**1. Introduction**

Cardiovascular diseases (CVDs) were responsible for an estimated 17.8 million deaths globally in 2017 and half of all people diagnosed with heart failure (HF) die within 5 years of diagnosis [1]. The major cause for CVD morbidity and mortality is HF, a complex clinical syndrome caused by many CV and other diseases that impairs the ability of the ventricle to fill with or eject blood. The key pathophysiological features involved in the development of HF are hypertrophy, fibrosis, apoptosis/ necrosis, microvasculature and extracellular matrix (ECM) abnormalities, and disturbances in electrophysiologic, adrenergic, and angiotensin signaling. Currently, heart transplantation is the gold standard treatment of patients with end-stage HF and the current 10-year survival rates of heart transplant recipients reach 53% [2].

During the last decades, mechanical circulatory support (MCS) devices with ventricular assist devices (VAD) have improved the outcomes of patients with advanced and end-stage HF, becoming a cornerstone therapy to bridge those patients to heart transplantation or recovery [3–7]. The synopsis of structural and molecular changes in the heart underlying the improved cardiac function after VAD implantation is called "reverse cardiac remodeling." Extensive investigations have been utilized to understand how the heart remodels to mechanical and volume unloading during MCS in a facet of stabilized neurohormonal and inflammatory responses [8–10]. MCS therapies lead to the improvement of HF symptoms with normalized cardiac size and shape with simultaneous biological remodeling on gene, molecular, cellular, and tissue levels [11–13]. Myocardial recovery is associated with improvements in structural, sarcomeric, sarcolemmal, and calcium handling-associated proteins expression and function [14–16]. Mechanical unloading has been shown to increase collagen crosslinking and myocardial stiffness [17], alter mitochondrial and metabolic processes [18], and promote repair and regeneration [19]. Moreover, studies focused on understanding the roles of biomarkers of neurohormonal activation, oxidative stress, and systemic inflammation pathways in patients with VAD support have identified a subset of vulnerable patients with risks of developing adverse events fostering the development of innovative applications of combined MSC and pharmacological agents [20, 21]. As a destination therapy MSC is critical in patients with the favorable restoration of cardiac function and this regenerative therapeutic strategy becomes a desirable alternative to heart transplantation [22]. Herein, we review and summarize research studies focused on understanding the roles of neurohormonal signaling, inflammation, signal transduction, cellular and subcellular remodeling, and transcriptional regulation in the failing human heart before and after MCS therapy.
