Dyssynchronous Ca ²⁺ Sparks in Myocytes From Infarcted Hearts

Abstract

The kinetics of contractions and Ca(2+) transients are slowed in myocytes from failing hearts. The mechanisms accounting for these abnormalities remain unclear. Myocardial infarction (MI) was produced by ligation of the circumflex artery in rabbits. We used confocal microscopy to record spatially resolved Ca(2+) transients during field stimulation in left ventricular (LV) myocytes from control and infarcted hearts (3 weeks). Compared with controls, Ca(2+) transients in myocytes adjacent to the infarct had lower peak amplitudes and prolonged time courses. Control myocytes showed relatively uniform changes in [Ca(2+)] throughout the cell after electrical stimulation. In contrast, in MI myocytes [Ca(2+)] increased inhomogeneously and localized increases in [Ca(2+)] occurred throughout the rising and falling phases of the Ca(2+) transient. Ca(2+) content of the sarcoplasmic reticulum did not differ between MI and control myocytes. Peak L-type Ca(2+) current density was reduced in MI myocytes. The macroscopic gain function was not different in control and MI myocytes when calculated as the amplitude of the Ca(2+) transient/peak I:(Ca). However, when calculated as the peak rate of rise of the Ca(2+) transient/peak I:(Ca), the gain function was modestly decreased in the MI myocytes. Application of isoproterenol (100 nmol/L) improved the synchronization of Ca(2+) release in MI myocytes at both 0.5 and 1 Hz. The poorly coordinated production of Ca(2+) sparks in myocytes from infarcted rabbit hearts likely contributes to the diminished and slowed macroscopic Ca(2+) transient. These abnormalities can be largely overcome when phosphorylation of Ca(2+) cycling proteins is enhanced by ss-adrenergic stimulation.

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

“…Disrupted T‐tubule density has previously been demonstrated in explanted end‐stage HF human hearts from different aetiologies, also including ischaemic heart disease 2, 45, 46, 47, 48, 49. Data from both larger animal models like pig and dogs49, 50 and smaller animal models like mice and rats report disrupted T‐tubule density also in earlier stages of the disease 51.…”

Cardiac BIN1 (cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health

“…Such knowledge is in great need for effective development of new diagnostic, prognostic, and therapeutic tools for HF, an endstage cardiac disease with poor clinical prognosis. The pathophysiologic hallmark of HF is a weakened cardiac calcium transient (Gómez et al, 1997;Litwin et al, 2000;Gómez et al, 2001), which can be attributed to t-tubule remodeling (Lyon et al, 2009;Louch et al, 2010;Wei et al, 2010) and dyad uncoupling (Gómez et al, 1997;Gómez et al, 2001;He et al, 2001;Louch et al, 2006;Bito et al, 2008;Louch et al, 2010). T-tubule remodeling marks the transition from hypertrophy to failure (Wei et al, 2010), contributing to the progression of HF (see reviews in (Brette and Orchard, 2003;Brette and Orchard, 2007;Louch et al, 2010;Ferrantini et al, 2013;Guo et al, 2013;Ibrahim and Terracciano, 2013)).…”

Excitation-contraction coupling and mitochondrial energetics

“…A major deficit in failing myocytes is the reduced Ca 2+ content of the SR, which is related to decreased expression and activity of the SR Ca 2+ -ATPase [84,92,146,153] and an increased Ca 2+ leak of the RyR2 due to hyperphosphorylation [84,94,112,122]. These defects, potentially aggravated by L-type Ca 2+ channel dysfunction [41,71,81,86,113,131,146,184] or t-tubular derangement [32,86,115,145,184] [17,81,113,115,146,184]. 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 …”