Deep phenotyping the right ventricle to establish translational MRI biomarkers for characterization of adaptive and maladaptive states in pulmonary hypertension

Abstract

Deep phenotyping the right ventricle (RV) is essential for understanding the mechanisms of adaptive and maladaptive RV responses to pulmonary hypertension (PH). In this study, feature selection coupled with machine learning classification/ranking of specific cardiac magnetic resonance imaging (MRI) features from cine-MRI, flow-sensitized, and extracellular-volume techniques were used to assess RV remodelling in monocrotaline (MCT) and Sugen hypoxia (SuHx) PH rats. Early physiological changes associated with RV adaptation were detected along with prediction of RV maladaptive outcomes. Key adaptation features included haemodynamic alterations of pulmonary blood flow ejection and wave reflection, mild RV dilatation, progressive RV hypertrophy with subtle extracellular volume growth of RV wall. A dominant component of maladaptation was the extracellular matrix increase at RV insertion points and septum, observations compatible with histopathologic and RNA-sequencing results. The upregulation of mammalian target of rapamycin (mTOR) paralleled by AMP-activated protein kinase (AMPK) deactivation was seen at 4-week MCT and 8-week SuHx, along with reduced sarcoplasmic/endoplasmic reticulum Ca2+ATPase (SERCA2) expression, strongly associated with the RV systolic malfunction seen at this stage in vivo. The here established MRI features can serve as potential imaging biomarkers to evaluate PH treatment efficacy in preclinical studies and build up translational markers for the PH clinic.