Prolonged Mechanical Unloading Reduces Myofilament Sensitivity to Calcium and Sarcoplasmic Reticulum Calcium Uptake Leading to Contractile Dysfunction

Soppa, Gopal; Lee, Joon; Stagg, Mark A.; Siedlecka, Urszula; Youssef, Samuel; Yacoub, Magdi H.; Terracciano, Cesare M.

doi:10.1016/j.healun.2008.05.005

Cited by 35 publications

(40 citation statements)

References 38 publications

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“…An animal study of failing hypertrophied hearts indicated that unloading resulted in a decrease of cardiac myocytes in size beyond normal values. 79 In human studies, cardiomyocyte size decreased with LVAD unloading although not beyond the size of normal cardiac myocytes 77 and, in one of these studies, electron microscopy suggested no evidence of cardiomyocyte atrophy or degeneration even with >6 months of LVAD support. Development of atrophy could mean that the heart would not be strong enough to be reloaded and might affect the durability and sustainability of recovery.…”

Section: Duration Of Unloadingmentioning

confidence: 94%

“…Studies with shorter periods of unloading were not associated with contractile dysfunction. 79,81 Another study showed normalization of SERCA and SERCA/phospholamban ratios early after LVAD implantation, with reversion back to failing levels with prolonged LVAD support. 82 There is also growing evidence that alterations in T-tubule structures (which are colocalized to areas of impaired Ca 2+ release) are an important cause of deterioration in cardiac myocyte function in a range of cardiac diseases.…”

Section: Duration Of Unloadingmentioning

confidence: 99%

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Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Birks

2013

Circulation Research

106

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Abstract-Heart failure is associated with remodeling that consists of adverse cellular, structural, and functional changes in the myocardium. Until recently, this was thought to be unidirectional, progressive, and irreversible. However, irreversibility has been shown to be incorrect because complete or partial reversal can occur that can be marked after myocardial unloading with a left ventricular assist device (LVAD). Patients with chronic advanced heart failure can show near-normalization of nearly all structural abnormalities of the myocardium or reverse remodeling after LVAD support. However, reverse remodeling does not always equate with clinical recovery. The molecular changes occurring after LVAD support are reviewed, both those demonstrated with LVAD unloading alone in patients bridged to transplantation and those occurring in the myocardium of patients who have recovered enough myocardial function to have the device removed. Reverse remodeling may be attributable to a reversal of the pathological mechanisms that occur in remodeling or the generation of new pathways. A reduction in cell size occurs after LVAD unloading, which does not necessarily correlate with improved cardiac function. However, some of the changes in both the cardiac myocyte and the matrix after LVAD support are specific to myocardial recovery. In the myocyte, increases in the cytoskeletal proteins and improvements in the Ca 2+ handling pathway seem to be specifically associated with myocardial recovery. Changes in the matrix are complex, but excessive scarring appears to limit the ability for recovery, and the degree of fibrosis in the myocardium at the time of implantation may predict the ability to recover. (Circ Res. 2013;113:777-791.)

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Section: Duration Of Unloadingmentioning

confidence: 94%

Section: Duration Of Unloadingmentioning

confidence: 99%

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Birks

2013

Circulation Research

106

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“…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 %).…”

Section: Animal Modelmentioning

confidence: 99%

“…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.…”

Section: Animal Modelmentioning

confidence: 99%

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

Biermann¹,

Bernhardt²,

Neef³

et al. 2014

Thorac cardiovasc Surg

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Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca 2+ transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca 2+ transients, we investigated Ca 2+ cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca 2+ content was reduced by~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca 2+ sparks and a diminished systolic Ca 2+ release, even though the expression of ryanodine receptors was increased by~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca 2+ influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type

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“…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.…”

Section: Molecular Changes In Myocardium After Vad Implantationmentioning

confidence: 99%

Ventricular Assist Device: Emerging Modality for Long Term Cardiac Support

Shah¹,

Kommu²,

Bhuriya³

et al. 2011

New Aspects of Ventricular Assist Devices

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Prolonged Mechanical Unloading Reduces Myofilament Sensitivity to Calcium and Sarcoplasmic Reticulum Calcium Uptake Leading to Contractile Dysfunction

Cited by 35 publications

References 38 publications

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

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

Ventricular Assist Device: Emerging Modality for Long Term Cardiac Support

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