoplasmic reticulum [162][163][164][165][166][167][168][169][170][171].…”