Chronotropic incompetence has shown to be associated with a decrease in exercise capacity in heart failure with preserved ejection fraction (HFpEF), yet β-blockers are commonly used in HFpEF despite the lack of robust evidence. This study aimed to evaluate the effect of β-blocker withdrawal on peak oxygen consumption (peak Vo₂) in patients with HFpEF and chronotropic incompetence. This is a multicenter, randomized, investigator-blinded, crossover clinical trial consisting of 2 treatment periods of 2 weeks separated by a washout period of 2 weeks. Patients with stable HFpEF, New York Heart Association functional classes II and III, previous treatment with β-blockers, and chronotropic incompetence were first randomized to withdrawing from (arm A: n = 26) versus continuing (arm B: n = 26) β-blocker treatment and were then crossed over to receive the opposite intervention. Changes in peak Vo₂ and percentage of predicted peak Vo₂ (peak Vo₂%) measured at the end of the trial were the primary outcome measures. To account for the paired-data nature of this crossover trial, linear mixed regression analysis was used. The mean age was 72.6 ± 13.1 years, and most of the patients were women (59.6%) in New York Heart Association functional class II (66.7%). The mean peakVo₂ and peak Vo₂% were 12.4 ± 2.9 mL/kg/min, and 72.4 ± 17.8%, respectively. No significant baseline differences were found across treatment arms. Peak Vo₂ and peak Vo₂% increased significantly after β-blocker withdrawal (14.3 vs 12.2 mL/kg/min [Δ +2.1 mL/kg/min]; P < 0.001 and 81.1 vs 69.4% [Δ +11.7%]; P < 0.001, respectively). β-blocker withdrawal improved maximal functional capacity in patients with HFpEF and chronotropic incompetence. β-blocker use in HFpEF deserves profound re-evaluation. (β-blockers Withdrawal in Patients With HFpEF and Chronotropic Incompetence: Effect on Functional Capacity [PRESERVE-HR]; NCT03871803; 2017-005077-39).

Heart failure with preserved ejection fraction (HFpEF) is remarkably common in elderly people with highly prevalent comorbid conditions. Despite its increasing in prevalence, there is no evidence-based effective therapy for HFpEF. We sought to evaluate whether inspiratory muscle training (IMT) improves exercise capacity, as well as left ventricular diastolic function, biomarker profile and quality of life (QoL) in patients with advanced HFpEF and nonreduced maximal inspiratory pressure (MIP). A total of 26 patients with HFpEF (median (interquartile range) age, peak exercise oxygen uptake (peak VO₂) and left ventricular ejection fraction of 73 years (66–76), 10 ml/min/kg (7.6–10.5) and 72% (65–77), respectively) were randomized to receive a 12-week programme of IMT plus standard care vs. standard care alone. The primary endpoint of the study was evaluated by positive changes in cardiopulmonary exercise parameters and distance walked in 6 minutes (6MWT). Secondary endpoints were changes in QoL, echocardiogram parameters of diastolic function, and prognostic biomarkers. The IMT group improved significantly their MIP (p < 0.001), peak VO₂ (p < 0.001), exercise oxygen uptake at anaerobic threshold (p = 0.001), ventilatory efficiency (p = 0.007), metabolic equivalents (p < 0,001), 6MWT (p < 0.001), and QoL (p = 0.037) as compared to the control group. No changes on diastolic function parameters or biomarkers levels were observed between both groups. In HFpEF patients with low aerobic capacity and non-reduced MIP, IMT was associated with marked improvement in exercise capacity and QoL.

Background: Fatigue and exercise intolerance are the most common symptoms in patients with long COVID. Aims: This study aimed to evaluate whether a home-based inspiratory muscle training (IMT) programme improves maximal functional capacity in patients’ long COVID after a previous admission due to SARS-CoV-2 pneumonia. Methods: This study was a single-centre, blinded assessor, randomised controlled trial. Twenty-six patients with long COVID and a previous admission due to SARS-CoV-2 pneumonia were randomly assigned to receive either a 12-week IMT or usual care alone (NCT05279430). The physiotherapist and participants were not blinded. Patients allocated to the IMT arm were instructed to train at home twice daily using a threshold inspiratory muscle trainer and to maintain diaphragmatic breathing during the training session. The usual care arm received no intervention. The primary endpoint was the change in peak oxygen consumption (peakVO2). Secondary endpoints were changes in quality of life (QoL), ventilatory efficiency and chronotropic response during exercise (evaluated by chronotropic index-CI_x- formula). We used linear mixed regression analysis for evaluating changes in primary and secondary endpoints. Results: The mean age of the sample and time to first visit after discharge were 50.4±12.2 years and 362±105 days, respectively. A total of 11 (42.3%) were female. At baseline, the mean of peakVO₂, ventilatory efficiency and CIx were 18.9±5 mL/kg/min, 29.4±5.2 and 0.64±0.19, respectively. The IMT arm improved their peakVO₂ significantly compared with usual care (+Δ 4.46 mL/kg/min, 95% CI 3.10 to 5.81; p<0.001). Similar positive findings were found when evaluating changes for CI_x and some QoL dimensions. We did not find significant changes in ventilatory efficiency. Conclusion: In long COVID patients with a previous admission due to SARS-CoV-2 pneumonia, IMT was associated with marked improvement in exercise capacity and QoL. Trial registration number: NCT05279430.

Aims The mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) are not yet elucidated. Chronotropic incompetence has emerged as a potential mechanism. We aimed to evaluate whether heart rate (HR) response to exercise is associated to functional capacity in patients with symptomatic HFpEF. Methods and results We prospectively studied 74 HFpEF patients [35.1% New York Heart Association Class III, 53% female, age (mean ± standard deviation) 72.5 ± 9.1 years, and 59.5% atrial fibrillation]. Functional performance was assessed by peak oxygen consumption (peak VO₂). The mean (standard deviation) peak VO₂ was 10 ± 2.8 mL/min/kg. The following chronotropic parameters were calculated: Delta‐HR (HR at peak exercise − HR at rest), chronotropic index (CI) = (HR at peak exercise − resting HR)/[(220 − age) − resting HR], and CI according to the equation developed by Keteyian et al. (CIK) (HR at peak exercise − HR at rest)/[119 + (HR at rest/2) − (age/2) − 5 − HR at rest]. In a bivariate setting, peak VO₂ was positively and significantly correlated with Delta‐HR (r = 0.35, P = 0.003), CI (r = 0.27, P = 0.022), CIK (r = 0.28, P = 0.018), and borderline with HR at peak exercise (r = 0.22, P = 0.055). In a multivariable linear regression analysis that included clinical, analytical, echocardiographic, and functional capacity covariates, the chronotropic parameters were positively associated with peak VO₂. We found a linear relationship between Delta‐HR and peak VO₂ (β coefficient of 0.03; 95% confidence interval: 0.004–0.05; P = 0.030); conversely, the association among CIs and peak VO₂ was exponentially shaped. Conclusions In patients with chronic HFpEF, the HR response to exercise was positively associated to patient's functional capacity.