Cardiac index refines risk stratification in tricuspid regurgitation beyond valve severity

Background Moderate and severe tricuspid regurgitation (TR) are common across the heart failure (HF) spectrum and confer an adverse prognosis. Although TR is traditionally regarded as a low-flow condition, both reduced and excessive forward flow may reflect maladaptive circulatory states. Purpose To investigate the relationship between cardiac index (CI), rest–exercise hemodynamics, multi-organ congestion, metabolic–inflammatory profiles, and clinical outcomes in patients with moderate and severe TR. Methods We prospectively enrolled patients with ≥moderate TR, without ≥moderate left-sided valve disease or primary TR. All underwent comprehensive laboratory profiling and ultrasound assessment at rest and during cardiopulmonary exercise. Patients were stratified by CI tertiles and followed for the composite endpoint of all-cause mortality or HF hospitalization. Results We analyzed 300 patients, including 178 with moderate TR, 96 with severe TR, and 26 with massive or torrential TR. TR etiology was atrial secondary in 165 patients, ventricular secondary in 67, and lead-associated in 68. CI decreased with increasing TR severity but showed wide inter-individual variability and a weak correlation with resting effective regurgitant orifice area (r = -0.18, p = 0.002). Ultrasound-based congestion differed across CI tertiles (Figure 1): the congestion score was lowest at intermediate CI and increased at both extremes, with advanced congestion (score ≥4) most prevalent in the high-CI tertile (65% vs 55% and 33% in low and intermediate CI; p<0.0001). Low CI identified a hypodynamic–uncoupled phenotype, characterized by impaired right ventricular–pulmonary arterial coupling, worse biatrial function, and reduced peak oxygen consumption (all p<0.01 vs other CI tertiles). In contrast, high CI defined a hyperdynamic–congestive phenotype, with markedly reduced systemic vascular resistance, heightened inflammatory activation (C-reactive protein, IL-6, circulating cell-free mitochondrial DNA), iron deficiency, and poorer nutritional status (all p<0.01 vs other CI tertiles). Over a median 18-month follow-up, CI showed a robust U-shaped association with outcomes, with the lowest risk at ~2.0 L/min/m² (Figure 2A). Both low and high CI tertiles were independently associated with a higher risk of the primary endpoint than intermediate CI (adjusted HRs of 2.11 [1.23–3.59] and 1.89 [1.08–3.31], respectively), consistently across TR severity and etiology. Among patients with moderate TR, stress-induced worsening of TR identified a subgroup with outcomes comparable to ≥severe TR at rest (Figure 2B). Conclusions In moderate and severe TR, CI integrates cardiac and extracardiac determinants of flow and provides incremental prognostic information beyond valve severity. Both low and high CI identify high-risk circulatory phenotypes, whereas intermediate CI denotes a balanced and prognostically favorable state.Figure 1Figure 2