Methods:
Data from the MyoVasc study (N=3,289), a prospective cohort study on chronic HF (NCT04064450), were analyzed. Participants underwent a 5 hour highly standardized examination at a dedicated study center. Assessment of chronic venous disorders was performed according to the clinical presentation (”C” of the CEAP classification) of chronic venous disease. Information on clinical outcome was derived from structured follow-up with subsequent validation via source data and independent adjudication of clinical endpoints. The primary endpoint of the study was worsening of HF defined as composite of cardiac death, HF hospitalization and ambulatory worsening requiring medical therapy.

Results:
The analysis sample comprised N=2,423 study participants (mean age: 65.6±10.5 years; female sex: 33.3%). In multivariable Poisson regression analysis, the presence of CVI was associated with a 1.2-fold higher prevalence of symptomatic HF stage C/D (prevalence ratio: 1.21 [95% confidence interval (CI) 1.05; 1.39]; P=0.009) independent of age, sex, clinical profile and medication. With regard to echocardiographic function, CVI was related to worse left ventricular ejection fraction (beta-estimate: -3.6 [95% confidence interval -5.6; -1.6]; P<0.001) and higher left ventricular E/e´ ratio (beta-estimate: 0.10 [95%CI -0.023; 0.18]; P=0.01) in multivariable regression analysis. In competing risk analyses with all-cause death as competing event, CVI was identified as strong predictor (hazard ratio (HR) 1.67 [95%CI 1.28; 2.18]; P=0.0002) for worsening of heart failure independent of age, sex, and traditional cardiovascular risk factors. CVI was also a strong predictor for cardiac death (HR 2.15 [95%CI 1.33; 3.46]; P=0.002). In sensitivity analysis using multivariable competing risk analyses for worsening of HF, adjusted for age, sex, and traditional cardiovascular risk factors, the predictive value of CVI for the progression of the HF syndrome varied between HF phenotypes: the strongest relationship of CVI with worsening of HF was found for individuals with heart failure with preserved ejection fraction (HR 2.10 [95%CI 1.17; 3.80]; P=0.014), followed by individuals with HF with borderline ejection fraction (HR 1.83 [95%CI 1.04; 3.22]; P=0.035) and HF with reduced ejection fraction (HR 1.30 [95%CI 0.85; 1.97]; P=0.23).

Conclusion:
In the present study, CVI was a strong predictor for HF progression, especially for the subgroup of individuals with heart failure with preserved ejection fraction. This suggests that CVI may be of clinical importance in development and progression of HF and merits further investigation, including deciphering the underlying pathomechanisms.