Lewis, Gregory D

Subjective and objective limitations to exercise and activity are hallmarks of heart failure (HF), regardless of underlying ejection fraction (EF). These limitations relate to cardiovascular abnormalities involving the systolic and diastolic properties of the heart, venous, and arterial vasculature, as well as noncardiovascular abnormalities, including impairments in pulmonary function, autonomic regulation, anemia, metabolism, and changes in mitochondria and skeletal muscle. The contribution of these abnormalities varies between patients with HF with preserved EF and those with HF with reduced EF, but, even within each HF subtype, there is substantial individual patient pathophysiologic variability, which suggests a potentially important role for phenotyping based on exercise reserve responses to individualize treatment. In this article, we review the current understanding of exercise reserve limitation with a focus on specific organ systems involved, both in patients with HF with preserved EF and HF with reduced EF, and how these interact to lead to symptoms of exercise intolerance and objective limitations in submaximal and peak aerobic capacity across the spectrum of HF.

Background Transplantation using hearts obtained through donation after circulatory death (DCD) is increasing, but data on recipient renal outcomes are limited. Methods and Results Patients at a single institution who underwent heart transplantation using organs procured through DCD or donation after brain death (DBD) from April 2016 to August 2022 were included in this retrospective cohort study. Hemodynamic measures were collected via right heart catheterization performed 1 week after transplantation. Posttransplantation renal outcomes included estimated glomerular filtration rate at 1 week, 4 weeks, and 16 weeks, and the incidence of acute kidney injury (AKI) and renal replacement therapy within 1 week. The analysis included 225 patients (55 recipients of DCD). Baseline characteristics were comparable between recipients of DCD and DBD. Renal outcomes within 1 week posttransplantation in recipients of DCD were similar to recipients of DBD, including percent change in estimated glomerular filtration rate (−37.9% [−58.6 to −6.2] versus −31.9% [−52.4 to −9.9]; P =0.91), incidence of AKI (47.3% versus 46.5%; P >0.99) and incidence of renal replacement therapy (3.6% versus 4.7%; P >0.99). Recipients of DCD with AKI within 1 week (“early AKI”) did not recover to baseline estimated glomerular filtration rate (75.8 [60.2–91.3] mL/min per 1.73 m 2 ) by week 16 (59.3 [46.9–73.6] mL/min per 1.73 m 2 ; P =0.002), whereas recipients without early AKI exhibited comparable estimated glomerular filtration rate to baseline by week 4 (84.5 [70.8–98.5] mL/min per 1.73 m 2 ; P =0.084). Similar trends were observed in recipients of DBD. Conclusions Recipients of DCD demonstrated similar renal outcomes compared with recipients of DBD, supporting the ongoing use of DCD transplantation. Early AKI was associated with persistent renal dysfunction for recipients of both DCD and DBD.

BACKGROUND: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome. METHODS: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome. RESULTS: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes. CONCLUSIONS: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037931.

BACKGROUND: Heart failure with preserved ejection fraction is associated with significant functional limitations, yet treatments for improving exercise performance have been elusive. We sought to explore the association between prespecified patient characteristics and changes in 6-minute walk distance that constitute a clinically significant response to dapagliflozin. METHODS: We performed a responder analysis to understand patient characteristics associated with clinically meaningful improvement in 6-minute walk test (6MWT) distance ≥15 m among patients randomized to 12 weeks of dapagliflozin versus placebo in the double-blind PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure). RESULTS: A total of 289 randomized patients had 6MWT distance completed at baseline and 12 weeks. Patients randomized to dapagliflozin improved walking distance by ≥15 m more frequently than those on placebo (n=64, 44% versus n=48, 34%). After adjusting for baseline covariates, patients randomized to dapagliflozin were more likely to experience a clinically meaningful improvement in 6MWT distance compared with those that received placebo (adjusted odds ratio, 1.66 [95% CI, 1.00–2.75]; P =0.05). Dapagliflozin-treated patients were also less likely to have a ≥15 m reduction in 6MWT distance compared with placebo-treated patients (adjusted odds ratio, 0.56 [95% CI, 0.33–0.94]; P =0.03). These results were consistent across all prespecified subgroups (all P values for interaction were not significant). CONCLUSIONS: Compared with those on placebo, patients with heart failure with preserved ejection fraction randomized to dapagliflozin were more likely to experience a clinically meaningful improvement and less likely to experience a deterioration in physical function over 12 weeks as measured by 6MWT distance. Beneficial response to dapagliflozin was consistent across prespecified subgroups. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03030235.