Association of tricuspid regurgitation severity with non-cardiovascular death in patients with heart failure: insights from the KUNIUMI Registry

Background Increasing severity of tricuspid regurgitation (TR) has been consistently associated with higher cardiovascular mortality in patients with heart failure (HF). However, whether TR severity influences non-cardiovascular death remains unclear. Beyond being a valvular lesion, TR reflects systemic venous congestion and has been linked to multi-organ dysfunction, hepatic and renal impairment, and frailty. Therefore, significant TR may represent a marker of systemic disease burden and could be associated with non-cardiovascular death. Purpose To investigate the association between TR severity and non-cardiovascular death in patients with HF and to determine whether this relationship differs across HF phenotypes. Methods We retrospectively analyzed 1,646 consecutive patients with HF enrolled in the KUNIUMI Registry chronic cohort between March 2019 and March 2021. TR was assessed by transthoracic echocardiography and quantified using vena contracta width according to current guideline recommendations. Patients were categorized into two groups: mild or less TR and moderate or severe TR. The primary outcome was non-cardiovascular death. Cardiovascular death was treated as a competing event, and cumulative incidence functions were estimated using the Fine-Gray subdistribution hazard model. Propensity score matching adjusting for age and clinical frailty scale ≥4 was performed. Subgroup analyses were conducted across HF phenotypes including HF with reduced ejection fraction (HFrEF), mildly reduced ejection fraction (HFmrEF), and preserved ejection fraction (HFpEF). Results During a median follow-up of 5.9 years (5.3-6.3 years), patients with moderate or severe TR had a significantly higher cumulative incidence of non-cardiovascular death compared with those with mild or less TR (subdistribution hazard ratio [sHR]=1.31, 95% confidence interval [CI]=1.03-1.68, P=0.03; Figure 1). This association persisted after propensity score matching. Across HF phenotypes, moderate or severe TR was consistently associated with increased non-cardiovascular mortality in patients with HFrEF, HFmrEF, and HFpEF. In multivariable Fine-Gray analysis adjusting for clinical covariates, moderate or severe TR independently predicted non-cardiovascular death (sHR=1.31, 95%CI=1.03-1.68, P=0.03; Figure 2). Conclusions Moderate or severe TR is independently associated with increased non-cardiovascular mortality in patients with HF, irrespective of HF phenotype. These findings indicate that TR reflects not only cardiac dysfunction but also systemic congestion and multi-organ vulnerability. The consistent association across HF phenotypes suggests that significant TR may serve as an integrative marker of overall disease burden beyond left ventricular dysfunction. Assessment of TR severity may therefore contribute to more comprehensive risk stratification and management strategies in patients with HF.