Effect of transmurally heterogeneous myocyte excitation–contraction coupling on canine left ventricular electromechanics

The excitation–contraction coupling properties of cardiac myocytes isolated from different regions of the mammalian left ventricular wall have been shown to vary considerably, with uncertain effects on ventricular function. We embedded a cell-level excitation–contraction coupling model with region-dependent parameters within a simple finite element model of left ventricular geometry to study effects of electromechanical heterogeneity on local myocardial mechanics and global haemodynamics. This model was compared with one in which heterogeneous myocyte parameters were assigned randomly throughout the mesh while preserving the total amount of each cell subtype. The two models displayed nearly identical transmural patterns of fibre and cross-fibre strains at end-systole, but showed clear differences in fibre strains at earlier points during systole. Haemodynamic function, including peak left ventricular pressure, maximal rate of left ventricular pressure development and stroke volume, were essentially identical in the two models. These results suggest that in the intact ventricle heterogeneously distributed myocyte subtypes primarily impact local deformation of the myocardium, and that these effects are greatest during early systole.     

Myostatin represses physiological hypertrophy of the heart and excitation–contraction coupling

Although myostatin negatively regulates skeletal muscle growth, its function in heart is virtually unknown. Herein we demonstrate that it inhibits basal and IGF-stimulated proliferation and differentiation and also modulates cardiac excitation–contraction (EC) coupling. Loss of myostatin induced eccentric hypertrophy and enhanced cardiac responsiveness to β-adrenergic stimulation in vivo . This was due to myostatin null ventricular myocytes having larger [Ca²⁺]_i transients and contractions and responding more strongly to β-adrenergic stimulation than wild-type cells. Enhanced cardiac output and β-adrenergic responsiveness of myostatin null mice was therefore due to increased SR Ca²⁺ release during EC coupling and to physiological hypertrophy, but not to enhanced myofilament function as determined by simultaneous measurement of force and ATPase activity. Our studies support the novel concept that myostatin is a repressor of physiological cardiac muscle growth and function. Thus, the controlled inhibition of myostatin action could potentially help repair damaged cardiac muscle by inducing physiological hypertrophy.     

Minor sarcoplasmic reticulum membrane components that modulate excitation–contraction coupling in striated muscles

In striated muscle, activation of contraction is initiated by membrane depolarisation caused by an action potential, which triggers the release of Ca²⁺ stored in the sarcoplasmic reticulum by a process called excitation–contraction coupling. Excitation–contraction coupling occurs via a highly sophisticated supramolecular signalling complex at the junction between the sarcoplasmic reticulum and the transverse tubules. It is generally accepted that the core components of the excitation–contraction coupling machinery are the dihydropyridine receptors, ryanodine receptors and calsequestrin, which serve as voltage sensor, Ca²⁺ release channel, and Ca²⁺ storage protein, respectively. Nevertheless, a number of additional proteins have been shown to be essential both for the structural formation of the machinery involved in excitation–contraction coupling and for its fine tuning. In this review we discuss the functional role of minor sarcoplasmic reticulum protein components. The definition of their roles in excitation–contraction coupling is important in order to understand how mutations in genes involved in Ca²⁺ signalling cause neuromuscular disorders.     

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

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 Ca²⁺ 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 Ca²⁺ release from the SR. We argue that this defect only becomes manifest in the presence of reduced Ca²⁺ reuptake capacity of the SR and that it may not be solely attributable to reduced gain of the Ca²⁺-induced Ca²⁺ release (CICR). We list several possible explanations for this defect that represent important avenues for future research.     

External Ca2+-dependent excitation–contraction coupling in a population of ageing mouse skeletal muscle fibres

In the present work, we investigate whether changes in excitation–contraction (EC) coupling mode occur in skeletal muscles from ageing mammals by examining the dependence of EC coupling on extracellular Ca²⁺. Single intact muscle fibres from flexor digitorum brevis muscles from young (2–6 months) and old (23–30 months) mice were subjected to tetanic contractile protocols in the presence and absence of external Ca²⁺. Contractile experiments in the absence of external Ca²⁺ show that about half of muscle fibres from old mice are dependent upon external Ca²⁺ for maintaining maximal tetanic force output, while young fibres are not. Decreased force in the absence of external Ca²⁺ was not due to changes in charge movement as revealed by whole-cell patch-clamp experiments. Ca²⁺ transients, measured by fluo-4 fluorescence, declined in voltage-clamped fibres from old mice in the absence of external Ca²⁺. Similarly, Ca²⁺ transients declined in parallel with tetanic contractile force in single intact fibres. Examination of inward Ca²⁺ current and of mRNA and protein assays suggest that these changes in EC coupling mode are not due to shifts in dihydropyridine receptor (DHPR) and/or ryanodine receptor (RyR) isoforms. These results indicate that a change in EC coupling mode occurs in a population of fibres in ageing skeletal muscle, and is responsible for the age-related dependence on extracellular Ca²⁺.     

The role of mammalian cardiac t-tubules in excitation–contraction coupling: experimental and computational approaches

The sarcolemmal membrane of mammalian cardiac ventricular myocytes is characterized by the presence of invaginations called transverse tubules (t-tubules). Transverse tubules occur at the Z-line as transverse elements with longitudinal extensions. While the existence of t-tubules has been known for some time, recent experimental studies have suggested that their structure and function are more complex than previously believed. There are, however, aspects of t-tubule function that are not currently amenable to experimental investigation, but can be investigated using computational and mathematical approaches. Such studies have helped elucidate further the possible role of t-tubules in cell function. This review summarizes recent experimental and complementary computational studies which highlight the important role of t-tubules in cardiac excitation–contraction coupling.     

Continuous axial contraction wave in the free wall of the guinea pig left ventricle

We studied the variation from the simultaneous contraction of the normal left ventricle (LV). The pattern of the contraction along the LV long axes was assessed on the LV free wall on seven guinea pig hearts in situ with ultra fast video system and epicardial markers by means of the latitude and the size of the areas defined by markers. We found that the contraction occurs as a continuous contraction wave from the apex towards the base, which might yield functional adaptation of these two regions to diastolic and systolic function, respectively.     

Postinfarction rupture of the left ventricular free wall: clinicopathologic correlates in 100 consecutive autopsy cases

Among 100 consecutive autopsied cases of postinfarction rupture of the left ventricular free wall, 51% of the deaths were in-hospital and 49% were out of hospital. There were 51 men (mean age, 72 years) and 49 women (mean age, 76 years); 81% had multivessel disease. All had severe obstruction of at least one major epicardial coronary artery (98 atherosclerotic, one thrombotic, and one embolic). Acute coronary thrombosis was present in 73 cases and occurred on an atherosclerotic plaque in 72, 49 (68%) of which had associated plaque rupture. In 83 cases, the ruptured infarction represented the subject's first myocardial infarction. Despite a history of hypertension in 55 cases, appreciable left ventricular hypertrophy was observed in only 19 cases. By histopathologic age of infarction, 13 ruptures occurred during the first day, 45 between days 2 and 5, and 22 on days 6 and 7; thus, 58% occurred within 5 days and 80% within 7 days. The mid-ventricle was the most frequent site of rupture (66%). Ruptures most frequently involved the lateral aspect of the left ventricular free wall (44%). In 66 cases, the rupture tract occurred along the interface between viable and necrotic myocardium. Our findings support the observations of others that the risk factors for postinfarction left ventricular free wall rupture include age greater than 60 years, female gender, preexisting hypertension, absence of left ventricular hypertrophy, first myocardial infarction, and midventricular or lateral wall transmural infarctions.