Advanced Molecular, Metabolic, and Imaging Approaches to Characterizing Right Ventricular Failure

Authors, Journal, Affiliations, Type, DOI

• Authors: Soni Savai Pullamsetti (Chair), Rebecca R. Vanderpool, Frances de Man, Vinicio A. de Jesus Perez, Anna R. Hemnes, Monica Mukherjee, Laura Mercer-Rosa, Edda Spiekerkoetter, Khodr Tello, Sébastien Bonnet (Vice Chair); on behalf of AHA councils
• Journal: Circulation 2026;153:e00–e00
• Affiliations: Justus Liebig University / Max Planck Institute (Germany); Ohio State University; VU University Medical Center (Netherlands); Stanford University; Vanderbilt University; Johns Hopkins University; Children's Hospital of Philadelphia; Université Laval (Canada)
• Type: AHA Scientific Statement (consensus/review)
• DOI: 10.1161/CIR.0000000000001422

Overview

This 2026 AHA Scientific Statement provides a comprehensive synthesis of RV failure in pulmonary hypertension (PH), covering the hemodynamic and molecular mechanisms driving RV dysfunction, tools for distinguishing adaptive from maladaptive RV remodeling, and future directions including multiomics integration, AI-driven risk stratification, and personalized treatment platforms. The Ees/Ea ratio (<0.7 = uncoupling threshold) and its noninvasive surrogates (TAPSE/sPAP, RV free wall strain) are established as the cornerstone of RV–PA coupling assessment. Sotatercept, an activin ligand trap, is highlighted as the most significant recent therapeutic advance, having received FDA approval for PAH with demonstrated improvements in PA pressures, RV–PA coupling, and RV mass in the STELLAR and SPECTRA trials.

Keywords

AHA Scientific Statements · biomarkers · heart failure · hypertension, pulmonary · omics/multiomics · ventricular remodeling

Key Takeaways

Hemodynamic Stress and RV–PA Uncoupling

• RV failure in PH results from chronic pressure overload → hypertrophic remodeling → eventual maladaptive remodeling with RV dilation, fibrosis, diastolic stiffness, and RV–PA uncoupling
• Ees/Ea ratio is the gold-standard measure of RV–PA coupling: optimal 1.5–2.0; uncoupling defined at Ees/Ea <≈0.7; below this threshold, RV cannot sustain contractility against afterload
• RV afterload is multifactorial: includes PVR, pulmonary arterial compliance, characteristic impedance, and pulsatile load — not PVR alone
• Advanced/maladaptive disease: RV dilation + functional tricuspid regurgitation accelerates haemodynamic instability
• Clinical manifestations of RV–PA uncoupling: reduced stroke volume, elevated RA pressure, impaired perfusion, susceptibility to ischaemia–reperfusion injury, systemic venous congestion
• Considerable clinical heterogeneity exists: some patients show maladaptation early without responding to therapy; others maintain RV adaptation for years

Inflammation and Fibrosis

• Inflammatory cytokines (TNF-α, IL-6, IL-1β) are elevated in PH and correlate with RV failure severity
• Monocyte-derived macrophages activate NLRP3 inflammasome — key mediator of proinflammatory environment in RV failure
• Mast cell recruitment and macrophage infiltration markedly increase during RV remodeling
• Inflammation activates fibroblasts → pathological ECM deposition → RV fibrosis → increased stiffness, impaired systolic and diastolic function → self-perpetuating cycle
• Key fibrotic signalling pathways: TGF-β, MMPs, integrins; α5β1 integrin upregulation linked to RV fibrosis and contractile dysfunction
• Anti-inflammatory agents (anakinra, tocilizumab for IL-1/IL-6 blockade) under investigation; TGF-β/integrin inhibitors in preclinical/early clinical trials

Mitochondrial Dysfunction and Metabolic Reprogramming

• Normal RV primarily uses fatty acid oxidation (FAO) for energy; during compensatory hypertrophy, a metabolic shift toward glucose metabolism occurs
• With PH progression, right ventricle increasingly relies on glycolysis even in presence of adequate oxygen — Warburg effect
• Maladaptive remodeling: progressive lipid accumulation in cardiomyocytes → lipotoxicity; increased reactive oxygen species → oxidative stress → impaired RV contractility
• Mitochondrial dysfunction → vulnerability to ischaemia–reperfusion injury → accelerates RV failure
• Tricarboxylic acid cycle gene expression decreases in RV decompensation in human samples
• Therapeutic strategies targeting FAO restoration, mitochondrial biogenesis, or efficiency show promise in preclinical models

Emerging Molecular Targets

• PARP1–PKM2 axis: PARP1 overactivation promotes PKM2 activity → metabolic dysfunction + oxidative stress + inflammation; PARP1 inhibition or PKM2 modulation protective in rodent PAB models
• Wnt/β-catenin signalling: Activates cardiac fibroblasts and promotes RV fibrosis; inhibition of Wnt–β-catenin–FOSL pathway ameliorates RV remodeling
• Estradiol/ERα: 17β-estradiol and ERα protect RV function via BMPR2/apelin upregulation — sex-specific determinant of RV adaptation
• BMPR2: Mutations (most common in hereditary PAH) associated with increased mortality/transplantation risk and more severe RV dysfunction independent of RV afterload; BMPR1A locus is a female-specific genetic determinant of improved RVEF (UK Biobank, n>30,000)
• FK506 (tacrolimus): Reduces RV fibrosis in mouse pressure-overload models via dual BMP signalling activation + immune modulation
• Sotatercept: FDA-approved activin ligand trap for advanced PAH; STELLAR trial showed improvements in PA pressures, PA compliance, PA–RV coupling; SPECTRA trial demonstrated decreased RV mass, increased haemoglobin and peak VO₂; potential general cardioprotective effects via direct cardiomyocyte action

Distinguishing Adaptive from Maladaptive RV Remodeling — Definitions

• Adaptive remodeling: Concentric RV hypertrophy; minimal chamber dilation; limited fibrosis; preserved systolic function; normal filling pressures — RV maintains cardiac output
• Maladaptive remodeling: Chamber dilation; insufficient contractility for given afterload; elevated filling pressures; progressive RV fibrosis; associated with symptomatic HF, decreased exercise tolerance, arrhythmias, and mortality
• Diastolic dysfunction may occur even in adaptive phase due to interstitial fibrosis and reduced titin β-adrenergic phosphorylation
• Transition mechanism is poorly understood; influenced by aetiology (CHD, left heart disease, lung disease), afterload severity, age, sex, comorbidities, and genetic predisposition

Imaging and Haemodynamic Measures

• Gold standard: Ees/Ea ratio via RV conductance catheter (invasive)
• Echocardiography: TAPSE/sPAP — key noninvasive RV–PA coupling index; prognostic across PH types; reflects longitudinal shortening only; influenced by angulation and loading conditions
• RV free wall strain/sPAP: Emerging measure superior to TAPSE/sPAP for predicting clinical outcomes in PAH
• 3D echocardiography / CMR volumetry: More comprehensive; RVEF changes in response to therapy recognised as robust marker of disease progression and treatment efficacy
• CMR tissue characterisation: LGE and T1/T2 mapping detect myocardial fibrosis and inflammation, both associated with maladaptive RV remodeling and worse outcomes
• 4D flow CMR: Clarifies RV and RA morphology over time; predicts PH vs RHC; assesses tricuspid insufficiency impact on RA function
• Cardiac PET: Detects metabolic shifts (oxidative phosphorylation → glycolysis) as early marker of RV dysfunction; ⁶⁸Ga-Dotatate (inflammation) and ¹¹C-CGP-12177 (β-adrenergic receptor) tracers offer mechanistic validation
• See Table 4 in source for imaging studies with prognostic evidence (RVEF, SV/ESV, TAPSE, TAPSE/sPAP, RV free wall strain/sPAP, FAC, GLS/sPAP)

Biomarkers of RV Dysfunction

• H19 lncRNA: Upregulated in decompensated RV failure; modulates TGF-β signalling and ECM deposition; potential prognostic marker and RNA-based therapeutic target
• SPARCL1 and CILP1: Novel ECM protein biomarkers strongly correlated with RV fibrosis and maladaptive remodeling; elevated in advanced RV failure
• FSTL3 (follistatin-like 3): Inflammatory glycoprotein reflecting active myocardial inflammation/fibrosis; elevated FSTL3 associated with poor outcomes in advanced RV dysfunction
• Succinate and lactate: Elevated circulating levels indicate mitochondrial dysfunction; succinate → oxidative stress + inflammation; lactate → Warburg reliance even with adequate O₂
• NID1, C1QTNF1, CRTAC1: Predictive biomarkers of maladaptive RV states from integrated transcriptome + proteome profiling; correlate with CMR measures and clinical outcomes
• LTBP-2: Fibrosis-related circulating protein improving long-term survival risk stratification in PAH
• Acylcarnitines: Elevated plasma levels associated with increased RV lipid content in PAH
• See Table 1 in source for comprehensive molecular mediators (signalling pathways, ECM/fibrosis, metabolic/mitochondrial)

Multiomics and Future Directions

• Multiomics studies (Tables 2 and 3) integrating transcriptomics, proteomics, and metabolomics identify distinct molecular signatures for adaptive vs maladaptive RV remodeling in animal models and human PAH cohorts
• Porcine RV models closely resemble human RV dysfunction in metabolic pathway changes
• AI and machine learning: Integration of omics + imaging data for predictive models, patient stratification, and clinical trial design
• Personalized treatment platforms: iPSC-derived cardiomyocytes, RV organoids, and living RV slices; robotic RV platform (Singh et al.) for real-time contractile reserve and mechanotransduction assessment
• Large-scale prospective studies needed to integrate advanced imaging metrics into simplified risk stratification models — ESC/ERS guidelines currently lack comprehensive ongoing risk assessment models

Limitations of the Document

• Primarily focused on RV failure in the context of chronic pressure overload (PH); acute RV failure (PE, ARDS, sepsis) is explicitly out of scope
• Most molecular and biomarker data are preclinical or from small human cohorts; limited prospective validation in large clinical cohorts
• Mechanistic pathways largely derived from animal models (rodent PAB, MCT, HxSu); translational relevance to human RV physiology requires confirmation
• Current imaging studies largely descriptive (correlative) rather than providing causal mechanistic insight
• ESC/ERS guidelines lack a comprehensive model for ongoing risk assessment in PH — highlights a practice gap

Key Concepts Mentioned

• concepts/RV-PA-Coupling — central concept; Ees/Ea ratio thresholds, noninvasive surrogates
• concepts/PAH-Risk-Stratification — RV function as key risk parameter
• concepts/Late-Gadolinium-Enhancement — CMR fibrosis detection in maladaptive RV remodeling
• concepts/HFpEF — RV dysfunction recognised in HFpEF context

Key Entities Mentioned

• entities/Pulmonary-Hypertension — primary disease context; sotatercept updated
• entities/CTEPH — Group 4 PH; RV failure implications
• entities/Heart-Failure — RV failure as major determinant of HF outcomes

Wiki Pages Updated

• Created: wiki/sources/rv-failure-aha-2026.md
• Created: wiki/concepts/RV-PA-Coupling.md
• Updated: wiki/entities/Pulmonary-Hypertension.md — RV failure section and sotatercept
• Updated: wiki/sourceindex.md
• Updated: wiki/wikiindex.md