Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. METHODS: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. RESULTS: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. CONCLUSIONS: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04461041.

Left Ventricular Fibrosis in Middle-Age Athletes and Physically Active Adults.

INTRODUCTION: Cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) and T1 mapping techniques enable the quantification of focal and diffuse myocardial LGE, respectively. Studies have shown evidence of fibrosis in middle-age athletes, but not relative to physically active (PA) adults who perform recommended physical activity levels. Therefore, we examined cardiac remodeling and presence of left ventricular (LV) LGE and T1 values in both recreational middle-age endurance athletes (EA) and PA adults. METHODS: Healthy EA and PA adults (45-65 yr) completed a standardized 3-T CMR protocol with ventricular volumetry, LV LGE, and T1 mapping. RESULTS: Seventy-two EA and 20 PA participants (mean age, 53 ± 5 vs 56 ± 4 yr; P < 0.01; V˙O2peak = 50 ± 7 vs 37 ± 9 mL·kg·min, P < 0.0001) were examined, with CMR data available in 89/92 participants. Focal LV LGE was observed in 30% of participants (n = 27/89): 33% of EA (n = 23/69; 33%) and 20% of PA (n = 4/20; 20%). LGE was present at the right ventricular hinge point (n = 21/89; 23.5%) or identified as ischemic (n = 2/89; 2%) or nonischemic (n = 4/89; 4%). Focal LV LGE was observed similarly in both EA and PA (P = 0.25). EA had larger LV chamber sizes and T1 native values (1169 ± 35 vs 1190 ± 26, P = 0.02) compared with PA, with similar LV ejection fraction. Global extracellular volume (ECV) was similar in both EA and PA (22.6% ± 3.5% vs 21.5% ± 2.6%, P = 0.26), with no relationship between global ECV and LV mass (r = -0.16, P = 0.19). CONCLUSIONS: Focal LGE at the right ventricular hinge point was detected at the same frequency in both groups, was unrelated to demographic or clinical indices, and was found without evidence of global ECV expansion in EA, suggesting a physiologic remodeling response. The long-term clinical implications of hinge-point LGE require clarification using prospective, long-term follow-up studies.

Hypoxia in early life is associated with lasting changes in left ventricular structure and function at maturity in the rat.

BACKGROUND: There is a growing population of adults with repaired cyanotic congenital heart disease. These patients have increased risk of impaired cardiac health and premature death. We hypothesized that hypoxia in early life before surgical intervention causes lasting changes in left ventricular structure and function with physiological implications in later life. METHODS: Sprague-Dawley rats reared initially hypoxic conditions (FiO(2)=0.12) for days 1-10 of life were compared to rats reared only in ambient air. Cellular morphology and viability were compared among LV cardiomyocytes and histological analyses were performed on LV myocardium and arterioles. Intracellular calcium transients and cell shortening were measured in freshly-isolated cardiomyocytes, and mitochondrial hexokinase 2 (HK2) expression and activity were determined. Transthoracic echocardiography was used to assess LV function in anesthetized animals. RESULTS: Cardiomyocytes from adult animals following hypoxia in early life had greater cellular volumes but significantly reduced viability. Echocardiographic analyses revealed LV hypertrophy and diastolic dysfunction, and alterations in cardiomyocyte calcium transients and cell shortening suggested impaired diastolic calcium reuptake. Histological analyses revealed significantly greater intima-media thickness and decreased lumen area in LV arterioles from hypoxic animals. Alterations in mitochondrial HK2 protein distribution and activity were also observed which may contribute to cardiomyocyte fragility. CONCLUSIONS: Hypoxia in early life causes lasting changes in left ventricular structure and function that may negatively influence myocardial and vascular responses to physiological stress in later life. These data have implications for the growing population of adults with repaired or palliated cyanotic congenital heart disease.