Clinical Recovery From End-Stage Heart Failure Using Left-Ventricular Assist Device and Pharmacological Therapy Correlates With Increased Sarcoplasmic Reticulum Calcium Content but Not With Regression of Cellular Hypertrophy

Abstract

Background-Left ventricular assist device (LVAD) treatment is known to lead to structural and functional cellular modifications in the heart. The relevance of these changes for clinical recovery is unknown. Methods and Results-We compared properties of cardiomyocytes obtained from tissue taken at explantation of the LVAD in patients with clinical recovery with those obtained from hearts of patients who did not show clinical recovery, thus requiring transplantation. Compared with myocytes taken at implantation, both the recovery and nonrecovery groups showed Ϸ50% reduction in cell capacitance, an index of cell size. However, action potential duration shortened, L-type Ca 2ϩ current fast inactivation was more rapid, and sarcoplasmic reticulum Ca 2ϩ content was increased in the recovery compared with the nonrecovery group. Conclusions-These results show that specific changes in excitation-contraction coupling, and not regression of cellular hypertrophy, are specifically associated with clinical recovery after LVAD and further identify sarcoplasmic reticulum Ca Key Words: mechanical devices Ⅲ electrophysiology Ⅲ heart failure Ⅲ myocytes Ⅲ sarcoplasmic reticulum H eart transplantation is currently the only effective longterm treatment for patients in end-stage heart failure. Recently, left ventricular assist device (LVAD) treatment has been used successfully as a bridge to transplantation, as destination therapy in patients with contraindications to transplantation, 1 or to obtain recovery in a small number of patients. 2,3 We have shown that in some patients with idiopathic dilated cardiomyopathy in end-stage heart failure, combined LVAD and pharmacological therapy induced clinical recovery to allow explantation of the device without recurrence of heart failure. 3 LVAD treatment results in numerous changes in cardiomyocyte phenotype, excitation-contraction coupling, gene expression, and function. 2 Whether these changes are beneficial is not known. Regression of hypertrophy is thought to be an important factor in recovery. 2 However, several studies have also shown that hypertrophy is not required as a compensatory response to pressure overload, 4 and its regression is not necessarily associated with normalization of electrophysiological parameters. 5 Cardiomyocytes isolated from biopsies taken at explantation of the LVAD in patients with clinical recovery showed reductions in cell volume and cell surface area. L-type Ca 2ϩ current and sarcoplasmic reticulum (SR) Ca 2ϩ content were increased in myocytes during recovery, suggesting a critical role for intracellular Ca 2ϩ homeostasis. 6 Increased SR Ca 2ϩ uptake in cardiac tissue after LVAD treatment has also been described previously. 7 However, whether these specific cellular changes are related to clinical recovery remained unclear.In this study, we compared findings in cardiomyocytes obtained from tissue taken from patients who recovered with those obtained from patients who, despite identical treatment, did not. This allowed correlation between cellular electroph...

Mechanical Unloading During Left Ventricular Assist Device Support Increases Left Ventricular Collagen Cross-Linking and Myocardial Stiffness

“…[1][2][3] This normalization of diastolic properties results from a regression of myocyte hypertrophy, including reduced LV mass, wall thickness, and myocyte diameter. 4,5 In addition, LVAD support has been associated with a trend toward normalization in cardiomyocyte function, 6 calcium cycling properties, 7 and expression of various genes. 8 In addition to changes in intrinsic myocardial properties, LVAD use is associated with changes in the characteristics and metabolism of the extracellular matrix (ECM).…”

Morphological and molecular changes of the myocardium after left ventricular mechanical support

“…Terracciano and co-workers have demonstrated that clinical recovery from terminal CHF after pharmacological and mechanical support is associated with modifications in excitation-contraction coupling, and sarcoplasmatic Ca 2+ homeostasis in particular, and not with a reduction of cardiomyocyte cell size. These findings underscore the importance of Ca 2+ cycling in CHF and its treatment [53].…”

Cellular Basis for Therapeutic Choices in Heart Failure

“…In studies on transplanted human hearts, previous ␤-blockade restored the RyR function, phosphorylation, and levels of the binding proteins toward reference, with improved myocardial compliance and response to isoproterenol. 16 These studies do not explain why the ARB valsartan can restore the function of the ryanodine receptor and normalize the calcium leak from the SR without improving resting cardiac function. 17 The abnormalities of intracellular cardiac calcium kinetics in heart failure could equally well lie in defective uptake of calcium into the SR by the sarcoplasmic-endoplasmic reticulum calciumuptake pump (SERCA) and, more specifically, the cardiac isoform SERCA2a.…”