Cardiomyocyte Dysfunction in Inherited Cardiomyopathies

Inherited cardiomyopathies form a heterogenous group of disorders that affect the structure and function of the heart. Defects in the genes encoding sarcomeric proteins are associated with various perturbations that induce contractile dysfunction and promote disease development. In this review we aimed to outline the functional consequences of the major inherited cardiomyopathies in terms of myocardial contraction and kinetics, and to highlight the structural and functional alterations in some sarcomeric variants that have been demonstrated to be involved in the pathogenesis of the inherited cardiomyopathies. A particular focus was made on mutation-induced alterations in cardiomyocyte mechanics. Since no disease-specific treatments for familial cardiomyopathies exist, several novel agents have been developed to modulate sarcomere contractility. Understanding the molecular basis of the disease opens new avenues for the development of new therapies. Furthermore, the earlier the awareness of the genetic defect, the better the clinical prognostication would be for patients and the better the prevention of development of the disease.

Force-length relations in isolated intact cardiomyocytes subjected to dynamic changes in mechanical load

We developed a dynamic force-length (FL) control system for single intact cardiomyocytes that uses a pair of compliant, computer-controlled, and piezo translator (PZT)-positioned carbon fibers (CF). CF are attached to opposite cell ends to afford dynamic and bidirectional control of the cell's mechanical environment. PZT and CF tip positions, as well as sarcomere length (SL), are simultaneously monitored in real time, and passive/active forces are calculated from CF bending. Cell force and length were dynamically adjusted by corresponding changes in PZT position, to achieve isometric, isotonic, or work-loop style contractions. Functionality of the technique was assessed by studying FL behavior of guinea pig intact cardiomyocytes. End-diastolic and end-systolic FL relations, obtained with varying preload and/or afterloads, were near linear, independent of the mode of contraction, and overlapping for the range of end-diastolic SLs tested (1.85–2.05 μm). Instantaneous elastance curves, obtained from FL relation curves, showed an afterload-dependent decrease in time to peak elastance and slowed relaxation with both increased preload and afterload. The ability of the present system to independently and dynamically control preload, afterload, and transition between end-diastolic and end-systolic FL coordinates provides a valuable extension to the range of tools available for the study of single cardiomyocyte mechanics, to foster its interrelation with whole heart pathophysiology.

Mild renal hypertension alters run training effects on the frequency response of rat cardiomyocyte mechanics

We examined the effects of run training on the frequency dependence of cardiomyocyte mechanics and intracellular calcium concentration ([Ca2+]i) dynamics in rats with mild renal hypertension. Male Fischer 344 rats aged 2–3 mo underwent a sham operation or stenosis of the left renal artery, which increased systolic blood pressure 20–30 mmHg. Half of the rats in each group underwent treadmill run training for >16 wk. Isolated cardiomyocytes were paced at 1.0 and 0.2 Hz in 2 mM external Ca2+ concentration at 29°C. Under these conditions, negative frequency responses, i.e., decreased value with increased frequency, were recorded for peak shortening, shortening velocity, and the integral of the [Ca2+]i transient in both groups. Run training amplified the negative frequency response for the integral of the [Ca2+]i transient in both groups, but it amplified the negative frequency response for the shortening dynamics only in the normotensive sham-operated and not in the hypertensive rats. These results, as well as others for relaxation parameters, suggest that renal hypertension altered the effects of run training on the frequency response for cardiomyocyte contractile apparatus and/or passive mechanical properties, which respond to [Ca2+]i.