Background: Vascular stiffness is known to contribute to the development and progression of heart failure (HF). Assessment of the augmentation index (AIx) offers a non-invasive approach for the ascertainment of vascular stiffness. However, the prognostic relevance of AIx has not yet been explored specifically for HF phenotypes.

Methods: In total, data of 3,289 individuals from the MyoVasc study (NCT04064450) were analyzed. All study participants underwent a detailed, standardized medical-technical examination during a five-hour visit in a dedicated study center. AIx was measured by an oscillometric method (Vascular Explorer, Enverdis, Jena, Germany) and normalized to a heart rate of 75/min (AIx₇₅). The present analysis focused on individuals with Amercian Heart Association/ American College of Cardiology (AHA/ACC) HF-Stage C/D. Subjects were stratified according to guidelines into HF with preserved left ventricular ejection fraction (LVEF) (HFpEF), HF with reduced (HFrEF) and HF with borderline LVEF (HFpEF_borderline). The study endpoint was worsening of HF, i.e. the composite of HF hospitalization or cardiac death. Natural cubic splines were fitted for HF phenotypes, to assess the relation between Aix₇₅ and outcome.

Results: Overall, AIx₇₅ was available in N=1,501 individuals with symptomatic HF (HFpEF N=565; HFpEF_borderline N=278; HFrEF N=350). The mean age was 67.6±10.0 years (34.6% female, mean AIx₇₅: 27.13±13.84). The median observational period was 3.01 years interquartile range 1.48; 4.0). For final analysis, data from 1,193 Individuals from the defined subgroups (HFpEF, HFpEF_borderline and HFrEF) were available.  After adjustment for age, sex, height, mean arterial pressure, traditional cardiovascular risk factors, comorbidities and medication, AIx₇₅ in the 1^st vs. 2^nd defined section correlated strongly with worsening of HF (adjusted hazard ratio (HR_adj.) 1.75 [95% confidence interval (CI) 1.24; 2.47], P=0.0014). Within the phenotypes, a U-Shaped distribution was detected for HFpEF, with an increased risk for worsening of HF in individuals with high (3^rd vs. 2^nd section, HR_adj. 2.92 [95% CI 1.53; 5.59], P=0.0012) and low AIx₇₅ (1^st vs. 2^nd section, HR_adj.3.49 [95% CI 1.43; 8.52], P=0.006). Although there was no significant association with the result for HFpEF_borderline, the association imposed as a hybrid form of the other phenotypes. In contrast, a lower AIx₇₅ was associated with an increased risk for worsening of HF in HFrEF (1^st vs. 2^nd section, HR_adj.  1.95 [95% CI 1.13; 3.38], P=0.017).

In multivariable linear regression analysis for AIx₇₅  using the same adjustment, revealed an association with LV mass index(LVMI, β-estimate _{per Standard Deviation (SD)} (β) -0.14 [95% CI  -0.20;-0.081], P=<0.0001), relative wall thickness (RWT) (β -0.11 [95% CI -0.17;-0.041], P=0.0012) and E/E’ ratio (β -0.082 [95% CI -0.15;-0.019] , P=0.011). When stratifying for HF phenotypes, an interaction was found between AIx₇₅ and LVMI in HFrEF (β -0.27 [95% CI-0.4;-0.14], P=<0.0001) as well as between AIx₇₅ and RWT in HFpEF_borderline (β -0.19 [95% CI-0.34;-0.053], P=0.0075).

Conclusion: The relation between Aix₇₅ and disease progression in HF varies phenotype-specifically, ranging from a U-shaped association of AIx₇₅ in HFpEF to a linear association in HFrEF. AIx₇₅ was inversely associated with LVMI, RWT and E/E’ in HF and an interaction between AIx₇₅ and LVMI in HFrEF and AIx₇₅ and RWT in HFpEF_borderline were detected.