Heart failure -- a challenge to our current concepts of excitation-contraction coupling

Abstract

Development of novel therapeutic strategies for congestive heart failure (CHF) seems to be hampered by insufficient knowledge of the molecular machinery of excitation-contraction (EC) coupling in both normal and failing hearts. Cardiac hypertrophy and failure represent a multitude of cardiac phenotypes, and available invasive and non-invasive techniques, briefly reviewed here, allow proper quantification of myocardial function in experimental models even in rats and mice. Both reduced fractional shortening and reduced velocity of contraction characterize myocardial failure. Only when myocardial function is depressed in vivo can meaningful studies be done in vitro of contractility and EC coupling. Also, we point out potential limitations with the whole cell patch clamp technique. Two main factors stand out as explanations for myocardial failure. First, a basic feature of CHF seems to be a reduced Ca(2+) load of the sarcoplasmic reticulum (SR) mainly due to a low phosphorylation level of phospholamban. Second, there seems to be a defect of the trigger mechanism of Ca(2+) release from the SR. We argue that this defect only becomes manifest in the presence of reduced Ca(2+) reuptake capacity of the SR and that it may not be solely attributable to reduced gain of the Ca(2+)-induced Ca(2+) release (CICR). We list several possible explanations for this defect that represent important avenues for future research.

Figure 1. Cardiomyocyte contractility

A, contraction relaxation cycles in posterior left ventricular papillary muscles during isometric contractions. Muscles from sham-operated animals (thick line) developed higher force more rapidly than papillary muscles from CHF animals (thin line). B, shortening velocity-force relationship at a muscle length (L_max) that gives maximal force development. The two examples illustrate contractions in a normal muscle (thick line) and in a muscle with reduced contractility (thin line). The corresponding powers (force × velocity) are illustrated above.

Figure 2. Effects of experimental conditions on cell shortening and velocity of shortening

A, fractional shortening and B, velocity of shortening in SHAM cells and CHF cells impaled with high resistance electrodes and low resistance patch pipettes. *Significantly different from SHAM; # significantly different from high resistance electrodes. C, fractional shortening at various voltages using patch pipettes and a post-conditioning potential of −50 mV. Solutions contained Cs⁺ instead of K⁺ and there was 0 Na⁺ in the pipette. D shows the same experiments repeated with K⁺ containing solutions and 6 mm Na⁺ in the pipette. From Sjaastad et al. (2002b) with permission.

Figure 3. Factors influencing SR Ca²⁺ load

Examples of cellular proteins, cell functions and experimental conditions that influence sarcoplasmic reticulum load are illustrated. SOC, store operated Ca²⁺ channels; V_m, membrane potential; SERCA-2, sarcoplasmic reticulum Ca²⁺-ATPase; PLB, phospholamban; RyR, ryanodine receptor. Illustration made by Tore Taraldsen, MD.

Figure 4. Summary of alterations in EC coupling in CHF

An L-type Ca²⁺ channel (1), both t-tubular (2) and sarcolemmal Na⁺-Ca²⁺ exchangers, a sarcolemmal voltage sensor (3), the sarcoplasmic reticulum Ca²⁺-ATPase, phospholamban and a sarcolemmal Ca²⁺-ATPase are illustrated. The following structures have altered function in CHF compared to sham: the Na⁺-Ca²⁺ exchanger both in trigger and relaxation mode, the voltage sensor, phospholamban and the sarcoplasmic reticulum Ca²⁺-ATPase. Illustration made by Tore Taraldsen, MD.