Relationship between action potential, contraction-relaxation pattern, and intracellular Ca 2+ transient in cardiomyocytes of dogs with chronic heart failure

Abstract

Abnormalities of contractile function have been identified in cardiomyocytes isolated from failed human hearts and from hearts of animals with experimentally induced heart failure (HF). The mechanism(s) responsible for these functional abnormalities are not fully understood. In the present study, we examined the relationship between action potential duration, pattern of contraction and relaxation, and associated intracellular Ca2+ transients in single cardiomyocytes isolated from the left ventricle (LV) of dogs (n = 7) with HF produced by multiple sequential intracoronary microembolizations. Comparisons were made with LV cardiomyocytes isolated from normal dogs. Action potentials were measured in isolated LV cardiomyocytes by perforated patch clamp, Ca2+ transients by fluo 3 probe fluorescence, and cardiomyocyte contraction and relaxation by edge movement detector. HF cardiomyocytes exhibited an abnormal pattern of contraction and relaxation characterized by an attenuated initial twitch (spike) followed by a sustained contracture ('dome') of 1 to 8 s in duration and subsequent delayed relaxation. This pattern was more prominent at low stimulation rates (58% at 0.2 Hz, n = 211, 21% at 0.5 Hz, n = 185). Measurements of Ca2+ transients in HF cardiomyocytes at 0.2 Hz manifested a similar spike and dome configuration. The dome phase of both the contraction/relaxation pattern and Ca2+ transients seen in HF cardiomyocytes coincided with a sustained plateau of the action potential. Shortening of the action potential duration by administration of saxitoxin (100 nM) or lidocaine (30 microM) reduced the duration of the dome phase of both the contraction/relaxation profile as well as that of the Ca2+ transient profile. An increase of stimulation rate up to 1 Hz caused shortening of the action potential and disappearance of the spike-dome profile in the majority of HF cardiomyocytes. In HF cardiomyocytes, the action potential and Ca2+ transient duration were not significantly different from those measured in normal cells. However, the contraction-relaxation cycle was significantly longer in HF cells (314 +/- 67 ms, n = 21, vs. 221 +/- 38 ms, n = 46, mean +/- SD), indicating impaired excitation-contraction uncoupling in HF cardiomyocytes. The results show that, in cardiomyocytes isolated from dogs with HF, contractile abnormalities and abnormalities of intracellular Ca2+ transients at low stimulation rates are characterized by a spike-dome configuration. This abnormal pattern appears to result from prolongation of the action potential.

Late sodium current in failing heart: Friend or foe?

“…The ratio between amplitudes of the spike and dome phases was suggested to be an index for the severity of HF (Gwathmey et al, 1987). Similar to the shape of abnormal contraction, abnormally prolonged Ca 2+ transients have also been observed in both ventricular muscle strips (Gwathmey et al, 1987) and cardiomyocytes isolated from failing hearts (Beuckelmann and Erdmann, 1992;Maltsev et al, 1998b) (Fig.10A). At the higher frequencies, these abnormalities account for the reversal of the force-frequency relationship in failing myocardium, leading to an increase in diastolic [Ca 2+ ] i and diastolic tension (Fig.10B "Control") (Feldman et al, 1988;Undrovinas et al, 2006).…”

“…It was shown that a partial I NaL inhibition and/or acceleration of I NaL decay rescue normal repolarization, decrease beat-to-beat AP duration variability, and improve Ca 2+ handling and contractility of the failing cells (Maltsev et al, 1998b;Maltsev et al, 2007;Undrovinas et al, 2006;Undrovinas et al, 1999). Thus, I NaL has emerged as a novel target for cardioprotection to treat the failing heart Maltsev et al, 2001;Noble and Noble, 2006).The focus of this review is to summarize the available data from experiment and numerical modeling of I NaL in normal and failing myocardium in order to integrate I NaL into the established electrophysiological and Ca 2+ regulation mechanisms in normal and failing cardiomyocytes.…”

Post-transcriptional silencing of SCN1B and SCN2B genes modulates late sodium current in cardiac myocytes from normal dogs and dogs with chronic heart failure

“…5 and 6), 2) decrease beat-to-beat APD variability, and 3) improvement of Ca 2ϩ handling and contractility (22,25,41,42,44). Accordingly, I NaL has emerged as a novel target for cardioprotection to treat the failing heart (24,26,34).…”

Reversal of Chronic Molecular and Cellular Abnormalities Due to Heart Failure by Passive Mechanical Ventricular Containment

“…14 Cardiomyocyte contraction and relaxation were recorded using an edge detection algorithm. 15 Contraction was evoked by electrical field stimulation at a frequency of 1.0 Hz. Percent cardiomyocyte shortening, peak velocity of shortening, and peak velocity of relengthening were measured in 5 to 10 cardiomyocytes from each dog selected at random.…”