The vascular endothelial function is impaired in the very early stage of atherosclerosis in diabetic patients. The goal of this study was to identify the mechanism underlying the improvement in vascular endothelial function by sitagliptin in type 2 diabetes mellitus patients. This study was an open-labeled prospective observational single arm trial. Forty patients were treated with 50 mg of sitagliptin once daily for 12-weeks. The flow-mediated dilation (FMD) and plasma adiponectin were measured at baseline and 12 weeks after initiating treatment. The %FMD was significantly increased after treatment (4.13 ± 1.59 vs 5.12 ± 1.55, P < 0.001), whereas the nitroglycerin-mediated dilation (NMD) did not change. The plasma adiponectin levels significantly increased (13.0 ± 11.3 vs 14.3 ± 12.8, P < 0.001). The changes in the FMD were significantly correlated with those of the plasma adiponectin (r = 0.322, P < 0.05). A multivariate linear regression analysis demonstrated that the improvement in the FMD is associated with the plasma adiponectin (P < 0.05). The treatment of type 2 diabetes mellitus patients with sitagliptin reverses vascular endothelial dysfunction, as evidenced by increase in the FMD, and improvement of the adiponectin levels (UMIN Clinical Trials Registry System as trial ID UMIN000004236).

To cite this article: Nakamura S, Takano H, Kubota Y, Asai K, Shimizu W. Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis. J Thromb Haemost 2014; 12: 1086-95.Summary. Background: The efficacy of thrombolytic therapy in patients with submassive pulmonary embolism (PE) remains unclear. Previous meta-analyses have not separately reported the proportion of patients with submassive PE. Objective: We assessed the effect of thrombolytic therapy on mortality, recurrent PE, clinical deterioration requiring treatment escalation and bleeding in patients with submassive PE. Methods: The MEDLINE, EMBASE and Cochrane Library databases were searched to identify all relevant randomized controlled trials comparing adjunctive thrombolytic therapy with heparin alone as initial treatments in patients with acute submassive PE, and reported 30-day mortality or in-hospital clinical outcomes. Results: A total of 1510 patients were enrolled in this meta-analysis. No significant differences were apparent in the composite endpoint of all-cause death or recurrent PE between the adjunctive thrombolytic therapy arm and the heparin-alone arm (3.1% vs. 5.4%; RR, 0.64 [0.32-1.28]; P = 0.2). Adjunctive thrombolytic therapy significantly reduced the incidence of the composite endpoint of all-cause death or clinical deterioration (3.9% vs. 9.4%; RR, 0.44; P < 0.001). There were no statistically significant associations for major bleeding when adjunctive thrombolytic therapy was compared with heparin therapy alone (6.6% vs. 1.9%; P = 0.2). Conclusions: This meta-analysis shows that adjunctive thrombolytic therapy does not significantly reduce the risk of mortality or recurrent PE in patients with acute submassive PE, but that adjuvant thrombolytic therapy prevents clinical deterioration requiring the escalation of treatment in patients with acute submassive PE. Bleeding risk assessment might be the most successful approach for improving clinical outcomes and patient-specific benefit.

Background Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium–glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. Methods This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency–to–high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. Results Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was – 0.57 and – 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. Conclusions This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. Trial Registration: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442.

BackgroundChronic obstructive pulmonary disease (COPD) is present in approximately one-third of all congestive heart failure (CHF) patients, and is a key cause of underprescription and underdosing of β-blockers, largely owing to concerns about precipitating respiratory deterioration. For these reasons, the aim of this study was to evaluate the impact of β-blockers on the long-term outcomes in CHF patients with COPD. In addition, we compared the effects of two different β-blockers, carvedilol and bisoprolol.MethodsThe study was a retrospective, non-randomized, single center trial. Acute decompensated HF patients with COPD were classified according to the oral drug used at discharge into β-blocker (n=86; carvedilol [n=52] or bisoprolol [n=34]) and non-β-blocker groups (n=46). The primary endpoint was all-cause mortality between the β-blocker and non-β-blocker groups during a mean clinical follow-up of 33.9 months. The secondary endpoints were the differences in all-cause mortality and the hospitalization rates for CHF and/or COPD exacerbation between patients receiving carvedilol and bisoprolol.ResultsThe mortality rate was higher in patients without β-blockers compared with those taking β-blockers (log-rank P=0.039), and univariate analyses revealed that the use of β-blockers was the only factor significantly correlated with the mortality rate (hazard ratio: 0.41; 95% confidence interval: 0.17–0.99; P=0.047). Moreover, the rate of CHF and/or COPD exacerbation was higher in patients treated with carvedilol compared with bisoprolol (log-rank P=0.033). In the multivariate analysis, only a past history of COPD exacerbation significantly increased the risk of re-hospitalization due to CHF and/or COPD exacerbation (adjusted hazard ratio: 3.11; 95% confidence interval: 1.47–6.61; P=0.003).ConclusionThese findings support the recommendations to use β-blockers in HF patients with COPD. Importantly, bisoprolol reduced the incidence of CHF and/or COPD exacerbation compared with carvedilol.

IntroductionProtection from lethal ventricular arrhythmias leading to sudden cardiac death is one of the most important problems after myocardial infarction. Cardiac sympathetic hyperactivity is related to poor prognosis and fatal arrhythmias and can be non-invasively assessed with heart rate variability, heart rate turbulence, T-wave alternans, late potentials, and 123I-meta-iodobenzylguanide (123I-MIBG) scintigraphy. Sodium glucose cotransporter 2 (SGLT2) inhibitors potentially reduce sympathetic nervous system activity that is augmented in part due to the stimulatory effect of hyperglycemia. The EMBODY trial is designed to determine whether the suppression of cardiac sympathetic activity induced by the SGLT2 inhibitor is accompanied by protection against adverse cardiovascular outcomes.MethodsThe EMBODY trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with acute MI and type 2 diabetes in Japan. A total of 98 patients will be randomized (1:1) to receive once-daily placebo or empagliflozin, an SGLT2 inhibitor, 10 mg. The primary end point is the change from baseline to 24 weeks in heart rate variability. Secondary end points include the change from baseline for other sudden cardiac death surrogate-markers such as heart rate turbulence, T-wave alternans, late potentials, and 123I-MIBG scintigraphy imaging. Adverse effects will be evaluated throughout the trial period.Planned OutcomesThe EMBODY trial will evaluate the potential cardioprotective effect of empagliflozin and will provide additional important new data regarding its preventative effects on sudden cardiac death.Trial RegistrationUnique Trial Number, UMIN000030158 (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034442).FundingNippon Boehringer Ingelheim and Eli Lilly and Company.

AimsChronic obstructive pulmonary disease (COPD) and heart failure (HF) are increasingly frequent in Asia and commonly coexist in patients. However, the prevalence of COPD among Asian patients with HF and its impact on HF treatment are unclear.Methods and resultsWe compared clinical characteristics and treatment approaches between patients with or without a history of COPD, before and after 1:2 propensity matching (for age, sex, geographical region, income level, and ethnic group) in 5232 prospectively recruited patients with HF and reduced ejection fraction (HFrEF, <40%) from 11 Asian regions (Northeast Asia: South Korea, Japan, Taiwan, Hong Kong, and China; South Asia: India; Southeast Asia: Thailand, Malaysia, Philippines, Indonesia, and Singapore). Among the 5232 patients with HFrEF, a history of COPD was present in 8.3% (n = 434), with significant variation in geography (11.0% in Northeast Asia vs. 4.7% in South Asia), regional income level (9.7% in high income vs. 5.8% in low income), and ethnicity (17.0% in Filipinos vs. 5.2% in Indians) (all P < 0.05). Use of mineralocorticoid receptor antagonists and diuretics was similar between groups, while usage of all β‐blockers was lower in the COPD group than in the non‐COPD group in the overall (66.3% vs. 79.9%) and propensity‐matched cohorts (66.3% vs. 81.7%) (all P < 0.05). A striking exception was the Japanese cohort in which β‐blocker use was high in COPD and non‐COPD patients (95.2% vs. 91.2%).ConclusionsThe prevalence of COPD in HFrEF varied across Asia and was related to underuse of β‐blockers, except in Japan.

The prevalence of SDB in patients with chronic HF is associated with worse survival, and ASV reduces all-cause mortality in patients with chronic HF concomitant with SDB.

BackgroundCOPD is concomitantly present in ~30% of patients with heart failure. Here, we investigated the pulmonary function test parameters for left ventricular (LV) diastolic dysfunction and the relationship between pulmonary function and LV diastolic function in patients with COPD.Patients and methodsOverall, 822 patients who underwent a pulmonary function test and echocardiography simultaneously between January 2011 and December 2012 were evaluated. Finally, 115 patients with COPD and 115 age- and sex-matched control patients with an LV ejection fraction of ≥50% were enrolled.ResultsThe mean age of the patients was 74.4±10.4 years, and 72.3% were men. No significant differences were found between the two groups regarding comorbidities, such as hypertension, diabetes mellitus, and anemia. The index of LV diastolic function (E/e′) and the proportion of patients with high E/e′ (defined as E/e′ ≥15) were significantly higher in patients with COPD than in control patients (10.5% vs 9.1%, P=0.009; 11.3% vs 4.3%, P=0.046). E/e′ was significantly correlated with the residual volume/total lung capacity ratio. Univariate and multivariate analyses revealed severe COPD (Global Initiative for Chronic Obstructive Lung Disease III or IV) to be a significant predictive factor for high E/e′ (odds ratio [OR] 5.81, 95% confidence interval [CI] 2.13–15.89, P=0.001 and OR 6.00, 95% CI 2.08–17.35, P=0.001, respectively).ConclusionOur data suggest that LV diastolic dysfunction as a complication of COPD may be associated with mechanical exclusion of the heart by pulmonary overinflation.