Jones, Philip G

BACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF. METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis–defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points. RESULTS: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis–derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo ( P =0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF ( P interaction >0.10), whereas the ketogenic effect diminished at higher LVEF ( P interaction =0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF. CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT03030235 and NCT02653482.

Background: The Kansas City Cardiomyopathy Questionnaire (KCCQ) has been psychometrically evaluated in multiple heart failure (HF) populations, but the comparability of its psychometric properties between men and women is unknown. Methods: Data from 3 clinical trials (1 in stable HF with preserved ejection fraction, 1 each in stable and acute HF with reduced ejection fraction) and 1 prospective cohort study (stable HF with reduced ejection fraction), incorporating 6773 men and 3612 women with HF, were used to compare the construct validity, internal and test-retest reliability, ability to detect change, predict mortality and hospitalizations and minimally important differences between the 2 sexes. Interactions of the KCCQ overall summary and subdomain scores by sex were independently examined. Results: The KCCQ-Overall Summary score correlated well with New York Heart Association functional class in both sexes across patients with stable (correlation coefficient: −0.40 in men versus −0.49 in women) and acute (−0.37 in men versus −0.34 in women) HF. All KCCQ subdomains demonstrated concordant relationships with relevant comparison standards with no significant interactions by sex in 19 of 21 of these construct validity analyses. All KCCQ scores were equally predictive and other psychometric evaluations showed similar results by sex: test-retest reliability (intraclass correlation coefficient 0.94 in men versus 0.92 in women), responsive to change (standardized response mean 1.01 in both sexes), as were the minimally important differences and internal reliability. Conclusions: The psychometric properties of the KCCQ, in terms of validity, prognosis, reliability, and sensitivity to change, are comparable in men and women with HF with preserved ejection fraction and HF with reduced ejection fraction.