Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abmormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval (CI) 2.3–9.2, P = 0.001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points (95% CI 2.0–9.6, P = 0.003)) and physical limitations scores (5.3 points (95% CI 0.7–10.0, P = 0.026)). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m (95% CI 5.6–34.7, P = 0.007)), KCCQ-OS (4.5 points (95% CI 1.1–7.8, P = 0.009)), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio (OR) = 1.73 (95% CI 1.05–2.85, P = 0.03)) and reduced weight (mean effect size, 0.72 kg (95% CI 0.01–1.42, P = 0.046)). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 (27.2%) versus 38 (23.5%) patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF.

n-3 FA are beneficial for cardiovascular health, reducing platelet aggregation, TG levels, and the risk of sudden death from myocardial infarction. The percentage of EPA + DHA in red blood cells (RBC), also known as the Omega-3 Index, has recently been proposed as a risk marker for death from coronary heart disease (CHD). The purpose of this study was to begin to explore the factors that can influence RBC EPA + DHA. We collected information on the number of servings of tuna or nonfried fish consumed per month, as well as on age, gender, ethnicity, smoking status, the presence of diabetes, and body mass index (BMI) in 163 adults in Kansas City who were not taking fish oil supplements. The average RBC EPA + DHA in this population was 4.9 +/- 2.1%. On a multivariate analysis, four factors significantly and independently influenced the Omega-3 Index: fish servings, age, BMI, and diabetes. The Index increased by 0.24 units with each additional monthly serving of tuna or nonfried fish (P < 0.0001), and by 0.5 units for each additional decade in age (P < 0.0001). The Index was 1.13% units lower in subjects with diabetes (P = 0.015) and decreased by 0.3% units with each 3-unit increase in BMI (P = 0.001). Gender or smoking status had no effect, and the univariate relationship with ethnicity vanished after controlling for fish intake. Given the importance of n-3 FA in influencing risk for death from CHD, further studies are warranted to delineate the nondietary factors that influence RBC EPA + DHA content.

Background-Omega-3 fatty acids (FAs) appear to reduce the risk of sudden death from myocardial infarction. This reduction is believed to occur via the incorporation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the myocardium itself, altering the dynamics of sodium and calcium channel function. The extent of incorporation has not been determined in humans. Methods and Results-We first determined the correlation between red blood cell (RBC) and cardiac omega-3 FA levels in 20 heart transplant recipients. We then examined the effects of 6 months of omega-3 FA supplementation (1 g responses among tissues were not significantly different). Conclusions-Although any of the tissues examined could serve as a surrogate for cardiac omega-3 FA content, RBC EPAϩDHA was highly correlated with cardiac EPAϩDHA; the RBC omega-3 response to supplementation was similar to that of the heart; RBCs are easily collected and analyzed; and they have a less variable FA composition than plasma. Therefore, RBC EPAϩDHA (also called the Omega-3 Index) may be the preferred surrogate for cardiac omega-3 FA status.

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Background COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness.Methods DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov, NCT04350593.

The aim of this study was to determine whether eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), or both, were responsible for the triglyceride (TG)-lowering effects of fish oil. EPA (91% pure) and DHA (83% pure), a fish oil concentrate (FOC; 41% EPA and 23% DHA) and an olive oil (OO) placebo (all ethyl esters) were tested. A total of 49 normolipidemic subjects participated. Each subject was given placebo for 2-3 wk and one of the n-3 supplements for 3 wk in randomized, blinded trials. The target n-3 fatty acid (FA) intake was 3 g/day in all studies. Blood samples were drawn twice at the end of each supplementation phase and analyzed for lipids, lipoproteins, and phospholipid FA composition. In all groups, the phospholipid FA composition changed to reflect the n-3 FA given. On DHA supplementation, EPA levels increased to a small but significant extent, suggesting that some retroconversion may have occurred. EPA supplementation did not raise DHA levels, however. FOC and EPA produced significant decreases in both TG and very low density lipoprotein (VLDL) cholesterol (C) levels (P < 0.01) and increases in low density lipoprotein (LDL) cholesterol levels (P < 0.05). DHA supplementation did not affect cholesterol, triglyceride, VLDL, LDL, or high density lipoprotein (HDL) levels, but it did cause a significant increase in the HDL2/HDL3 cholesterol ratio. We conclude that EPA appears to be primarily responsible for TG-lowering (and LDL-C raising) effects of fish oil.

Background: Sodium glucose cotransporter 2 inhibitors (SGLT2i) prevent heart failure (HF) hospitalizations in patients with Type 2 Diabetes (T2D), and improve outcomes in those with HF and reduced ejection fraction (EF), regardless of T2D. Mechanisms of HF benefits remain unclear, and effects of SGLT2i on hemodynamics (filling pressures) are not known. EMBRACE-HF Trial was designed to address this knowledge gap. Methods: EMBRACE-HF is an investigator-initiated, randomized, multi-center, double-blind, placebo-controlled trial. From July 2017 to November 2019, patients with HF (regardless of EF, with or without T2D) and previously implanted pulmonary artery (PA) pressure sensor (CardioMEMS) were randomized across 10 US centers to empagliflozin 10 mg daily or placebo and treated for 12 weeks. The primary endpoint was change in PA diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8-12). Secondary endpoints included health status (Kansas City Cardiomyopathy Questionnaire (KCCQ)), natriuretic peptides and 6-minute walking distance. Results: Overall, 93 patients were screened, and 65 were randomized (33 empagliflozin, 32 placebo). Mean age was 66 years, 63% were male, 52% had T2D, 54% NYHA class III/IV; mean EF 44%, median NT-proBNP 637 pg/mL and mean PADP 22 mmHg. Empagliflozin significantly reduced PADP, with effects beginning at week 1, and amplified over time; average PADP (weeks 8-12) was 1.5 mmHg lower (95% CI (0.2, 2.8); p = 0.02); and at week 12, PADP was 1.7 mmHg lower (95% CI (0.3, 3.2); p = 0.02) with empagliflozin vs placebo. Results were consistent for PA systolic and PA mean pressures. There was no difference in mean loop diuretic management (daily furosemide equivalents) between treatment groups. No significant differences between treatment groups were observed in KCCQ, natriuretic peptide levels and 6-minute walking distance. Conclusions: In patients with HF and CardioMEMS PA pressure sensor, empagliflozin produced rapid reductions in PA pressures that were amplified over time and appeared to be independent of loop diuretic management. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03030222.

Little is known about the fate of the lipolytic products produced by the action of lipoprotein lipase (LPL) on circulating triglyceride-rich lipoproteins in humans. We studied eight lean, healthy male subjects after an overnight fast. Subjects received infusions of lipid emulsions containing triolein labeled with 3 H on both the glycerol backbone and the fatty acid portion of the molecule; 14 C glycerol and 14 C oleate were coinfused to quantify the systemic and forearm release of 3 H glycerol and 3 H oleate resulting from LPL action. There was significant forearm uptake of both whole plasma triglyceride (presumed to represent primarily VLDL; extraction fraction 2.6 ؎ 0.6%, P < 0.005 vs. zero) and radiolabeled triglyceride derived from the lipid emulsion (a surrogate for chylomicrons; extraction fraction 31 ؎ 4%, P < 0.005 vs zero). Systemic clearance and forearm fractional extraction of glycerol was greater than that of oleate (P < 0.001 and P < 0.02, respectively). The systemic and forearm fractional release of LPL-generated glycerol were similar at 51 ؎ 4 and 59 ؎ 1%, respectively (NS). In contrast, the forearm fractional release of LPL-generated oleate was less than systemic fractional release (14 ؎ 2 vs. 36 ؎ 4%, P < 0.0001). These results indicate that there is escape, or spillover, of the lipolytic products of LPL action on triglyceride-rich lipoproteins in humans. They further suggest that LPL-mediated fatty acid uptake is an inefficient process, but may be more efficient in muscle than in adipose tissue. Diabetes 53:521-527, 2004 A lthough it is generally accepted that the action of hormone-sensitive lipase (HSL) in adipocytes is the primary source of plasma free fatty acids (FFAs) in normal postabsorptive individuals (1), the ubiquitous presence of lipoprotein lipase (LPL) (2) represents a potential additional source of plasma FFAs. Available evidence suggests that VLDL triglyceride is not an important source of plasma FFAs. Wolfe et al. (3) administered biosynthetic labeled VLDL to dogs and found that Ͼ95% of VLDL-triglyceride fatty acids were taken up directly into tissues without traversing the plasma FFA pool; in contrast, glycerol produced by the action of LPL on VLDL triglyceride was quantitatively released into the circulation.Chylomicrons, on the other hand, appear to be a significant source of FFAs during meal absorption. However, the magnitude of the chylomicron contribution to total FFA flux is controversial. Olivecrona et al. (4) gave chylomicrons labeled with 14 C glycerol and 3 H palmitate to rats, and found that ϳ90% of the administered 3 H was recovered in adipose tissue, whereas only trace amounts of 14 C could be found in adipose tissue. Recently, studies in which both chylomicrons and lipid emulsions containing labeled oleate were administered to mice found that 80 -90% of the label was recovered in plasma (5). Roust and Jensen (6) gave a meal containing radiolabeled triglyceride to human subjects and found that approximately one-third of dietary fatty acids were released into the sy...