Molecular determinants of right ventricular diastolic dysfunction: stratifying evidence from validated to inferred mechanisms

Background Right ventricular (RV) diastolic dysfunction is increasingly recognised as prognostically important, yet its molecular underpinnings remain fragmented. The RV has distinct embryologic origins, a compliant N2BA-dominant titin isoform profile, and chamber-specific proteomic signatures. Whether cellular mechanisms of diastolic impairment validated in LV tissue translate to the RV is uncertain. Purpose To appraise the molecular and cellular mechanisms implicated in RV diastolic dysfunction, stratify each by human RV evidence strength, and identify critical translational gaps. Methods As part of a state-of-the-art review, eight putative mechanistic pathways were evaluated against a three-tier evidence hierarchy: Validated (demonstrated in human RV tissue with correlation to invasive diastolic indices), Supported (present in human RV tissue without direct diastolic correlation), or Inferred (demonstrated only in preclinical models or extrapolated from LV data). Each was assessed for primary diastolic impact (passive stiffness via beta/Eed versus active relaxation via Tau). Results Three mechanisms met Validated criteria, all derived almost exclusively from PAH cohorts. RV fibrosis and ECM remodelling correlated with invasive stiffness (beta, Eed) in PAH histology, though causality remained unclear and HFpEF replication was absent. Titin N2B hypophosphorylation increased passive sarcomeric stiffness in RV biopsies, though isoform switching was unconfirmed in human PAH with small samples. Blunted beta-adrenergic/PKA signalling caused sarcomeric hypophosphorylation, increasing stiffness. One mechanism met Supported criteria: sarcomeric protein dynamics, where myosin heavy-chain isoform shifts and DRX/SRX state dysregulation were present in human RV tissue but only in HFrEF-PH, not PAH, with chamber-level diastolic impact uncertain. Four mechanisms remained Inferred. Metabolic dysfunction had strong preclinical support but no human RV mechanistic data. Sex hormone effects showed human prognostic associations but could not isolate myocardial from afterload effects. Calcium handling abnormalities (increased sensitivity, T-tubule disruption, SERCA2a dysfunction) were demonstrated in HFpEF septal biopsies but stratified RV phenotyping was absent. Cytoskeletal stiffening via microtubule detyrosination reduced viscoelasticity in rodent RV but human data remained LV-only. Conclusions Only three molecular mechanisms of RV diastolic dysfunction are validated in human tissue, all from PAH. Four pathways remain inferred from preclinical or LV extrapolation. Longitudinal human RV tissue studies with contemporaneous invasive phenotyping represent an explicit priority to bridge the gap between molecular mechanisms and clinical diastolic assessment.