Right ventricular remodeling in restrictive ventricular septal defect

Abstract

Restrictive ventricular septal defect (rVSD) presents with little/no hemodynamic aberrations despite a patent septal defect. Clinically, these patients are observed with the hope that the defect will functionally close over time without the need for surgical repair and development of heart failure. Without evidence supporting a definitive therapeutic strategy, rVSD patients may have increased risk of a poor outcome. We tested the hypothesis that rVSD results in subclinical RV diastolic dysfunction and molecular remodeling. Five pigs underwent surgical rVSD creation. Echocardiography, hemodynamics, myocyte contractility experiments, and proteomics/Western blot were performed 6-weeks post-rVSD and in controls. *p < 0.05. LV and RV hemodynamics in rVSD were comparable to controls. The tricuspid valve early/late diastolic inflow velocity ratio (TV E/A ratio) decreased from 1.6 ± 0.05 in controls to 1.0 ± 0.08* in rVSD, indicating RV diastolic dysfunction. rVSD RV myocytes showed abnormalities in contraction (departure velocity (Vd) − 51%*, Vd time +55%*) and relaxation (return velocity (Vr) −50%*, Vr time +62%*). Mitochondrial proteins (fatty acid, TCA cycle) increased 2-fold*, indicating heightened RV work. Desmin protein upregulated 285%* in rVSD RV myocardium, suggesting cytoskeletal remodeling. rVSD causes RV diastolic dysfunction, myocyte functional impairment, and mitochondrial/cytoskeletal protein upregulation in our model. Desmin upregulation may hinder sarcomeric organization/relaxation, representing a key subclinical early marker for future RV dysfunction. TV E/A measurements are a non-invasive modality to assess rVSD patients for diastolic dysfunction. Translational research applications may lead to fundamental changes in the clinical management of rVSD by providing evidence for early repair of the defect.

Immunohistochemical distribution of desmin in the human fetal heart

“…In this regard, desmin expression in the atrium is not related to MHC isozyme switching attributable to stress, but rather is a feature of a-MHC isozyme maturation. Monreal et al (2010) reported that, in ventricular septal defect, desmin upregulation in the adult myocardium is related to right ventricular remodeling. In the context of myocardial overload and remodeling, it was speculated that in fetuses, involvement of the venous wall in atrial development caused mechanical stress, thus inducing desmin expression.…”

The pig as an animal model for human pathologies: A proteomics perspective

“…Despite this adaptation, electron transport proteins of hibernating myocardium did not normalise after revascularisation . The analysis of myocytes in failing hearts with restrictive ventricular septal defects showed increased desmin and mitochondrial proteins, suggesting mitochondrial/cytoskeletal protein up‐regulation in diastolic dysfunction . In right ventricular hypertrophy, expression of calsarcin‐1 and vinculin increased, as did certain metabolic enzymes, whereas F 1 ‐ATPase beta‐chain and HSP 70 decreased .…”

The Right Heart in Congenital Heart Disease, Mechanisms and Recent Advances

“…Impairment in ventricular contractility was also suggested in patients with RVPO. In the study of Monreal et al, impairment in contraction and relaxation of RV cardiomyocytes were observed in a restrictive VSD experimental model [34]. Previous studies in animals and in adults with PAH have shown that right ventricular contractility measured by ventricular elastance is usually increased but often insufficient to compensate for the increase in afterload and ventriculo-arterial uncoupling which occurs [35].…”

“…Experimental studies suggest that cardiomyocytes hypertrophy and significant fibrosis can be associated with late impaired contractility [46]. Cytoskeletal remodeling may also induce right ventricular dysfunction via desmin protein upregulation [34]. …”