Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

Figures

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  Figure 1. Schematic of excitation–contraction (EC) coupling in cardiac myocyte. Ca2+, calcium; CIRC, Ca2+-induced Ca2+ release; SERCA, sarcoplasmic/endoplasmic reticulum Ca2+ ATPase; PLB, phospholamban; RyR, ryanodine receptor; NCX, sodium–calcium exchanger; LTCC, L-type Ca2+ channel; TRP channels, transient receptor potential channels; TCA, tricarboxylic acid (Krebs) cycle; CrP, creatine phosphate; CK, creatine kinase [25,26].

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  Figure 2. Calcium transients as detected with aequorin in trabeculae from non-failing (green) and failing (red) human myocardium with associated isometric contraction (green and red, respectively). L1 is the first fast component of SR Ca2+ release, and L2 is the much slower Ca2+ release and reuptake before restoring [Ca2+]i to diastolic levels. Furthermore, there was a prolonged time to peak twitch force and slowed relaxation response.

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  Figure 3. Dobutamine effect on survival. Heart failure was induced in rats by banding the aorta. Dobutamine is a catecholamine that acts on α1, β1, and β2 adrenergic receptors. Stimulation of these receptors by dobutamine produces a relatively strong inotropic effect. Treatment by dobutamine resulted in a significantly higher and earlier mortality rate. This demonstrates the negative impact of increased inotropy in the treatment of heart failure.

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  Figure 4. The impact of calcium overload on systolic and diastolic function. In trabeculae from a patient with heart failure, there was a slowed contractile response as well as slowed reuptake of Ca2+ by the SR and delayed return to normal diastolic Ca2+ levels. When diastolic Ca2+ concentration was reduced and restored to pre-Ca2+ loading concentrations, there was first an overshoot in the Ca2+ transient amplitude showing increased SR Ca2+ re-uptake, which was followed by a normalization of amplitude and time course of the Ca2+ transient. Associated with these changes in Ca2+ transient amplitude and time course and a decrease in diastolic Ca2+ concentration, there was a tremendous increase in contractile force. This figure demonstrates the negative impact of elevated diastolic Ca2+ on not only diastolic force and muscle relaxation, but systolic force as well.

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  Figure 5. Treatment of animals with dilated cardiomyopathy with carteolol, a beta blocker. (a) Survival of turkey poults with furazolidone-induced heart failure (DCM). Carteolol is a β-blocker. Animals treated with carteolol had significantly improved survival (blue) compared to untreated animals with heart failure (red). (b) Effect of carteolol on echocardiography-derived ejection fraction. Animals with heart failure treated with carteolol had restored ejection fractions (blue) compared to untreated animals with heart failure (red). Untreated animals continued to have worsening of their heart failure, demonstrating that there was progressive heart failure (red, 29 days). (c) Left ventricular end-systolic pressure was also maintained in turkeys treated with carteolol (blue) compared to non-treated animals with heart failure (red). (d) Changes at the level of the contractile elements may explain in part the beneficial effects seen with carteolol treatment. Myofibrillar Ca2+ ATPase was significantly reduced in animals with heart failure (red). Carteolol treatment tended to restore myofibillar Ca2+ ATPase activity (blue) to levels similar to what was seen in control animals (green).…