Calcium Overload and Cardiac Function

Abstract

The changes in cardiac function caused by calcium overload are reviewed. Intracellular Ca²⁺ may increase in different structures [e.g. sarcoplasmic reticulum (SR), cytoplasm and mitochondria] to an excessive level which induces electrical and mechanical abnormalities in cardiac tissues. The electrical manifestations of Ca²⁺ overload include arrhythmias caused by oscillatory (V_os) and non-oscillatory (V_ex) potentials. The mechanical manifestations include a decrease in force of contraction, contracture and aftercontractions. The underlying mechanisms involve a role of Na⁺ in electrical abnormalities as a charge carrier in the Na⁺-Ca²⁺ exchange and a role of Ca²⁺ in mechanical toxicity. Ca²⁺ overload may be induced by an increase in [Na⁺]_i through the inhibition of the Na⁺-K⁺ pump (e.g. toxic concentrations of digitalis) or by an increase in Ca²⁺ load (e.g. catecholamines). The Ca²⁺ overload is enhanced by fast rates. Purkinje fibers are more susceptible to Ca²⁺ overload than myocardial fibers, possibly because of their greater Na⁺ load. If the SR is predominantly Ca²⁺ overloaded, V_os and fast discharge are induced through an oscillatory release of Ca²⁺ in diastole from the SR; if the cytoplasm is Ca²⁺ overloaded, the non-oscillatory V_ex tail is induced at negative potentials. The decrease in contractile force by Ca²⁺ overload appears to be associated with a decrease in high energy phosphates, since it is enhanced by metabolic inhibitors and reduced by metabolic substrates. The ionic currents I_os and I_ex underlie V_os and V_ex, respectively, both being due to an electrogenic extrusion of Ca²⁺ through the Na⁺-Ca²⁺ exchange. I_os is an oscillatory current due to an oscillatory release of Ca²⁺ in early diastole from the Ca²⁺-overloaded SR, and I_ex is a non-oscillatory current due to the extrusion of Ca²⁺ from the Ca²⁺-overloaded cytoplasm. I_os and I_ex can be present singly or simultaneously. An increase in [Ca²⁺]_i appears to be involved in the short- and long-term compensatory mechanisms that tend to maintain cardiac output in physiological and pathological conditions. Eventually, [Ca²⁺]_i may increase to overload levels and contribute to cardiac failure. Experimental evidence suggests that clinical concentrations of digitalis increase force in Ca²⁺-overloaded cardiac cells by decreasing the inhibition of the Na⁺-K⁺ pump by Ca²⁺, thereby leading to a reduction in Ca²⁺ overload and to an increase in force of contraction.

Purkinje Cells From RyR2 Mutant Mice Are Highly Arrhythmogenic But Responsive to Targeted Therapy

“…The basis for this heightened proclivity of PCs to develop arrhythmic behavior is not fully known, although the diminished T-tubular density8, altered action potential morphology33, altered kinetics of Ca 2+ handling (Fig 2) and increased intracellular Na + load10 may all be contributory factors. In addition, the participation of IP 3 -sensitive Ca 2+ channels as part of the excitation-contraction coupling machinery may also influence this arrhythmogenic behavior9.…”

“…Underlying ultrastructural features such as a decreased T-tubular density8, the presence of IP 3 -sensitive Ca 2+ channels9, and susceptibility to Ca 2+ overload due to greater Na + load10 may in part account for the propensity of these specialized cells to develop abnormal Ca 2+ release events. Moreover, recent data suggest that higher diastolic Ca i -voltage coupling gain in Purkinje fibers may underlie the generation delayed after-depolarizations (DADs) and triggered beats11.…”

On the mechanisms of arrhythmias in the myocardium of mXinα-deficient murine left atrial-pulmonary veins

“…The effects of digitalis glycosides on cardiac arrhythmias are well documented (Gheorghiade et al, 2004; Vassalle and Lin, 2004). In our laboratory, we used strophanthidin to induce cardiac arrhythmias in the ventricular tissues of large animal (such as dog) (Lin and Vassalle, 1978) and failing human myocardium (Lee et al, 2004).…”

“…In our laboratory, we used strophanthidin to induce cardiac arrhythmias in the ventricular tissues of large animal (such as dog) (Lin and Vassalle, 1978) and failing human myocardium (Lee et al, 2004). Strophanthidin can induce calcium overload and triggered rhythms (Lin and Vassalle, 1978; Vassalle and Lin, 2004). While the combination of ISO and strophanthidin increased the incidence of AF in the mXinα+/+ LA-PV preparations (Fig.…”

Association of a congenital long QT syndrome type 1 with Takotsubo cardiomyopathy

“…Among others, high levels of catecholamines have been discussed as one potential mechanism causing the development of TC. On the other hand, it was demonstrated that electrical disturbances may be caused by toxic catecholamine excess 1. However, the simultaneous occurrence of both TC and congenital electrical disease has to this date been reported in only two cases 2, 3.…”