Epiphenomenon or Prognostically Relevant Interventional Target? A Novel Proportionality Framework for Severe Tricuspid Regurgitation

Abstract

Background Tricuspid regurgitation (TR) frequently develops in patients with long-standing pulmonary hypertension, and both pathologies are associated with increased morbidity and mortality. This study aimed to improve prognostic assessment in patients with severe TR undergoing transcatheter tricuspid valve intervention (TTVI) by relating the extent of TR to pulmonary artery pressures. Methods and Results In this multicenter study, we included 533 patients undergoing TTVI for moderate-to-severe or severe TR. The proportionality framework was based on the ratio of tricuspid valve effective regurgitant orifice area to mean pulmonary artery pressure. An optimal threshold for tricuspid valve effective regurgitant orifice area/mean pulmonary artery pressure ratio was derived on 353 patients with regard to 2-year all-cause mortality and externally validated on 180 patients. Patients with a tricuspid valve effective regurgitant orifice area/mean pulmonary artery pressure ratio ≤1.25 mm²/mm Hg (defining proportionate TR) featured significantly lower 2-year survival rates after TTVI than patients with disproportionate TR (56.6% versus 69.6%; P=0.005). In contrast with patients with disproportionate TR (n=398), patients with proportionate TR (n=135) showed more pronounced mPAP levels (37.9±9.06 mm Hg versus 27.9±8.17 mm Hg; P<2.2×10^-16) and more severely impaired right ventricular function (tricuspid annular plane systolic excursion: 16.0±4.11 versus 17.0±4.64 mm; P=0.012). Moreover, tricuspid valve effective regurgitant orifice area was smaller in patients with proportionate TR when compared with disproportionate TR (0.350±0.105 cm² versus 0.770±0.432 cm²; P<2.2×10^-16). Importantly, proportionate TR remained a significant predictor for 2-year mortality after adjusting for demographic and clinical variables (hazard ratio, 1.7; P=0.006). Conclusions The proposed proportionality framework promises to improve future risk stratification and clinical decision-making by identifying patients who benefit the most from TTVI (disproportionate TR). As a next step, randomized controlled studies with a conservative treatment arm are needed to quantify the net benefit of TTVI in patients with proportionate TR.

Keywords: pulmonary hypertension; transcatheter tricuspid valve intervention; tricuspid regurgitation.

Figure 1. Graphical hypothesis of the proposed proportionality framework for severe TR adjusted to pulmonary artery pressure levels.

The proposed proportionality framework puts TR severity into context with pulmonary artery pressure levels, which are unlikely to be ameliorated upon TTVI. The expected benefit of transcatheter repair would accordingly be limited in patients with proportionate TR, because PH as the disease‐triggering pathology persists and further challenges the potentially impaired right ventricle. Taken together, the proportionality framework could thus improve future risk stratification and clinical decision‐making by addressing the crucial question: Is this case of TR a prognostically relevant interventional target, or does it merely represent an indicator of worse prognosis in patients with PH? mPAP indicates mean pulmonary artery pressure; TR, tricuspid regurgitation; and TV EROA, tricuspid valve effective regurgitant orifice area.

Figure 2. General information about the study population from recruitment to follow‐up.

A, Flowchart for patient recruitment and definition of derivation and validation cohorts. B, Kaplan–Meier survival plot for the entire study population. C, Density plot showing time to censoring (survivors) and time to death (nonsurvivors) in consecutively enrolled patients. D, Kaplan–Meier survival plot comparing survival rates between patients from derivation and validation cohorts. HR indicates hazard ratio; IQR, interquartile range; mPAP, mean pulmonary artery pressure; TTVI, transcatheter tricuspid valve intervention; and TV EROA, tricuspid valve effective regurgitant orifice area.

Figure 3. A TV EROA/mPAP ratio ≤1.25 mm²/mm Hg, defining proportionate TR, translates into lower survival rates in patients with severe TR undergoing TTVI.

A, Scatter plot showing the distribution of patients with proportionate and disproportionate TR (derivation cohort). Notably, no correlation between TV EROA and mPAP levels could be detected (correlation coefficient by Pearson [R]: −0.0764; P=0.152). B, Kaplan–Meier survival plot comparing survival rates between patients with proportionate and disproportionate TR (derivation cohort). C, Scatter plot showing the distribution of patients with proportionate and disproportionate TR (validation cohort). D, Kaplan–Meier survival plot comparing survival rates between patients with proportionate and disproportionate TR (validation cohort). E, Correlation plot (R=correlation coefficient by Pearson) displaying invasively measured and predicted mPAP levels among patients from the validation cohort. Blue line: linear regression line. Gray area: 95% CI. F, Kaplan–Meier survival plot comparing survival rates between patients with proportionate and disproportionate TR based on predicted mPAP levels (validation cohort). HR indicates hazard ratio; mPAP, mean pulmonary artery pressure; TR, tricuspid regurgitation; TTVI, transcatheter tricuspid valve intervention; and TV EROA, tricuspid valve effective regurgitant orifice area.

Figure 4. Kaplan–Meier survival plot comparing survival rates between patients with proportionate and disproportionate TR (entire study population).

HR indicates hazard ratio; mPAP, mean pulmonary artery pressure; TR, tricuspid regurgitation; TTVI, transcatheter tricuspid valve intervention; and TV EROA, tricuspid valve effective regurgitant orifice area.

Figure 5. Comparison of residual TR as a confounder for mortality after TTVI (entire study population).

A, Alluvial diagrams comparing pre‐ and postprocedural TR severity in accordance with TR proportionality. B, Pie charts comparing rates of procedural success in accordance with TR proportionality (see Methods section for definition of procedural success). C, Kaplan–Meier survival plot comparing survival rates in accordance with procedural success. D, Kaplan–Meier survival plot comparing survival rates in accordance with TR reduction and TV EROA/mPAP ratio. HR indicates hazard ratio; mPAP, mean pulmonary artery pressure; TR, tricuspid regurgitation; TTVI, transcatheter tricuspid valve intervention; and TV EROA, tricuspid valve effective regurgitant orifice area.

Figure 6. A conceptual framework to determine whether individual cases of TR represent a prognostically relevant interventional target or merely an indicator of worse prognosis in patients suffering from pulmonary hypertension (graphical summary).

A novel proportionality framework to correct the degree of TR severity expressed as TV EROA for the levels of mPAP shows that patients with a TV EROA/mPAP ratio >1.25 mm²/mm Hg (defining disproportionate TR) feature significantly better 2‐year survival rates after transcatheter tricuspid valve intervention than patients with proportionate TR (69.6% [95% CI, 64.0–75.6] versus 56.6% [95% CI, 47.5–67.5]; P=0.005). mPAP indicates mean pulmonary artery pressure; mPCWP, mean postcapillary wedge pressure; PVR, pulmonary vascular resistance; RV, right ventricular; RV FAC, right ventricular fractional area change; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation; TTVI, transcatheter tricuspid valve intervention; and TV EROA, tricuspid valve effective regurgitant orifice area.