Improvement of myocardial mitochondrial function after hemodynamic support with left ventricular assist devices in patients with heart failure

Lee, Sun Hi; Doliba, Nicolai M.; Osbakken, Mary D.; Öz, Mehmet C.; Mancini, Donna

doi:10.1016/s0022-5223(98)70136-9

Cited by 104 publications

(58 citation statements)

References 22 publications

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“…58 Most of these result in depletion of myocardial ATP, phosphocreatine, and creatine kinase, with decreased efficiency of mechanical work. 58 Generally, improvement in cardiomyocyte metabolic dysfunction occurs after LVAD unloading, 59 although the mechanisms involved are still unclear.…”

Section: Metabolic Enzymesmentioning

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: Metabolic Enzymesmentioning

confidence: 99%

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Birks

2013

Circulation Research

102

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“…In end-stage heart failure (HF) patients undergoing transplantation, the rate of respiration in fibers per mg protein (Sharov et al 2000) or in isolated mitochondria per mg mitochondrial protein (Lee et al 1998) was similar in both ventricles. In fibers from atrial appendages, the respiration rate with all substrates is lower compared to ventricles, showing the decrease in mitochondrial content, but when OXPHOS was corrected for the amount of mitochondria (using the maximum uncoupled respiration) the respiration was similar in the three chambers .…”

Section: Anatomical Sites In the Heartmentioning

confidence: 99%

“…A few studies have shown that some treatments for severe HF improved mitochondrial function and structure, e.g., longterm implantation of left ventricular assist devices improved OXPHOS capacity (Lee et al 1998), beta-blocker therapy reversed part of the defect in ETC activity (Scheubel et al 2002), and administering a beta-adrenoceptor agonist increases cristae-to-matrix ratio and mitochondrial size (Unverferth et al 1980). An evolving trend in the treatment of cardiac disease is the use of metabolic modulators, including therapeutic targets aimed at improving mitochondrial energy production (reviewed by Murray et al 2007) to prevent or reverse the low energy status of the failing heart.…”

Section: Mitochondrial Function In the Prevention And Treatment Cardimentioning

confidence: 99%

Mitochondria in the human heart

Lemieux

Hoppel

2009

J Bioenerg Biomembr

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The heart relies mainly on mitochondrial metabolism to provide the energy needed for pumping blood to oxygenate the organs of the body. The study of mitochondrial function in the human heart faces many obstacles and elucidation of the role of mitochondria in cardiac diseases has relied mainly on studies with animal models. Cardiac diseases are the leading cause of mortality worldwide. With the emergence of new therapies to treat and prevent heart disease, some aiming at metabolic modulation, a need for acquiring a better understanding of mitochondrial function in the human heart becomes apparent. Our review is aimed at specific evaluation of the human heart in terms of (1) methods to understand mitochondrial function, with particular emphasis on integrated function, (2) data on the role of mitochondrial dysfunction in cardiovascular disease, and (3) possible applications of this knowledge in the treatment of patients with cardiac disease.

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“…9 It has been suggested that mechanical unloading provides enough improvement to make cardiac transplantation unnecessary in some patients, 10 although others have disagreed with this contention. 11 Recent studies comparing tissue removed at LVAD implantation to the heart at transplantation have suggested that LVAD support improves the structure and function of cardiac myocytes, leading to decreased cell size, 12,13 increased contractility of cells 13,14 and muscles, 15 improved function of intracellular organelles, 15,16 and altered gene expression. 15,17,18 An important compensatory mechanism for maintaining adequate tissue perfusion during functional impairment of the heart is augmentation of cardiac output by the sympathetic nervous system.…”

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confidence: 99%

Mechanical Unloading Restores β-Adrenergic Responsiveness and Reverses Receptor Downregulation in the Failing Human Heart

et al. 2001

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Background-Mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in clinically documented reversal of chamber dilation and improvement of cardiac function. We tested the hypothesis that LVAD support normalizes the ability of cardiac muscle to respond to sympathetic nervous system stimulation by reversing the downregulation of ␤-adrenergic receptors. Methods and Results-Human LV tissue was obtained from nonfailing hearts of unmatched organ donors and failing hearts at the time of transplantation, with or without LVAD. Baseline contractile parameters and inotropic response to a ␤-adrenergic agonist were measured in isolated trabecular muscles. ␤-Adrenergic receptor density was quantified by radioligand binding. Results showed a significant increase in the response to ␤-adrenergic stimulation after LVAD (developed tension increased by 0.76Ϯ0.09 g/mm 2 in nonfailing, 0.38Ϯ0.07 in failing, and 0.68Ϯ0.10 in failingϩLVAD; PϽ0.01), accompanied by an increased density of ␤-adrenergic receptors (58.7Ϯ9.6 fmol/mg protein in nonfailing, 26.2Ϯ3.8 in failing, and 63.0Ϯ8.3 in failingϩLVAD; PϽ0.05). These changes were unrelated to the duration of support. Conclusions-Data demonstrate that mechanically supporting the failing human heart with an LVAD can reverse the downregulation of ␤-adrenergic receptors and restore the ability of cardiac muscle to respond to inotropic stimulation by the sympathetic nervous system. This indicates that functional impairment of cardiac muscle in human heart failure is reversible.

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Improvement of myocardial mitochondrial function after hemodynamic support with left ventricular assist devices in patients with heart failure

Abstract: Cardiomyocyte mitochondrial function is improved by long-term therapy with a left ventricular assist device. This improvement suggests that cardiomyocyte metabolic dysfunction in heart failure may be reversed with left ventricular assist device support.

Cited by 104 publications

References 22 publications

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Molecular Changes After Left Ventricular Assist Device Support for Heart Failure

Mitochondria in the human heart

Mechanical Unloading Restores β-Adrenergic Responsiveness and Reverses Receptor Downregulation in the Failing Human Heart

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