Cardiac index integrates cardiac and extracardiac dysfunction in tricuspid regurgitation across the heart failure spectrum

Background

Moderate and severe tricuspid regurgitation (TR) are common across the heart failure (HF) spectrum and confer an adverse prognosis. Although TR is traditionally considered a low-flow condition, both reduced and excessive forward flow may identify vulnerable patients.

Aim

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 across the HF spectrum.

Methods

We prospectively enrolled 300 patients with atrial secondary, non-atrial secondary, or lead-associated moderate or severe TR, without ≥moderate left-sided valve disease. 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

HF with preserved ejection fraction was the predominant phenotype in the whole population and across CI tertiles. CI decreased with increasing TR severity but showed wide inter-individual variability and 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), independent of TR severity.

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, both low and high CI tertiles were independently associated with a higher risk of the primary endpoint compared with the intermediate CI tertile (adjusted HRs 2.11 [1.23–3.59] and 1.89 [1.08–3.31], respectively). Modeled continuously, CI showed a robust U-shaped association with outcomes, with the lowest risk at ~2.0 L/min/m² (Figure 2). This pattern was consistent across TR severity, TR etiology, and HF phenotype.

Conclusions

In moderate and severe TR, CI profiling integrates cardiac and extracardiac determinants of flow and provides incremental prognostic information beyond TR grading and staging. Both low and high CI identify high-risk phenotypes, whereas intermediate CI denotes a balanced and prognostically favorable state.Figure 1For image description, please refer to the figure legend and surrounding text.Figure 2For image description, please refer to the figure legend and surrounding text.