Contractile Reserve and Calcium Regulation Are Depressed in Myocytes From Chronically Unloaded Hearts

Abstract

Background-Chronic cardiac unloading of the normal heart results in the reduction of left ventricular (LV) mass, but effects on myocyte contractile function are not known. Methods and Results-Cardiac unloading and reduction in LV mass were induced by heterotopic heart transplantation to the abdominal aorta in isogenic rats. Contractility and [Ca 2ϩ ] i regulation in LV myocytes were studied at both 2 and 5 weeks after transplantation. Native in situ hearts from recipient animals were used as the controls for all experiments. Contractile function indices in myocytes from 2-week unloaded and native (control) hearts were similar under baseline conditions (0.5 Hz, 1.2 mmol/L [Ca 2ϩ ] o , and 36°C) and in response to stimulation with high [Ca 2ϩ ] o (range 2.5 to 4.0 mmol/L). In myocytes from 5-week unloaded hearts, there were no differences in fractional cell shortening and peak-systolic [Ca 2ϩ ] i at baseline; however, time to 50% relengthening and time to 50% decline in [Ca 2ϩ ] i were prolonged compared with controls. Severe defects in fractional cell shortening and peak-systolic [Ca 2ϩ ] i were elicited in myocytes from 5-week unloaded hearts in response to high [Ca 2ϩ ] o . However, there were no differences in the contractile response to isoproterenol between myocytes from unloaded and native hearts. In 5-week unloaded hearts, but not in 2-week unloaded hearts, LV protein levels of phospholamban were increased (345% of native heart values). Protein levels of sarcoplasmic reticulum Ca 2ϩ ATPase and the Na ϩ /Ca 2ϩ exchanger were not changed. Conclusions-Chronic unloading of the normal heart caused a time-dependent depression of myocyte contractile function, suggesting the potential for impaired performance in states associated with prolonged cardiac atrophy. (Circulation.

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

“…1d, e) were not significantly different. These findings confirm that the intracellular Ca 2+ transients remain unchanged in early cardiac atrophy [22,46].…”

“…Cardiac atrophy was induced in syngeneic male Lewis rats (270±5 g, n= 34, Charles River, Sulzfeld, Germany) by heterotopic abdominal heart transplantation as previously described [12,14,21,22,29,40,41,45,46]. The donor heart was harvested under deep anaesthesia (thiopental-sodium, 100 mg/kg body weight) and was transplanted into the abdominal cavity of the recipient rat under isoflurane anaesthesia (2-2.5 %).…”

“…The transplanted (atrophic) and the orthotopic (control) hearts of the recipient animal were removed in deep anaesthesia (thiopental-sodium, 100 mg/kg body weight) 2 weeks after transplantation. An unloading period of 2 weeks was chosen to induce a stable cardiac atrophy in accordance with previous studies [12,14,40,41] while avoiding the detrimental effects of prolonged unloading on cardiac excitation-contraction coupling and contractility [21,22,29,45]. For all experiments, the orthotopic hearts served as corresponding controls.…”

Ventricular Assist Device: Emerging Modality for Long Term Cardiac Support

“…35 Cellular structure and function also improves and reverts back toward normal. [36][37][38][39] Thus, the reduction in left ventricular volumes is not just a function of the unloading provided by the VAD but actually reflects alterations in the dynamics of myocyte function.…”

“…To date, an average of only 5%-10% of patients who undergo mechanical circulatory support demonstrate adequate recovery of ventricular function to allow device explantation. 33,34 There is also concern that prolonged mechanical unloading reduces cardiac cell function, as well as cell size, in a time-dependent manner [35][36][37][38][39][40] which may lead to myocardial atrophy. Unloading induced atrophy can be an important impediment to myocardial recovery and removal of the VADs for bridge-to-recovery, limiting the efficacy of VAD treatment.…”