Prognostic comparison between moderate multivalve and single valve disease: a multicenter observational study

Background Current guidelines prioritize management according to the predominant lesion in valvular heart disease (VHD), with limited evidence regarding moderate multivalve disease (MVD). The prognostic implications of native moderate MVD relative to single-valve disease (SVD) remain incompletely defined. Methods In this multicenter retrospective cohort, 26,570 adults with ≥moderate native VHD (2008–2020) were identified. After excluding prior intervention and mixed lesions, patients with moderate MVD (two moderate lesions without severe involvement) were compared with moderate-to-severe SVD. Patients undergoing valve intervention within 90 days were excluded for natural-history analyses. The primary endpoint was cardiac death; secondary endpoints included all-cause death, heart failure hospitalization (HHF), and cardiac death or HHF. Multivariable Cox models adjusted for clinical covariates were applied. Results SVD accounted for 80.2% of VHD and MVD for 15.2%; moderate MVD represented 5.5%. Among MVD, regurgitation-dominant phenotypes were most prevalent, particularly MR+TR and AR+TR, and were characterized by older age, female predominance, atrial fibrillation, renal dysfunction, atrial enlargement, and pulmonary hypertension. TR combined with left-sided regurgitant disease (MR+TR and AR+TR) was associated with higher risks of cardiac death, all-cause death, and the composite endpoint compared with isolated moderate MR (aHR 1.28, 95% CI 1.07–1.52; p=0.006) and isolated moderate AR (aHR 1.61, 1.28–2.02; p<0.001) and severe AR (aHR 1.59, 1.16–2.19; p=0.004). Among Secondary Mitral Regurgitation in Aortic valve disease, , AS+MR and AR+MR demonstrated different prognostic patterns. AS+MR demonstrated persistently higher adjusted risks for cardiac death, all-cause death and composite outcomes compared to isolated AS or MR, while AR+MR showed attenuated risks after adjustment. AS+MR exhibited the highest risk (vs moderate AS: aHR 3.32, 2.16–5.12; p<0.001; vs severe AS: aHR 2.26, 1.46–3.48; p<0.001; vs moderate MR: aHR 2.15, 1.46–3.18; p<0.001). AR+MR showed no significant adjusted excess risk. AR+MS was associated with higher mortality than moderate AR (aHR 2.33, 1.19–4.58; p=0.014) and moderate MS (aHR 3.56, 1.74–7.28; p<0.001), whereas AS+MS showed no significant difference. Across phenotypes, pulmonary hypertension and elevated filling pressures were stronger predictors of cardiac death than left ventricular systolic function. Conclusion Moderate multivalve disease demonstrates heterogeneous but frequently adverse prognosis. TR-linked and pressure–volume phenotypes may confer mortality risk comparable to or exceeding severe SVD, underscoring the need for integrated hemodynamic assessment beyond isolated lesion grading.