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Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia.The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients.In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life.Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p 0.001). Patients who received empagliflozin had significant improvements in peak OEmpagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222).

Background: SGLT2 inhibitors (SGLT2i) improve prognosis in HFrEF patients. We recently demonstrated in a porcine model of non-diabetic HFrEF that empagliflozin (EMPA) ameliorates adverse cardiac remodeling and improves LV systolic function. However, the effect of EMPA on left atrial (LA) dilatation has not yet been studied Hypothesis:: Empagliflozin ameliorates left atrial dilatation in non-diabetic HFrEF patients Methods: The EMPATROPISM clinical trial investigated the efficacy and safety of EMPA in non-diabetic HFrEF patients. 84 patients were randomized to EMPA 10mg daily for 6 months or placebo on top of optimal medical treatment, and were evaluated with cardiac magnetic resonance (CMR). LA Volumes were quantified by CMR using the Simpson method (the number of slices in the usual short axis SSFP cine sequence was increased to cover both LV and the whole of LA. The primary endpoint was change in LVEDV. Prespecified secondary endpoints were changes in maximal and minimal LA volumes (ΔMax LA Vol and ΔMin LA Vol) at the end of 6 months between both arms Results: 80 patients completed the follow up period. There were no differences at baseline in LVEDV (220±75 vs 209±68mL for EMPA vs placebo, p=0.5) or LVEF (36±8 vs 37±8%, p=0.7). There were no differences at baseline in both groups in either maximal or minimal LA volume (Table). In the primary endpoint, EMPA-treated patients showed decrease in LVEDV and increase in LVEF (ΔLVEDV -25±25 vs -1±25mL, p Conclusions: In HFrEF patients without diabetes, treatment with empagliflozin ameliorates left atrial dilatation. As LA volume is a surrogate for chronic filling pressures, this reduced LA volume suggest improved diastolic function with EMPA

Background: SGLT2 inhibitors (SGLT2i) improve prognosis in HFrEF patients. We recently demonstrated in a porcine model of non-diabetic HFrEF that empagliflozin (EMPA) ameliorates adverse cardiac remodeling and improves LV systolic function. However, the effect of EMPA on interstitial myocardial fibrosis (IMF) and aortic stiffness has not yet been studied Hypothesis: Empagliflozin ameliorates IMF and aortic stiffness in non-diabetic HFrEF patients Methods: The EMPATROPISM clinical trial (NCT 03485222) investigated the efficacy and safety of EMPA in non-diabetic HFrEF patients. 84 patients were randomized to EMPA 10mg daily for 6 months or placebo on top of optimal medical treatment, and were evaluated with cardiac magnetic resonance (CMR). IMF was assessed by CMR using extracellular volume (ECV) by T1 mapping. Aortic stiffness was quantified by pulse wave velocity (PWV) by CMR. The primary endpoint was change in LVEDV. Prespecified secondary endpoints were changes in ECV (ΔECV) and PWV (ΔPWV) at 6 months between both arms Results: 80 patients completed the follow up period. There were no differences at baseline in LVEDV (220±75 vs 209±68mL for EMPA vs placebo, p=0.5) or LVEF (36±8 vs 37±8%, p=0.7). There were no differences at baseline in both groups in either ECV or PWV (Table). In the primary endpoint, EMPA-treated patients showed decrease in LVEDV and increase in LVEF (ΔLVEDV -25±25 vs -1±25mL, p Conclusions: In HFrEF patients without diabetes, treatment with empagliflozin ameliorates IMF and aortic stiffness. This may explain the benefits of SGLT2i in HFrEF even in the absence of diabetes

Introduction Cardiac resynchronization therapy with defrilator (CRT-D) has been shown to reduce mortality in HFrEF. The width and morphology of the QRS are essential when deciding on the implantation of these devices. QRS fragmentation (fQRS) has been shown to be a good predictor of cardiovascular events in certain patients, but its role in patients with CRT-D has not been studied. The aim of this study is to determine whether the presence of a fQRS at the time of CRT-D implantation can predict clinical events. Methods All patients who underwent CRT-D implantation from 2010 to 2017 were included. Patients' ECG were evaluated at the time of implantation, and the incidence of clinical events during follow-up was also assessed. fQRS was defined as the presence of an RSR' pattern with a notch in the R wave or in the ascending or descending branch of the S wave in two continuous leads on the ECG. Results We studied 131 patients (mean age 73 years, 76.5% male). The mean follow-up period was 37±26 months. No difference in baseline characteristics was found (Table 1); the proportion of fQRS was 48.9%. 25 patients (19.1%) had hospital admissions secondary to cardiovascular causes (heart failure, arrhythmic events, acute coronary syndrome, and death from other causes). We performed a multivariate logistic regression analysis aiming at an association between the presence of fQRS and the increased risk of hospital admissions due to cardiovascular causes OR 2.92 (95% CI: 1.04–8.21, P=0.04). Conclusion The presence of a fQRS at the time of implantation of a CRT-D is an independent predictor of hospital admissions due to cardiovascular causes. Therefore this could be a useful marker to identify the population at high risk of cardiovascular events, for this we consider necessary to conduct future studies and thus assess the value of the fQRS for the selection of patients requiring closer monitoring thus avoiding further hospital admissions. Funding Acknowledgement Type of funding source: None

We appreciate the comments made by Katsiki and colleagues [1] on our paper [2]. We described that empagliflozin administration, in a non-diabetic animal model of heart failure (HF), significantly i...

The sodium-glucose cotransporter type 2 inhibitors reduce mortality and heart failure (HF) hospitalizations. The underlying mechanisms remain unclear but seem to be irrespective of glucose-lowering properties. This study aims to evaluate the impact of empagliflozin on myocardial biomechanics and correlation with markers of adverse remodeling. Following myocardial infarct induction to create a model of HF, 14 pigs were randomly assigned in a 1:1 ratio to receive either empagliflozin 10 mg daily or placebo for 2 months. Speckle-tracking echocardiography (STE) and feature-tracking cardiac magnetic resonance (FTCMR) were performed at baseline and at the end of the study to analyze myocardial deformation. The results were correlated with markers of adverse cardiac remodeling. Empagliflozin significantly improved STE indices. These parameters significantly correlated with adverse cardiac remodeling. In contrast, FTCMR indices showed only a trend toward improved myocardial deformation and without significant correlation with adverse cardiac remodeling. The correlation between both techniques to assess myocardial deformation was low. Empagliflozin enhances myocardial deformation, assessed by STE techniques, in a non-diabetic porcine model of ischemic HF. This may be related to a mitigation of adverse cardiac remodeling following ischemia reperfusion injury. In contrast, FTCMR technique needs further development and validation.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder associated with high cardiovascular (CV) risk. Some of the therapeutic strategies are contraindicated in patients with concomitant heart disease. However, the newest antidiabetic medications, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown to significantly reduce CV mortality and heart failure (HF) hospitalizations. The mechanism behind these surprising cardiac benefits remains unclear. Areas covered: This article reviews the pharmacokinetic, pharmacodynamics, efficacy, and safety data for the different SGLT2 inhibitors. Specific attention is devoted to the postulated mechanisms of action for their benefit. The therapeutic efficacy and potential use in different indications outside T2DM such as HF, T1DM, and renal disease are also discussed. Expert opinion: SGLT2 inhibitors have an excellent pharmacokinetic and pharmacodynamic profile. Importantly, SGLT2 inhibitors are a safe and efficacious treatment option for T2DM. Given their cardiac benefits (reduction in HF and death) and the low incidence of adverse events, SGLT2 inhibitors are being currently studied as a treatment for HF also in nondiabetic individuals. These agents seem to represent a shift in the treatment of HF patients regardless their glycemic profile.

The purpose of this study was to investigate the effect of empagliflozin on diastolic function in a nondiabetic heart failure with reduced ejection fraction (HFrEF) scenario and on the pathways causing diastolic dysfunction.This group demonstrated that empagliflozin ameliorates adverse cardiac remodeling, enhances myocardial energetics, and improves left ventricular systolic function in a nondiabetic porcine model of HF. Whether empagliflozin also improves diastolic function remains unknown. Hypothetically, empagliflozin would improve diastolic function in HF mediated both by a reduction in interstitial myocardial fibrosis and an improvement in cardiomyocyte stiffness (titin phosphorylation).HF was induced in nondiabetic pigs by 2-h balloon occlusion of proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Cardiac function was evaluated with cardiac magnetic resonance (CMR), 3-dimensional echocardiography, and invasive hemodynamics. In vitro relaxation of cardiomyocytes was studied in primary culture. Myocardial samples were obtained for histological and molecular evaluation. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus.Despite similar initial ischemic myocardial injury, the empagliflozin group showed significantly improved diastolic function at 2 months, assessed by conventional echocardiography (higher e' and color M-mode propagation velocity, lower E/e' ratio, myocardial performance Tei index, isovolumic relaxation time, and left atrial size), echocardiography-derived strain imaging (strain imaging diastolic index, strain rate at isovolumic relaxation time and during early diastole, and untwisting), and CMR (higher peak filling rate, larger first filling volume). Invasive hemodynamics confirmed improved diastolic function with empagliflozin (better peak LV pressure rate of decay (-dP/dt), shorter Tau, lower end-diastolic pressure-volume relationship (EDPVR), and reduced filling pressures). Empagliflozin reduced interstitial myocardial fibrosis at the imaging, histological and molecular level. Empagliflozin improved nitric oxide signaling (endothelial nitric oxide synthetase [eNOS] activity, nitric oxide [NO] availability, cyclic guanosine monophosphate (cGMP) content, protein kinase G [PKG] signaling) and enhanced titin phosphorylation (which is responsible for cardiomyocyte stiffness). Indeed, isolated cardiomyocytes exhibited better relaxation in empagliflozin-treated animals. Myocardial consumption of glucose and ketone bodies negatively and positively correlated with diastolic function, respectively.Empagliflozin ameliorates diastolic function in a nondiabetic HF porcine model, mitigates histological and molecular remodeling, and reduces both left ventricle and cardiomyocyte stiffness.

The sodium-glucose cotransporter (SGLT) inhibitors represent a new alternative for treating patients with diabetes mellitus. They act primarily by inhibiting glucose reabsorption in the renal tubule and therefore, decreasing blood glucose levels. While little is yet known about SGLT subtype 1, SGLT2 inhibitors have demonstrated to significantly reduce cardiovascular mortality and heart failure hospitalizations. This cardioprotective benefit seems to be independent of their glucose-lowering properties; however, the underlying mechanism(s) remains still unclear and numerous hypotheses have been postulated to date. Moreover, preclinical research has suggested an important role of SGLT1 receptors on myocardial ischemia. Following acute phase of cardiac injury there is an increased activity of SGLT1 cotransport that ensures adequate energy supply to the cardiac cells. Nonetheless, a long-term upregulation of this receptor may not be that beneficial and whether its inhibition is positive or not should be further addressed. This review aims to present the most cutting-edge insights into SGLT receptors.

Cardiac metabolism represents a complex network of numerous pathways responsible for an adequate supply of ATP to the incessant contractile apparatus. Impairments of such pathways are associated with myocardial dysfunction. The newest antidiabetic drugs, the SGLT2 inhibitors, have been demonstrated to reduce cardiovascular mortality and heart failure hospitalizations. The mechanisms underlying these benefits are still uncertain; however, they may play a decisive role in restoring energy efficiency to the damaged heart. Areas covered: This article reviews normal cardiac metabolism and contribution of different substrates to fuel supply. Specific attention is devoted to alterations of these pathways and their association with myocardial dysfunction. In addition, the impact of the novel SGLT2 inhibitors on cardiac mortality and heart failure hospitalizations is discussed. Various postulated mechanisms responsible for such benefits are also discussed. Expert opinion: Metabolic alterations seem to play a crucial role in etiology and progression of heart failure. The cardiovascular benefits of the novel SGLT2 inhibitors have attracted more attention to this field. With effects beyond lowering glucose levels, these agents have been reported to induce changes in cardiac metabolism and to exert anti-inflammatory properties that may contribute to their large cardiovascular beneficial effects by improving contractile bioenergetics. Therefore, SGLT2 inhibitors may become an alternative drug to treat heart failure patients, regardless of diabetic status.

The SGLT2 inhibitor empagliflozin reduced cardiovascular mortality by 38% and heart failure (HF) hospitalizations by 35% in diabetic patients. We have recently demonstrated the efficacy of empagliflozin in ameliorating HF and improving cardiac function in a non-diabetic porcine model of HF mediated via a switch in myocardial metabolism that enhances cardiac energetics. Therefore, we hypothesized that the cardiac benefits of empagliflozin can also be extended to non-diabetic HF patients. The EMPA-TROPISM clinical trial is a randomized, double-blind, parallel group, placebo-controlled, trial comparing the efficacy of and safety of empagliflozin in non-diabetic HF patients. Eighty patients with stable HF for over 3 months, LVEF

Beta-blockers (BBs) remain underused in elderly patients with reduced ejection fraction (REF). Our aim was to determine the prognostic impact of different doses of BB in this setting.A single-center observational study was conducted. Inclusion criteria were age≥75 and EF≤0.35. Six months after diagnosis, patients were divided into 3 groups depending on BB dose: no BB (NBB), low dose (50% of the target dose) (LD), and high dose (≥50%) (HD). Two different analytical approaches were employed: multivariate Cox model and propensity-score (PS) matching. Outcomes were all-cause death and heart failure (HF) admission. We included 559 patients (134 NBB, 259 LD, and 166 HD) with median follow-up of 29.9months. There were 212 deaths (NBB: 70 (52.2%); LD: 94 (36.3%); and HD: 48 (28.9%)) and 171 HF admissions (NBB: 42 (31.3%); LD: 85 (32.8%); and HD: 44 (26.5%)). On multivariate analysis, both LD and HD were associated with improved survival, with no differences between them (HD vs. NBB=0.67, 95% CI=[0.46-0.98], p=0.037; HD vs. LD=1.03, 95% CI=[0.72-1.46], p=0.894; and LD vs. NBB=0.65, 95% CI=[0.48-0.90], p=0.009). However, BB therapy failed to show benefits in HF admissions (p=NS, for each comparison). PS-matched analysis included 198 patients, with similar results to those mentioned above.BB therapy was associated with a significant reduction in mortality among elderly patients with REF, regardless of dose. Nevertheless, it was not associated with a decrease in HF admissions. Further studies are needed to determine the optimal BB dose in these patients.

Background Acute infections are known cardiovascular disease (CVD) triggers, but little is known regarding how CVD risk varies following inpatient versus outpatient infections. We hypothesized that in‐ and outpatient infections are associated with CVD risk and that the association is stronger for inpatient infections. Methods and Results Coronary heart disease (CHD) and ischemic stroke cases were identified and adjudicated in the ARIC (Atherosclerosis Risk in Communities Study). Hospital discharge diagnosis codes and Medicare claims data were used to identify infections diagnosed in in‐ and outpatient settings. A case‐crossover design and conditional logistic regression were used to compare in‐ and outpatient infections among CHD and ischemic stroke cases (14, 30, 42, and 90 days before the event) with corresponding control periods 1 and 2 years previously. A total of 1312 incident CHD cases and 727 incident stroke cases were analyzed. Inpatient infections (14‐day odds ratio [OR]=12.83 [5.74, 28.68], 30‐day OR=8.39 [4.92, 14.31], 42‐day OR=6.24 [4.02, 9.67], and 90‐day OR=4.48 [3.18, 6.33]) and outpatient infections (14‐day OR=3.29 [2.50, 4.32], 30‐day OR=2.69 [2.14, 3.37], 42‐day OR=2.45 [1.97, 3.05], and 90‐day OR=1.99 [1.64, 2.42]) were more common in all CHD case periods compared with control periods and inpatient infection was a stronger CHD trigger for all time periods (P, See Editorial by https://doi.org/10.1161/JAHA.118.011175

We appreciate the comments by Baker and colleagues on our paper [(1)][1]. We described that empagliflozin ameliorates adverse cardiac remodeling, enhances systolic function, switches myocardial fuel utilization, and improves myocardial energetics in a nondiabetic heart failure (HF) model. Baker and

The SGTL2 inhibitor empagliflozin (Empa) reduces HF. We have recently demonstrated 1) the mechanism is due to a switch in myocardial metabolism towards ketone bodies (KB) consumption; and 2) KB infusion improves LV systolic function in a porcine HF model. However, there is no information about the