Functional and prognostic impact of hypertensive response to exercise across the heart failure spectrum
Authors: De Biase N , Del Punta L , Balletti A , Armenia S , Buralli S , Mengozzi A , Taddei S , Metra M , Pagnesi M , Borlaug B A , Williams B , Masi S , Pugliese N R 
Published: May 2023

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Conflicting data exist regarding the prognostic significance of hypertensive response to exercise (HRE), commonly defined according to absolute peak systolic blood pressure (SBP) values. Limited evidence is available regarding the impact of workload-indexed HRE in patients at different stages of the heart failure (HF) spectrum as defined by the American College of Cardiology/American Heart Association HF staging system.

Purpose
We evaluated the SBP/Workload slope during exercise across the HF spectrum and investigated the haemodynamic, functional and prognostic correlates of HRE.

Methods
We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C); among the latter, 143 had preserved (HFpEF) and 226 reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. For each patient, we recorded the first (i.e., within the first minute of exercise) and last (i.e., at peak effort) BP measurement during the ramp protocol. The SBP/Workload slope (Figure 1) was calculated as the ratio of the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles; HRE was defined as the highest sex-specific SBP/Workload slope tertile in each HF stage. The primary outcome was a composite of all-cause mortality and hospitalization for cardiovascular reasons.

Results
Median SBP/Workload slope was 0.53 mmHg/W, interquartile range 0.36-0.72 mmHg/W; the slope was 39% steeper in women than in men (p&lt;0.0001). After adjusting for age and sex, SBP/Workload slope in controls (0.43, 0.35-0.57 mmHg/W) was similar to HFrEF (0.47, 0.30-0.63 mmHg/W) but significantly lower than Stages A-B (0.61, 0.47-0.75 mmHg/W) and HFpEF (0.63, 0.42-0.86 mmHg/W). In all HF stages, patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (Hazard Ratio 2.05, 95% confidence interval 1.81-5.18), while rest and peak SBP were not. Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B (p=0.005) and HFpEF (p&lt;0.001), but not HFrEF. After adjusting for age, sex, body mass index, rest and peak SBP, rest and peak cardiac output, and rest and peak left ventricular ejection fraction, patients with the highest SBP/Workload slope had a 47% higher risk of the primary outcome than subjects in the lowest tertile (Figure 2).

Conclusion
HRE, as evaluated by the SBP/Workload slope, is associated with distinct pathophysiological features and impaired functional capacity across the HF spectrum, especially in Stages A-B and in patients with HFpEF. Patients with HRE in these subgroups may be at increased risk of adverse cardiovascular outcomes.