Right ventricular diastolic dysfunction across experimental disease models: unpacking diversity beyond pulmonary hypertension - a systematic review
J Healy, C Kocx, A Hemnes, D Kaye, F Haddad, S Lal, D S CelermajerAbstract
Background
Most preclinical understanding of right ventricular (RV) diastolic dysfunction derives from pulmonary hypertension (PH) models. However, 29 experimental disease models identified in a parent systematic review encompass not only PH-specific paradigms (MCT, SuHx, chronic hypoxia) but also ischaemia, metabolic injury, congenital mimics, and acute lung injury. The extent to which these non-PH models produce distinct RV diastolic phenotypes remains unclear.
Purpose
To systematically characterise the range and mechanistic diversity of RV diastolic dysfunction across experimental disease models, comparing PH-specific paradigms with non-PH pathological substrates.
Methods
A PRISMA-compliant systematic review was conducted across MEDLINE, Embase and Cochrane databases. Twenty-nine in-vivo mammalian disease models reporting invasive or imaging-based RV diastolic parameters were identified and categorised: PH-specific (MCT, SuHx, chronic hypoxia; n=21 studies) or non-PH disease (coronary ligation/MI, ARDS, ischaemia, Western diet/metabolic, TOF repair, conduction block; n=8 studies). Diastolic (RVEDP, Tau, dP/dtmin, EDPVR), systolic, mechanistic (fibrosis, hypertrophy, energetics, inflammation), and imaging domains were extracted across species (rat, mouse, dog, pig) and stratified by temporal phase.
Results
PH-specific models (n=21) produced a consistent diastolic signature. RVEDP was elevated from 1-4 weeks in MCT, SuHx, and hypoxia, with Tau prolongation subacutely and sustained at 1-3 months. dP/dtmin was reduced across MCT, SuHx, and MI from 1-4 weeks. EDPVR stiffening was noted subacutely. Fibrosis, hypertrophy, oxidative stress, and mitochondrial dysfunction were established by 1-3 months. RA enlargement was evident from 1-4 weeks with sustained dilatation at intermediate phases. Interventricular uncoupling was consistent from the subacute phase. Non-PH disease models (n=8) showed divergent, fragmented patterns. MI models (coronary ligation, n=3) demonstrated subacute RVEDP elevation and dP/dtmin reduction with fibrosis, but Tau data were limited to acute ischaemia. ARDS/micro-embolism models showed acute RVEDP elevation and compliance loss but lacked longitudinal follow-up. A Western diet/PAB model showed intermediate metabolic remodelling. A single TOF repair model provided the only chronic (180-day) disease data. No non-PH disease model provided serial P-V loop data. Tau was unrecorded in chronic disease models and EDPVR was not recorded at intermediate or chronic timepoints in any disease model.
Conclusions
PH-specific experimental models produce a well-characterised RV diastolic phenotype, but non-PH disease models (ischaemia, ARDS, metabolic, congenital) remain critically underrepresented with fragmented diastolic reporting. Dedicated investigation of disease-specific RV diastolic remodelling beyond PH, with serial invasive phenotyping, represents an explicit research priority.