Reverse Remodeling With Left Ventricular Assist Devices

Abstract

This review provides a comprehensive overview of the past 25+ years of research into the development of left ventricular assist device (LVAD) to improve clinical outcomes in patients with severe end-stage heart failure and basic insights gained into the biology of heart failure gleaned from studies of hearts and myocardium of patients undergoing LVAD support. Clinical aspects of contemporary LVAD therapy, including evolving device technology, overall mortality, and complications, are reviewed. We explain the hemodynamic effects of LVAD support and how these lead to ventricular unloading. This includes a detailed review of the structural, cellular, and molecular aspects of LVAD-associated reverse remodeling. Synergisms between LVAD support and medical therapies for heart failure related to reverse remodeling, remission, and recovery are discussed within the context of both clinical outcomes and fundamental effects on myocardial biology. The incidence, clinical implications and factors most likely to be associated with improved ventricular function and remission of the heart failure are reviewed. Finally, we discuss recognized impediments to achieving myocardial recovery in the vast majority of LVAD-supported hearts and their implications for future research aimed at improving the overall rates of recovery.

Keywords: biology; heart failure; myocardium; technology; therapeutics.

Figure 1.

Basic principles of the hemodynamics of continuous flow left ventricular assist device (LVAD) support. A. Each device is characterized by an RPM-dependent relationship between pressure gradient and flow. B. LVAD support increases aortic pressure and decreases LV pressure such that they can become uncoupled. As a result of the time-varying pressure gradient between aorta and LV (C) LVAD flow also varies over time (D). E. LVAD support leads to LV unloading characterized by leftward shift of the pressure-volume loop and loss of isovolumic phases.

Figure 2.

A. Time-dependent LVAD-associated reverse structural remodeling as indexed by leftward shifts towards normal of the end-diastolic pressure-volume relationship. B. Volume at a filling pressure of 30 mmHg (V₃₀) as a function of duration of support in comparison to normal (open circles) and hearts that did not undergo LVAD support (diamonds); squares and triangles are data from patients supported by LVAD for 0–40 days and >40 days, respectively.

Figure 3.

Effects of Mechanical Unloading on Cardiomyocyte and Non-Cardiomyocyte Components of LV Remodeling. LVAD support is associated with regression of cardiomyocyte hypertrophy, improved calcium handling, improved mitochondrial ultrastructure, improved cytoskeletal organization, no change in cardiomyocyte apoptosis, improved cardiomyocyte regeneration, no change or increase in myocardial fibrosis, macrophage phenotype switch, endothelial cell activation, increased microvascular density, and increased fibrosis of the coronary adventitia.

Figure 4.

A) Transcriptional Changes in Failing Human Hearts following Mechanical Unloading with LVAD Support demonstrating persistent dysregulation in >90% of coding and non-coding transcripts in Ischemic and Non-Ischemic Heart Failure (adopted from Yang et al.) B) Transcriptional Changes in Mouse Model of Myocardial Recovery using conditional expression of TNF-associated factor 2 (TRAF2) demonstrating persistent dysregulation of HF transcriptional profile in the recovered mouse hearts (ttA-TRAF2 dox) by Venn-diagram, hierarchical clustering, and principal component analysis (Topkara et al.).