Massar Omar

Introduction: To investigate the effect of empagliflozin on right ventricular (RV) function in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes and reverse left ventricular (LV) remodelling in HFrEF. The impact on RV function remains uncertain. Methods: The Empire HF trial was an investigator-initiated, double-blind, randomized, placebo-controlled trial of 190 participants with a left ventricular ejection fraction (LVEF) of 40% or lower, with New York Heart Association (NYHA) Class I−III symptoms. Participants were randomized to receive either empagliflozin (at a dose of 10 mg once daily) or placebo, on top of recommended therapy for 12 weeks. The primary endpoint of this exploratory substudy was changes in RV free wall strain (RVFWS) across the whole cohort. RVFWS was also stratified into tertiles based on baseline RVFWS. Secondary endpoints included changes in tricuspid annular plane systolic excursion (TAPSE) and RV S’ velocity. Results: Between June 2017 and September 2019, a total of 190 patients were enrolled, of whom 160 were included in this substudy. Baseline characteristics were balanced between the groups (mean age of 64 ± 11 years, 86% male, mean LVEF: 29 ± 8%, 79% in NYHA Class II, 83 patients (52%) had an implanted cardiac device, and tricuspid valve regurgitation was absent/trace in 136 (85%) and mild in 24 (15%)). A high proportion of the population were on optimal medical treatment for HFrEF, and device therapy remained unchanged during follow-up. The overall mean RVFWS was −16.7 ± 6.1%, with the empagliflozin group at −16.4 ± 6.2% and the placebo group at −16.9 ± 5.9%. No differences were observed in RVFWS between the groups. When stratified by baseline RVFWS into tertiles, patients in the lowest tertile demonstrated a significant improvement with empagliflozin (treatment effect: −2.9% [95% CI: −5.0 to −0.3]; P = .027). This finding was independent of LVEF, plasma volume, and weight loss, and remained unchanged after additional adjustment for LV remodelling and the presence of resynchronization therapy. No significant treatment effect was observed in the middle or highest tertiles of RVFWS, nor in the overall or lowest tertiles of TAPSE or RV S’. Conclusion: This exploratory substudy of the Empire HF, treatment with empagliflozin exerted no overall effect on RV function in stable HFrEF patients, but significantly improved RVFWS in patients in the lowest tertile of RVFWS after 12 weeks of treatment. Trial Registration: ClinicalTrials.gov, Unique Identifier: NCT03198585

Aims: Obesity increases the risk of heart failure (HF), partly due to hypervolaemia and excess epicardial adipose tissue (EAT). We aimed to investigate the effect of the sodium glucose co-transporter 2 inhibitor empagliflozin on estimated extracellular volume (eECV) and ventricular EAT mass in non-diabetic patients with overweight or obesity and risk of HF to evaluate the drug’s potential for HF prevention. Methods and results: In this randomized, double-blind, placebo-controlled trial, we recruited non-diabetic patients with body mass index (BMI) > 28 kg/m2 and risk of HF. Patients were randomized 1:1 to 180-day empagliflozin 10 mg or placebo. The primary endpoints were the baseline-adjusted mean differences in change of eECV and ventricular EAT mass in the intention-to-treat population with Bonferroni-adjustment for multiplicity. From September 2021 to July 2024, we randomized 191 patients (empagliflozin: 94, placebo: 97) with median age 68 years and median BMI 31.9 kg/m2. Analyses of eECV and EAT included 191 and 165 patients, respectively. Compared to placebo, empagliflozin significantly reduced eECV (empagliflozin, mean change [SD]: −0.154 L [0.257]; placebo, mean change: −0.029 L [0.261]; estimated treatment difference [ETD]: −0.123 L, 97.5% confidence interval [CI]: −0.211 to −0.035, Padj = 0.004) but did not affect EAT mass [empagliflozin, mean change: −2.3 g [13.4]; placebo, mean change: −3.7 g [15.8]; ETD: 1.5 g, 97.5% CI: −3.8 to 6.7, Padj = 1.00]. Conclusion: In high-risk patients with overweight or obesity, treatment with empagliflozin resulted in a potentially favourable reduction in eECV compared to placebo. Meanwhile, the drug did not affect EAT mass. Registration: ClinicalTrials.gov: NCT05042973

Objectives To investigate the effect of empagliflozin on right ventricular (RV) function in patients with HFrEF. Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes and reverse left ventricle (LV) remodeling in heart failure with reduced ejection fraction (HFrEF). The impact on RV function remains uncertain. Methods The Empire HF trial was a randomized, double-blind trial of 190 participants with HFrEF (LVEF ≤40%) randomized (1:1) to empagliflozin (10mg/daily) or matching placebo for 12 weeks. The primary endpoint was changes in RV free wall strain (RVFWS) across the whole cohort. RVFWS was also stratified into tertiles based on baseline RVFWS. Secondary endpoints included changes in TAPSE and RV S’ velocity. Results Baseline characteristics were balanced between the groups (mean age of 64±11 years, 86% male, mean LVEF 29±8%, 79% in NYHA class II). The overall mean RVFWS was −16.7±6.1%, with the empagliflozin group at −16.4±6.2% and the placebo group at −16.9±5.9%. No differences were observed in RVFWS between the groups. When stratified by baseline RVFWS into tertiles, patients in the lowest tertile demonstrated a significant improvement with empagliflozin (treatment effect: −2.9% [95% CI: −5.0 to −0.3]; P=0.027), independent of LVEF, plasma volume, or weight loss changes. No significant treatment effect was observed in the middle or highest tertiles of RVFWS, nor in the overall or lowest tertiles of TAPSE or RV S’. Conclusions Empagliflozin exerted no overall effect on RV function in stable HFrEF patients, but significantly improved RVFWS in patients in the lowest tertile of RVFWS after 12 weeks of treatment. Trial Registration ClinicalTrials.gov, Unique Identifier: NCT03198585

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors reduce risk of hospitalization for heart failure in patients who have heart failure with preserved ejection fraction (HFpEF), but the hemodynamic mechanisms underlying these benefits remain unclear. This study sought to determine whether treatment with dapagliflozin affects pulmonary capillary wedge pressure (PCWP) at rest and during exercise in patients with HFpEF. METHODS: This was a single-center, double-blinded, randomized, placebo-controlled trial testing the effects of 10 mg of dapagliflozin once daily in patients with HFpEF. Patients with New York Heart Association class II or III heart failure, ejection fraction ≥50%, and elevated PCWP during exercise were recruited. Cardiac hemodynamics were measured at rest and during exercise using high-fidelity micromanometers at baseline and after 24 weeks of treatment. The primary end point was a change from baseline in rest and peak exercise PCWPs that incorporated both measurements, and was compared using a mixed-model likelihood ratio test. Key secondary end points included body weight and directly measured blood and plasma volumes. Expired gas analysis was performed evaluate oxygen transport in tandem with arterial lactate sampling. RESULTS: Among 38 patients completing baseline assessments (median age 68 years; 66% women; 71% obese), 37 completed the trial. Treatment with dapagliflozin resulted in reduction in the primary end point of change in PCWP at rest and during exercise at 24 weeks relative to treatment with placebo (likelihood ratio test for overall changes in PCWP; P P =0.029) and maximal exercise (ETD, −5.7 mm Hg [95% CI, −10.8 to −0.7]; P =0.027). Body weight was reduced with dapagliflozin (ETD, −3.5 kg [95% CI, −5.9 to −1.1]; P =0.006), as was plasma volume (ETD, −285 mL [95% CI, −510 to −60]; P =0.014), but there was no significant effect on red blood cell volume. There were no differences in oxygen consumption at 20-W or peak exercise, but dapagliflozin decreased arterial lactate at 20 W (−0.70 ± 0.77 versus 0.37 ± 1.29 mM; P =0.006). CONCLUSIONS: In patients with HFpEF, treatment with dapagliflozin reduces resting and exercise PCWP, along with the favorable effects on plasma volume and body weight. These findings provide new insight into the hemodynamic mechanisms of benefit with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04730947.

We compared longitudinal changes in cardiac function assessed by 2D speckle tracking in patients with HFpEF stratified by natriuretic peptide (NP) levels and healthy controls. LVGLS, LA reservoir strain, and RVFWS were higher in normal NP-HFpEF than high NP-HFpEF at index evaluation, indicating better myocardial function. LA reservoir strain was lower in normal NP-HFpEF than controls, but there were no significant differences in LVGLS or RVFWS at baseline. Over 3.1 years of follow up, LVGLS, LA reservoir strain and RVFWS deteriorated in patients with HFpEF, with no difference in the rate of change in patients with normal or high NP levels. In contrast, there was no change in biventricular or LA function in controls over the same interval. These data suggest that HFpEF with normal NP represents an earlier stage of HFpEF, rather than a fundamentally different phenotype.

Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in left heart disease (LHD). This study sought to characterize the pathophysiology of PVD across the spectrum of PH in LHD. Patients with PH-LHD [mean pulmonary artery (PA) pressure >20 mmHg and PA wedge pressure (PAWP) ≥15 mmHg] and controls free of PH or LHD underwent invasive haemodynamic exercise testing with simultaneous echocardiography, expired air and blood gas analysis, and lung ultrasound in a prospective study. Patients with PH-LHD were divided into isolated post-capillary PH (IpcPH) and PVD [combined post- and pre-capillary PH (CpcPH)] based upon pulmonary vascular resistance (PVR n = 69) and IpcPH-LHD (n = 55), participants with CpcPH-LHD (n = 40) displayed poorer left atrial function and more severe right ventricular (RV) dysfunction at rest. With exercise, patients with CpcPH-LHD displayed similar PAWP to IpcPH-LHD, but more severe RV–PA uncoupling, greater ventricular interaction, and more severe impairments in cardiac output, O₂ delivery, and peak O₂ consumption. Despite higher PVR, participants with CpcPH developed more severe lung congestion compared with both IpcPH-LHD and controls, which was associated lower arterial O₂ tension, reduced alveolar ventilation, decreased pulmonary O₂ diffusion, and greater ventilation-perfusion mismatch. Pulmonary vascular disease in LHD is associated with a distinct pathophysiologic signature marked by greater exercise-induced lung congestion, arterial hypoxaemia, RV–PA uncoupling, ventricular interdependence, and impairment in O₂ delivery, impairing aerobic capacity. Further study is required to identify novel treatments targeting the pulmonary vasculature in PH-LHD. Impact of pulmonary vascular disease on the heart and lungs in heart failure.