Hypertensive response to exercise indexed to oxygen consumption: associations with cardio-vascular-renal function and prognosis across the spectrum of heart failure with preserved ejection fraction

Abstract

Background and aims: In patients with established arterial hypertension and preserved left ventricular ejection fraction, the clinical significance of a hypertensive response to exercise (HRE) remains debated. This study aimed to determine whether HRE, defined by the slope of systolic blood pressure (SBP) increase indexed to oxygen consumption (VO2) to account for metabolic demand, is associated with distinct pathophysiological abnormalities and an increased risk of adverse outcomes. Methods: We conducted a prospective, multicenter cohort study, enrolling consecutive patients with established hypertension and preserved left ventricular ejection fraction, with or without heart failure (HF) from three European centers. All participants underwent an extensive clinical and laboratory workup, transthoracic echocardiography at rest, and a maximal cardiopulmonary exercise test combined with exercise stress echocardiography (CPET-ESE). Patients were divided according to tertiles of SBP/VO2 slope, and HRE was defined as the highest tertile. The study population was prospectively followed for the composite endpoint of all-cause death and HF-related hospitalizations. Results: The final population included n=970 patients, with 425 (44%) females. Median age was 71 (62-77) years, median BMI was 27.7 (24.7-30.4) kg/m2. 308 patients (32%) had established HFpEF. Patients with HRE demonstrated a more adverse cardiometabolic and inflammatory profile, including a higher prevalence of significant albuminuria (albumin-to-creatinine ratio >=30 mg/g. Echocardiography revealed greater left ventricular mass, impaired myocardial systolic function (reduced global longitudinal strain), left atrial dilation and dysfunction, and increased lung ultrasound B-lines at rest and peak effort. Furthermore, patients with HRE exhibited reduced total arterial compliance and impaired right ventricular-pulmonary arterial coupling during exercise. Cardiopulmonary testing confirmed a significantly lower peak VO₂ in the HRE group, attributable to deficits in both central (reduced cardiac output) and peripheral (lower arteriovenous oxygen difference) determinants of oxygen delivery. Over a median follow-up of 24 months, a steeper SBP/VO₂ slope was independently associated with a 21% increased risk of the primary composite endpoint (Hazard Ratio 1.21, 95% Confidence Interval 1.05-1.39), independent of absolute peak SBP and VO2. Conclusions: A hypertensive response to exercise, when normalized for metabolic demand, identifies a high-risk phenotype characterized by diffuse vascular stiffening, renal microvascular damage, subclinical cardiac dysfunction, and reduced functional reserve. This metric offers independent prognostic value for predicting death and heart failure hospitalization, suggesting it potential use as a marker to refine risk stratification and potentially tailor therapeutic strategies in this population.