Reverse remodeling following insertion of left ventricular assist devices (LVAD): A review of the morphological and molecular changes

Abstract

Left ventricular assist devices (LVAD) are used to "bridge" patients with end-stage heart failure until transplantation of a donor heart can be performed ("bridge to transplantation"). However, in a subset of patients, support by LVAD sporadically results in improved cardiac function, with heart transplantation no longer necessary even after removal of the LVAD ("bridge to recovery"). Also, LVAD appears to be an optional treatment alternative to heart transplantation in patients with contraindications for organ replacement ("destination therapy"). The processes resulting in these effects have descriptively been termed "reverse remodeling". Although the molecular mechanisms are incompletely understood at present, there are several aspects of the reverse remodeling process that have been identified in the past. Alterations of many molecular pathways are involved in the development of chronic heart failure. Some of these appear to be reversible and have been shown to be regulated by LVAD treatment. LVAD lead to lowered cardiac pressure and volume overload in the myocardium followed by decreased ventricular wall tension, reduced cardiomyocyte hypertrophy, improved coronary perfusion and decreased chronic ischemia. Improved coronary flow and myocardial perfusion as well as decreased ventricular wall tension may possibly alter the molecular systems involved in the development of chronic cardiac insufficiency. Aside from describing the morphological changes, this review focuses on the roles of signal transduction, transcriptional regulation, apoptosis, stress proteins, matrix remodeling, and neurohormonal signaling in the failing human heart before and after mechanical circulatory support.

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

“…These conflicting results indicate the difficulties in proper assessment of changes of interstitial fibrosis rather than differences between the studied cohorts. As indicated previously we think [10], that the striking differences obtained concerning this parameter by various groups is due to methodological problems. Computerized semiquantitative analysis of Sirius Red stained myocardial specimens yield density data such as sectional profile areas per unit area or threedimensional quantities per unit volume.…”

“…the heart) decreases in size due to hypertrophy regression. Thus, one approach to circumvent the reference trap problem in the measurement of interstitial fibrosis in future studies would be to assess the heart volume based on MRI studies and extrapolate the volume fraction of interstitial connective tissue measured on histological sections to the absolute volume of fibrosis [10,[37][38][39][40].…”

“…The structural and molecular changes occurring in the myocardium during CHF ("cardiac remodeling") have been intensively studied in the *Address correspondence to this author at the Institute of Pathology and Neuropathology, University Hospital of Essen, University of DuisburgEssen, Hufelandstrasse 55, 45147 ESSEN, Germany; Tel: ++49 (0)201 723 3357; Fax: ++49 (0)201 723 3378; E-mail: hideo.baba@uk-essen.de past [7,8]. There is now compelling evidence that prolonged near-total unloading of the left ventricle in CHF is associated with numerous morphological and molecular changes in the myocardium ("reverse remodeling") [9,10], which can be accompanied by functional improvement and decreased cardiac dilation [11]. Despite encouraging data on morphological and molecular changes of the affected heart, clinical cardiac recovery sufficient to allow device removal ("weaning") is reported to occur only in a small subset of individuals [12][13][14][15][16].…”

Cardiovascular autonomic control in patients undergoing left ventricular assist device (LVAD) support and pharmacologic therapy

“…The unloading of the failing myocardium by LVAD implantation, combined with optimal pharmacotherapeutic interventions results in multiple favourable physiological changes including partial restoration of hemodynamic responses to exercise [18], 'reverse remodelling' [28] of the myocardium which has been well described at both macrostructural [29] and cellular levels [30]. Burkhoff et al [29] suggest restoration of the 'normal neurohormonal milieu' is a precursor to such adaptations but descriptions of this autonomic normalisation are scarce.…”

Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy

“…LVAD therapy decreases LV dimensions, reduces inflammation, and increases LV ejection fraction (EF) during mechanical support (11). As a consequence of pressure-volume unloading, the abnormalities in cardiac and peripheral hormonal and cytokine levels seen after HF (such as elevated cardiac TNF-␣ and circulating creatinine and bilirubin) may be reversed, and these changes can promote myocardial recovery (38), and even LVAD removal. However, weaning of LVAD is uncommon and no patients in the current study achieved myocardial recovery sufficient for device weaning.…”