Yoshiaki Kubota

The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Improves Vascular Endothelial Function in Type 2 Diabetes

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).

Impact of sleep-disordered breathing and efficacy of positive airway pressure on mortality in patients with chronic heart failure and sleep-disordered breathing: a meta-analysis.

BackgroundsTo conduct a meta-analysis to investigate whether sleep-disordered breathing (SDB) is an independent risk factor for mortality and whether positive airway pressure (PAP) decreases mortality in patients with chronic heart failure (HF). The impact of SDB and the effects of PAP on mortality in patients with chronic HF remain unclear.MethodsWe searched the MEDLINE, EMBASE, and Cochrane databases. Clinical trials that addressed mortality and the effect of PAP on mortality in chronic HF patients with SDB were included in this meta-analysis.ResultsEleven studies (1,944 participants in total) that addressed mortality in chronic HF patients with SDB were included in this study. Patients with SDB showed a significantly increased mortality risk compared to those without SDB [risk ratio (RR) 1.66 (1.19–2.31)]. In sub-analyses, a significant increase in risk of mortality was observed for central sleep apnea versus no-SDB [RR 1.48 (1.15–1.91)], whereas no significant increase in risk was observed for obstructive sleep apnea versus no-SDB. Five randomized controlled studies (395 participants) that assessed the effect of PAP in chronic HF patients with SDB were analyzed. Adaptive servo-ventilation (ASV) significantly reduced all-cause mortality in chronic HF patients with SDB [RR 0.13 (0.02–0.95)], whereas continuous PAP did not significantly reduce all-cause mortality [RR 0.71 (0.32–1.57)].ConclusionsThe 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.

Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis

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.

Impact of β-blocker selectivity on long-term outcomes in congestive heart failure patients with chronic obstructive pulmonary disease

Background Chronic 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. Methods The 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. Results The 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). Conclusion These 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.

Therapeutic vascular angiogenesis for intractable macroangiopathy-related digital ulcer in patients with systemic sclerosis: a pilot study

OBJECTIVE SSc causes intractable ischaemic ulcers. To avoid major amputation, we examined the safety and efficacy of therapeutic vascular angiogenesis for digital ulcers due to SSc. METHODS A single-centre, open-label pilot study was conducted in patients with an ischaemic digital ulcer [n = 40, mean age 65 years (s.d. 8), Rutherford class III-5 or III-6) due to lcSSc (n = 11) or arteriosclerosis obliterans (ASO; n = 29). Bone marrow mononuclear cells (0.4-5.1 × 10(10) cells in total) were administered into the ischaemic limbs. We evaluated short-term safety and efficacy by means of a pain scale, (99m)Tc-tetrofosmin scintigraphy and transcutaneous oxygen tension (TcPO2) before and 4 weeks after treatment. Also, the 2-year outcome was compared. RESULTS There was a case of amputation in each group within 4 weeks after therapy. The pain scale significantly decreased in both groups [lcSSc 93 mm (s.d. 9) to 11 (s.d. 16), P < 0.01; ASO 77 mm (s.d. 22) to 16 (s.d. 13), P < 0.01] and TcPO2 significantly improved [lcSSc 9.0 mmHg (s.d. 9) to 35 (s.d. 14), P < 0.01; ASO 18 mmHg (s.d. 10) to 29 (s.d. 21), P < 0.05). At the 2-year follow-up, the limb amputation rate was 9.1% in lcSSc and 20.7% in ASO (P = 0.36), while the recurrence rate was 18.2% in lcSSc and 17.2% in ASO (P = 0.95). All-cause mortality was 27.3% in lcSSc and 17.2% in ASO (P = 0.65). CONCLUSION In patients with lcSSc, bone marrow mononuclear cell implantation provides clinical benefit and is safe, without major adverse reactions, and may become an effective strategy. TRIAL REGISTRATION UMIN-CTR, http://www.umin.ac.jp/ctr/index-j.htm, no. UMIN000004112.

Superiority of the extracellular volume fraction over the myocardial T1 value for the assessment of myocardial fibrosis in patients with non-ischemic cardiomyopathy

PURPOSE This study aimed to assess the efficacies of the myocardial T1 value and the extracellular volume fraction (ECV) for determining the severity of myocardial fibrosis in patients with non-ischemic cardiomyopathy. MATERIALS AND METHODS Myocardial fibrosis is considered the most important indicator of cardiac damage associated with non-ischemic cardiomyopathy. Recently, modified Look-Locker inversion recovery imaging (MOLLI) has been used for T1 mapping and measurement of the ECV for the assessment of myocardial fibrosis. The present study included 22 patients (mean age, 61.5±12.7; 21 male) with non-ischemic heart failure. Motion corrected myocardial T1 mapping was automatically performed using a MOLLI sequence, and the ECV was estimated from the pre- and post-contrast blood and myocardial T1 values corrected for the hematocrit level. All endomyocardial biopsy specimens were obtained from the inferoposterior left ventricular wall. The percentage of myocardial fibrosis (%F) was determined after Elastica Masson-Goldner staining as follows: (fibrosis area/[fibrosis area+myocardial area])×100. RESULTS No correlation was noted between the %F and the pre- (r=0.290, p=0.191) or post-contrast T1 values (r=-0.190, p=0.398); however, a significant correlation was noted between the %F and ECV (r=0.750, p<0.001). CONCLUSIONS In this study, the ECV reflected the extent of myocardial fibrosis, but the pre- and post-contrast T1 values did not. The ECV may be used to estimate the severity of myocardial fibrosis in patients with non-ischemic cardiomyopathy.

Plaque Characteristics in Coronary Artery Disease Patients with Impaired Glucose Tolerance.

Background Impaired glucose tolerance (IGT) patients are known to have a high risk of cardiovascular events and their prognosis has been reported to be poor. The present study aimed to compare coronary plaque characteristics among coronary artery disease (CAD) patients with normal glucose tolerance (NGT), those with IGT, and those with diabetes mellitus (DM) by using optical coherence tomography (OCT). Methods The present study included 101 coronary artery disease patients (mean age, 67.9 ± 10.4 years; 82.4% male). OCT was performed for target and non-target vessels during percutaneous coronary intervention. The patients were divided into the following 3 groups: the NGT, IGT, and DM groups. Results A total of 136 non-target residual plaques were found in 101 patients (27, 30, and 44 in the NGT, IGT, and DM groups, respectively). The size of the lipid core expressed as the mean angle of the lipid arc was significantly greater in the IGT and DM groups than in the NGT group (163.0 ± 58.7°, 170.1 ± 59.3°, and 130.9 ± 37.7°, respectively, P < 0.05). The fibrous cap covering the lipid core was significantly thinner in the IGT group than in the NGT group (77.0 ± 23.4 μm vs. 105.6 ± 47.0 μm, P = 0.040). Conclusion The coronary plaques in CAD patients are more vulnerable when having IGT compared to those with NGT, and similar to those with DM. This finding may explain the high risk of cardiovascular events in CAD patients with IGT.

COPD advances in left ventricular diastolic dysfunction.

Background COPD 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 methods Overall, 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. Results The 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). Conclusion Our data suggest that LV diastolic dysfunction as a complication of COPD may be associated with mechanical exclusion of the heart by pulmonary overinflation.

Clinical Characteristics and Outcome of Alcohol Septal Ablation With Confirmation by Nitroglycerin Test for Drug-Refractory Hypertrophic Obstructive Cardiomyopathy With Labile Left Ventricular Outflow Obstruction.

Careful evaluation, including provocation tests, is needed to specify an indication for septal reduction therapy in patients with drug-refractory hypertrophic obstructive cardiomyopathy. This study aimed to evaluate the outcome of alcohol septal ablation (ASA) using an intravenous nitroglycerin test (IV-NTG). Of consecutive 156 patients, after excluding cases of severe valvular disease and repeat septal reduction therapy, we investigated the clinical characteristics of patients with labile obstruction (n = 32) and the outcomes after ASA using the IV-NTG test; comparisons were made with those exhibiting basal obstruction (a resting gradient of ≥30 mm Hg). The patients with labile obstruction had less left ventricular mass (141 ± 47 vs 182 ± 59 g, p = 0.003) and less brain natriuretic peptide values (414 ± 576 vs 744 ± 625 pg/ml, p <0.001) than those with basal obstruction. Immediately after ASA, the gradients improved from 15 ± 7 to 5 ± 5 mm Hg and the IV-NTG-provoked gradients improved from 74 ± 25 to 13 ± 9 mm Hg, respectively. At 1-year follow-up, the New York Heart Association functional class had improved from 2.7 ± 0.5 to 1.3 ± 0.5. There was no sudden cardiac death during the follow-up period (5.1 ± 3.0 years), and 8-year survival free from cardiovascular death was 94%. In conclusion, patients with labile obstruction had less-severe left ventricular hypertrophy but exhibited symptoms comparable to those with basal obstruction. The IV-NTG test is a useful method for rapidly confirming acute reduction of the latent gradient after the ASA procedure, and the outcome of ASA for labile obstruction was favorable.

Endothelial dysfunction may promote keloid growth

Keloid is a cutaneous fibroproliferative disorder. It results from impaired wound healing that generates persistent inflammation and extensive deposition of collagen fibers in the wound/scar. Keloids tend to be worse in hypertensive patients. The present prospective cross‐sectional study assessed whether endothelial dysfunction, which occurs in hypertension, associates with keloid formation and progression. This study included randomly selected patients with keloids who were assessed for surgical keloid treatment in 2013–2014. A series of nonkeloid patients admitted to the hospital was also recruited during this period. To measure endothelial function, all patients underwent digital reactive hyperemia peripheral arterial tonometry. Test results were expressed as reactive hyperemia index (RHI) and augmentation index (AI). In total, 57 patients with keloids and 19 nonkeloid controls were recruited. Keloid patients did not differ from the controls in terms of demographic or clinical variables, but had significantly worse RHI and AI values. Moreover, poor RHI and AI values associated with keloid development on binomial logistic regression. The keloid patients were then divided into four groups depending on whether their keloids started at age 0–12, 13–18, 19–29, or ≥30 years. Patients whose keloids arose before and well after puberty tended to have lower RHI than the controls, but these differences did not achieve statistical significance. However, these two groups did have significantly poorer AI values than the controls. Thus, endothelial dysfunction could cause keloid formation and/or aggravation. This indicates that vascular endothelial cells are important for wound healing.