BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs.-2.28 ml per minute per 1.73 m 2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.

Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONSEmpagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).

We previously evaluated the short-term follow-up preliminary data of mesenchymal stem cells (MSCs) transplantation in patients with ischemic stroke. The present study was conducted to evaluate the long-term safety and efficacy of i.v. MSCs transplantation in a larger population. To accomplish this, we performed an open-label, observerblinded clinical trial of 85 patients with severe middle cerebral artery territory infarct. Patients were randomly allocated to one of two groups, those who received i.v. autologous ex vivo cultured MSCs (MSC group) or those who did not (control group), and followed for up to 5 years. Mortality of any cause, long-term side effects, and new-onset comorbidities were monitored. Of the 52 patients who were finally included in this study, 16 were the MSC group and 36 were the control group. Four (25%) patients in the MSC group and 21 (58.3%) in the control group died during the follow-up period, and the cumulative surviving portion at 260 weeks was 0.72 in the MSC group and 0.34 in the control group (log-rank; p 5 .058). Significant side effects were not observed following MSC treatment. The occurrence of comorbidities including seizures and recurrent vascular episodes did not differ between groups. When compared with the control group, the follow-up modified Rankin Scale (mRS) score was decreased, whereas the number of patients with a mRS of 0-3 increased in the MSC group (p 5 .046). Clinical improvement in the MSC group was associated with serum levels of stromal cell-derived factor-1 and the degree of involvement of the subventricular region of the lateral ventricle. Intravenous autologous MSCs transplantation was safe for stroke patients during long-term follow-up. This therapy may improve recovery after stroke depending on the specific characteristics of the patients. STEM

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Huguenard and Prince, 1994a). The hyperpolarization of membrane potentials induced by the activation of GABA B receptors evokes rebound burst discharges in TC neurons (Crunelli and Leresche, 1991; McCormick and Bal, 1994). This characteristic firing pat-

Heart failure is accompanied by severely impaired ␤-adrenergic receptor (␤AR) function, which includes loss of ␤AR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of ␤AR function is agonist-stimulated receptor phosphorylation by the ␤AR kinase (␤ARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in ␤AR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of ␤ARK1 or the ␤ 2 AR were mated into a genetic model of murine heart failure (MLP ؊͞؊ ). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both MLP ؊͞؊ and MLP ؊͞؊ ͞␤ 2 AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP ؊͞؊ ͞␤ARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP ؊͞؊ ͞␤ARKct mice, as measured by LV dP͞dtmax, was increased significantly compared with the MLP ؊͞؊ mice but less than controls. Importantly, heightened ␤AR desensitization in the MLP ؊͞؊ mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the ␤ARK1 inhibitor. We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal ␤AR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit ␤ARK1 as a novel mode of therapy.One of the most important mechanisms for rapidly regulating ␤-adrenergic receptor (␤AR) function is agonist-stimulated receptor phosphorylation by G protein-coupled receptor kinases (GRKs) resulting in decreased sensitivity to further catecholamine stimulation (1, 2). ␤ARK1 is a member of the multigene GRK family that regulates a wide variety of receptors that couple to heterotrimeric G proteins (1, 2). Desensitization of agonistoccupied receptors by the cytosolic ␤AR kinase (␤ARK1) requires a membrane-targeting event before its activation and receptor phosphorylation, which is mediated by a direct physical interaction between residues within the carboxyl terminus of ␤ARK1 and the dissociated membrane-anchored ␤␥ subunits of G proteins (G␤␥) (3, 4).Heart failure is a disease characterized by left ventricular (LV) dysfunction associated with a complex of symptoms that relate to inadequate perfusion of tissues and pulmonary congestion. Although the fundamental molecular abnormality that causes this progressive deterioration in cardiac function is unknown, one of the leading candidates is abnormal ␤AR signaling. Chronic human heart failure is characterized by severely attenuated ␤AR signaling, resulting from diminished receptor number and impaired receptor function (5...

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