Clinical phenotypes and survival in multivalvular heart disease: differential prognostic impact of valve combinations

Background Multivalvular heart disease (MVD) is frequently encountered in clinical practice, yet prognostic stratification remains largely based on individual valve severity rather than valve combinations. Whether distinct multivalvular phenotypes confer differential mortality risk remains unclear. Purpose To examine the phenotypes of different multivalvular diseases and their prognostic significance in relation to mortality. Methods We conducted a multicenter retrospective cohort study including 1,797 hospitalized patients with ≥2 clinically significant valvular lesions identified on echocardiography. Significant stenosis was defined as grade ≥3 (0-5 scale) and significant regurgitation as grade ≥4 (0-6 scale). Patients were categorized into seven prespecified multivalvular phenotypes based on valve combinations: mitral regurgitation (MR) and tricuspid regurgitation (TR), aortic regurgitation (AR) and MR, aortic stenosis (AS) and MR, AR and AR, AS and TR, AR, MR, and TR (3-valve disease) and AS, MR, and TR (3-valve disease). Long-term all-cause mortality was assessed using Kaplan-Meier survival analysis with log-rank testing. Multivariable Cox proportional hazards models with multiple imputation were constructed to evaluate independent associations, adjusting for age, sex, heart failure, diabetes mellitus, chronic kidney disease, atrial fibrillation, arterial hypertension, coronary artery disease, acute decompensated heart failure, acute coronary syndrome, left ventricular ejection fraction, hemoglobin, and serum creatinine. Results MR-TR was the dominant phenotype (59.5%). Kaplan-Meier analysis demonstrated significant survival differences across phenotypes (log-rank p<0.0001) (Figure). The AR-MR phenotype exhibited the most favorable long-term survival, whereas AS-MR-TR showed the worst prognosis with early and sustained survival separation. In multivariable analysis, AS-MR-TR was independently associated with increased mortality (HR 1.61, 95% CI 1.26-2.06, p=0.00017), as was AS-TR (HR 1.31, 95% CI 1.00-1.70, p=0.048). Independent predictors of mortality included older age, CKD (HR 1.32, p=0.0076), lower LVEF (p<0.001), lower hemoglobin (p<0.001), and higher creatinine (p=0.042). Conclusions Multivalvular heart disease is prognostically heterogeneous. Valve combination, rather than valve count alone, defines distinct risk phenotypes. Triple-valve disease, including aortic stenosis, identifies a particularly high-risk structural substrate associated with excess mortality. Phenotype-based stratification may improve clinical risk assessment in multivalvular disease.