Prolonged mechanical unloading affects cardiomyocyte excitation‐contraction coupling, transverse‐tubule structure, and the cell surface

Ibrahim, Michael; Masri, Abeer A. Al; Navaratnarajah, Manoraj; Siedlecka, Urszula; Soppa, Gopal; Moshkov, Alexey; Al-Saud, Sara Abou; Gorelik, Julia; Yacoub, Magdi H.; Terracciano, Cesare M.

doi:10.1096/fj.10-156638

Cited by 71 publications

(76 citation statements)

References 52 publications

(92 reference statements)

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“…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. 82 One study showed irregular distribution of the T-tubules and profound disruption of the openings of the T-tubules and the cell surface in cardiac myocytes after prolonged unloading 82 with a smaller proportion of T-tubule openings in their ordinary position.…”

Section: Duration Of Unloadingmentioning

confidence: 99%

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Birks

2013

Circulation Research

102

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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: 99%

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Birks

2013

Circulation Research

102

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“…Direct evidence for this mechanism was demonstrated by mechanical unloading of the ischaemic failing heart in the rat by heterotopic abdominal heart transplantation; this procedure reversed t-tubule remodelling and normalised local Ca 2+ release (Ibrahim et al 2012). The same procedure used for prolonged mechanical unloading of normal hearts led to loss of t-tubule structure and impaired Ca 2+ signalling (Ibrahim et al 2010), indicating that there is a 'Goldilocks zone' of mechanical load. The synchronisation between myocytes also appears to be important, as dyssynchronous heart failure in the dog is characterised by loss of t-tubule structure and impaired calcium release that can be reversed by cardiac resynchronisation therapy (Sachse et al 2012;Li et al 2015).…”

Section: Mechanisms Of T-tubule Remodellingmentioning

confidence: 99%

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

2017

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Transverse (t)-tubules are invaginations of the plasma membrane that form a complex network of ducts, 200-400 nm in diameter depending on the animal species, that penetrates deep within the cardiac myocyte, where they facilitate a fast and synchronous contraction across the entire cell volume. There is now a large body of evidence in animal models and humans demonstrating that pathological distortion of the t-tubule structure has a causative role in the loss of myocyte contractility that underpins many forms of heart failure. Investigations into the molecular mechanisms of pathological t-tubule remodelling to date have focused on proteins residing in the intracellular aspect of t-tubule membrane that form linkages between the membrane and myocyte cytoskeleton. In this review, we shed light on the mechanisms of ttubule remodelling which are not limited to the intracellular side. Our recent data have demonstrated that collagen is an integral part of the t-tubule network and that it increases within the tubules in heart failure, suggesting that a fibrotic mechanism could drive cardiac junctional remodelling. We examine the evidence that the linkages between the extracellular matrix, t-tubule membrane and cellular cytoskeleton should be considered as a whole when investigating the mechanisms of t-tubule pathology in the failing heart.

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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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Prolonged mechanical unloading affects cardiomyocyte excitation‐contraction coupling, transverse‐tubule structure, and the cell surface

Cited by 71 publications

References 52 publications

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

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

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