Effects of Angiotensin-Neprilysin Inhibition on the Biomechanics of Failing Right Ventricular Myocardium

Project: Research

Investigators

  • Danial Sharifikia (PI)

Description

Pulmonary hypertension (PH) is a disease resulting in increased right ventricular (RV) afterload, myocardial hypertrophy, ventricular remodeling and transmural RV fiber re-orientation. RV failure remains the main cause of mortality for nearly 70% of PH patients and, despite recent developments of therapeutics for management of PH, lung transplantation remains the only curative treatment. While current heart failure therapies (such as Valsartan) target the renin-angiotensin-aldosterone (RAAS) system, Sacubitril/Valsartan (Sac/Val) is a dual acting drug composed of a 1:1 mixture of neprilysin inhibitor Sacubitril and angiotensin receptor blocker Valsartan that targets both the RAAS and the natriuretic peptides system. Sac/Val has shown promising outcomes in reducing the risk of death for heart failure in a large placebo-controlled trial and we hypothesize it has the potential to positively affect RV remodeling in PH. In the first stage of the current proposal we aim to analyze the effects of Sac/Val treatment on the biomechanical behavior of failing RV myocardium. Chronic hypertension will be induced in Sprague-Dawley rats in four different cohorts (controls, PH, Sac/Val treatment and Valsartan treatment). Terminal invasive hemodynamic measurements will be performed after the treatment window to evaluate RV pressure-volume loops. The specimens will then undergo biaxial mechanical testing to characterize the mechanical behavior of RV free wall. Furthermore, structural architecture of collagen and myofibers will be analyzed via transmural histological staining. PH results in transmural re-orientation of RV myofibers which affects the filling and ejection mechanics of the RV, torsional motion of the heart and transmural wall stress. Knowledge of the kinematics of myocardial fibers helps better understanding/monitoring the contribution of fiber-level structures to tissue function; however, the depth limit of current imaging modalities often complicates the study of fiber kinematics transmurally. In an effort to understand the underlying mechanisms of fiber re-orientation in PH, in the second stage of the study, structurally-informed computational models and a novel imaging framework will be developed and verified with histological staining to analyze high-frequency ultrasound images for characterization of myofiber re-orientation under loading. This helps better understanding the underlaying biomechanics of RV remodeling in PH and Sac/Val-treated conditions.
Award amount$62,032.00
Award date01/01/2020
Program typePredoctoral Fellowship
Award ID20PRE35210429
Effective start/end date01/01/202012/31/2021
StatusActive