Hemodynamic and Metabolic-Inflammatory Phenotyping Across the Cardiac Index Spectrum in Moderate and Severe Tricuspid...

Moderate and severe tricuspid regurgitation (TR) is associated with poor outcomes, yet current grading systems do not fully capture circulatory heterogeneity. We investigate the relationship of cardiac index (CI) with rest-exercise hemodynamics, metabolic and inflammatory profiles, and clinical outcomes in moderate and severe TR.

We prospectively enrolled 300 outpatients with atrial secondary, nonatrial secondary, and lead-associated moderate and severe TRs without ≥moderate left-sided valve disease. All underwent comprehensive laboratory profiling and ultrasound evaluation at rest and during cardiopulmonary exercise. Patients were stratified by CI tertiles and followed clinically (primary end point: all-cause mortality or heart failure hospitalization).

CI decreased with TR severity but showed wide interindividual variability. In patients with low CI, severe forward flow limitation was associated with more advanced right ventricle-pulmonary arterial uncoupling and biatrial dysfunction (P<0.05 versus the other tertiles), identifying a hypodynamic-uncoupled profile. Conversely, high CI identified a hyperdynamic-congestive phenotype characterized by advanced congestion, reduced systemic vascular resistance, and heightened systemic inflammation, metabolic-nutritional derangements, and mitochondrial dysfunction (P<0.05 versus the other tertiles). Intermediate CI showed the most favorable hemodynamic and laboratory profile. A U-shaped relationship between CI and adverse outcomes was observed, with the lowest risk at intermediate values. This pattern persisted across TR severity, cause, staging systems, and adiposity categories (P<0.05 for all).

In moderate and severe TRs, CI profiling captures cardiac and extracardiac determinants of flow and independently predicts outcomes beyond conventional TR grading and staging. Both low and high CIs identify high-risk patients, while an intermediate CI indicates a balanced, prognostically favorable state. CI profiling may refine risk stratification, guide individualized treatment strategies, and optimize patient selection and timing for tricuspid valve interventions.