Left ventricular assist device-induced reverse remodeling: it's not just about myocardial recovery

Abstract

The abnormal structure, function and molecular makeup of dilated cardiomyopathic hearts can be partially normalized in patients supported by a left ventricular assist device (LVAD), a process called reverse remodeling. This leads to recovery of function in many patients, though the rate of full recovery is low and in many cases is temporary, leading to the concept of heart failure remission, rather than recovery. Areas covered: We summarize data indicative of ventricular reverse remodeling, recovery and remission during LVAD support. These terms were used in searches performed in Pubmed. Duplication of topics covered in depth in prior review articles were avoided. Expert commentary: Although most patients undergoing mechanical circulatory support (MCS) show a significant degree of reverse remodeling, very few exhibit sufficiently improved function to justify device explantation, and many from whom LVADs have been explanted have relapsed back to the original heart failure phenotype. Future research has the potential to clarify the ideal combination of pharmacological, cell, gene, and mechanical therapies that would maximize recovery of function which has the potential to improve exercise tolerance of patients while on support, and to achieve a higher degree of myocardial recovery that is more likely to persist after device removal.

Keywords: Heart failure; exercise tolerance; extracellular matrix; heart assist device; inflammation; micro-RNAs; myocardial remission; sympathetic activation.

Figure 1

A. End-diastolic pressure-volume relations (EDPVRs) of ex-vivo hearts explanted at the time of heart transplant. “CHF” are patients with severe heart failure transplanted without LVAD support. “LVAD” are patients with severe heart failure who were transplanted after a prolonged period of LVAD support. “Normal” are normal donor hearts not suitable for heart transplantation. Data from Levin et al (5). Reproduced with permission from Levin HR, Oz MC, Chen JM, Packer MP, Rose EA, Burkhoff D. Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading. Circulation 1995; 91:2717. B. Ex-vivo EDPVRs from hearts transplanted without any support, those supported by a full support axial flow pump and those supported with a partial support LVAD that provides less ventricular unloading. Data from Jacobs et al (12). Reprinted from Klotz S, Burkhoff D, Garrelds IM, Boomsma F, Danser AH. The impact of left ventricular assist device-induced left ventricular unloading on the myocardial renin-angiotensin-aldosterone system: therapeutic consequences? Eur Heart J 2009. with permission from Elsevier.

Figure 2

Rates of recovery at different institutions according to whether or not adjuvant medical therapy is used during LVAD support with the goal of optimizing reverse remodeling and increasing the percentage of patients who can potentially be explanted. Data from Drakos and Mehra (30). Reprinted from Drakos SG, Mehra MR. Clinical myocardial recovery during long-term mechanical support in advanced heart failure: Insights into moving the field forward. J Heart Lung Transplant 2016; 35:413–20., with permission from Elsevier.

Figure 3

Rates of spontaneously improved LV function as a function of underlying etiology. Data from Giverts and Mann (25). Reproduced from Givertz MM, Mann DL. Epidemiology and natural history of recovery of left ventricular function in recent onset dilated cardiomyopathies. Curr Heart Fail Rep 2013; 10:32, with permission of Springer.

Figure 4

Numbers of genes with abnormal abundances observed in the heart failure state and during the reverse remodeling in an experimental model of heart failure induced by inflammation. This study revealed a number of abnormally expressed genes that normalize during recovery from heart failure, that are persistently abnormal during recovery, and genes that are newly, abnormally expressed during recovery. See text for further details. Data from Topkara et al (40). Republished with permission of The American Society for Clinical Investigation. JCI Insight. 2016;1(4):e86038. doi:10.1172/jci.insight.86038

Figure 5

A scheme by which mechanical and neurohormonal factors interact to modulate extracellular matrix metabolism that can help explain why, during LVAD support, extracellular matrix increases in some patients and decreases in other patients. Reprinted from Klotz S, Danser JAH, Burkhoff D. Impact of left ventricular assist device (LVAD) support on the cardiac reverse remodeling process. Prog Biophys Mol Biol 2008. with permission from Elsevier.

Figure 6

Hemodynamic changes during exercise in LVAD patients. Patients with better intrinsic LV function can exercise more. See text for details. Reproduced with permission from Martina J, Jonge N, Rutten M, et al. Exercise hemodynamics during extended continuous flow left ventricular assist device support: the response of systemic cardiovascular parameters and pump performance. Artif Organs 2013; 37:754–62.