Structural and functional cardiac profile after prolonged duration of mechanical unloading: potential implications for myocardial recovery

Abstract

Clinical and experimental studies have suggested that the duration of left ventricular assist device (LVAD) support may affect remodeling of the failing heart. We aimed to (1) characterize the changes in calcium/calmodulin-dependent protein kinase type II (CaMKII)δ, growth signaling, structural proteins, fibrosis, apoptosis and gene expression before and after LVAD support and (2) assess whether the duration of support correlated with improvement or worsening of reverse remodeling. LV apex tissue and serum pairs were collected in patients with dilated cardiomyopathy (n=25, 23 male) at LVAD implantation and after LVAD support at cardiac transplantation/LVAD explantation. Normal cardiac tissue was obtained from healthy hearts (n=4) and normal serum from aged-matched controls (n=4). The duration of LVAD support ranged from 48 to 1170 days (median duration 270 days). LVAD support was associated with CaMKIIδ activation, increased nuclear myocyte enhancer factor-2 (MEF2), sustained histone deacetylase-4 (HDAC4) phosphorylation, increased circulating and cardiac myostatin (MSTN) and MSTN signaling mediated by SMAD2, ongoing structural protein dysregulation and sustained fibrosis and apoptosis (all p<0.05). Increased CamKIIδ phosphorylation, nuclear MEF2, cardiac MSTN significantly correlated with duration of support. Phosphorylation of SMAD2 and apoptosis decreased with shorter duration of LVAD support but increased with longer duration of LVAD support. Further study is needed to define the optimal duration of LVAD support in patients with dilated cardiomyopathy.

Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis

“…A timely blockade of ACTRII after MI, at a time when pro-hypertrophic signaling has remitted, could be beneficial to prevent worsening wall thinning or aid in myocardial recovery programs. A second population that may benefit are HF patients supported with LV assisted devices (LVAD); these patients have increased MSTN levels and are at risk of myocardial atrophy with prolonged durations of LVAD support (1,11).…”

Myostatin as a Biomarker of Muscle Wasting and other Pathologies-State of the Art and Knowledge Gaps

“…In recent years, a number of studies were conducted on circulating and cardiac myostatin in cardiomyopathies of various origins. Myostatin was found to be upregulated in myocardial cells of patients with dilated cardiomyopathy, but not with ischemic cardiomyopathy [ 170 ], and higher in abundance both in myocardium and in serum [ 171 ]. Fernandez-Sola et al, demonstrated cardiac myostatin upregulation in hearts with cardiomyopathy of hypertensive, alcoholic, valve and coronary origins [ 172 ].…”

What Means Fourth Industrial Revolution for Medicine

“…Clinical studies reveal that prognosis is similar with that in heart transplant (9)(10)(11). The most interesting observation was that, after being unloaded by the mechanical device for several months, some patients (not all) recover the contractility of the native myocytes.…”