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Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

A 15 year-old-Japanese girl was admitted to our ward because of syncope. Electrocardiography (ECG) demonstrated sinus bradycardia with heart rate of 52/min. Holter ECG showed no arrhythmia related to syncope. Coronary enhanced computed tomography and cardiac magnetic resonance imaging showed no abnormal findings. Head-up tilt test revealed syncope with sinus arrest. (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy revealed focally decreased uptake on the anterior wall of the left ventricle but generally maintained uptake of MIBG. Finally, she was diagnosed with cardioinhibitory vasovagal syncope (CIVS). Sympathetic nerve abnormalities seemed to be related to CIVS in this patient.

A 62-year-old woman with activity-dependent two-to-one atrioventricular block (2:1AVB) and a normal left ventricular ejection fraction was referred to our department for the evaluation of exclusively exercise-induced marked symptoms. The treadmill test helped establish a clear correlation between 2:1AVB and symptoms. The test results demonstrated that exercise-induced marked symptoms were attributed to abrupt transient hypotension combined with relative bradycardia, probably due to increased diastolic mitral and tricuspid regurgitation because of 2:1AVB during moderate-to-heavy exercise. After pacemaker implantation for 2:1AVB, the symptoms and transient hypotension disappeared, and her exercise capacity improved.

A 16-year-old Japanese man was admitted to our hospital because of syncope during exercise. His father and his younger brother had permanent pacemaker implantation because of sick sinus syndrome. Several examinations revealed first-degree atrioventricular block, complete right bundle branch block, sick sinus syndrome, and ventricular tachycardia with normal cardiac function. As no abnormalities were evident on coronary angiography, right ventricular endomyocardial biopsy was performed. It showed myocardial disarrangement and lipofuscin accumulation in hypertrophic myocytes. Moreover, electron microscopy showed a few degenerative myocytes, Z-band streaming, disarrangement, increased small capillaries with Weibel-Palade bodies in endothelial cells, and endothelial proliferations. Genetic analysis of the proband, his father, and his younger brother revealed a missense mutation, D1275N, in SCN5A, a gene which encodes sodium ion channel protein, are related to cardiomyopathy and arrhythmia. The proband was diagnosed with a cardiac conduction defect (CCD) and underwent permanent pacemaker implantation. These pathological findings suggest various myocardial changes presented in CCD patients with a missense mutation, D1275N, in SCN5A.

Uric acid is generated with reactive oxygen species via xanthine oxidase (XO), and hyperuricemia, which is identified as the excess of uric acid in the blood, has been associated with vascular endothelial dysfunction. However, the effects of urate-lowering medicines on endothelial function have not been fully elucidated. Thus this study determined and compared the effects of benzbromarone (urate transporter 1 inhibitor) and febuxostat (XO inhibitor) on endothelial function.This randomized, cross-over, open-label study initially recruited 30 patients with hyperuricemia. They were divided into two groups, treated initially with benzbromarone or febuxostat for three months and then were switched for the next three months. Endothelial function was defined as reactive hyperemia indexes (RHI) determined using Endo-PAT 2000 before and at three and six months after medication using the two agents. Blood levels of asymmetric dimethylarginine (ADMA) and high-molecular-weight (HMW) adiponectin were also compared. We finally analyzed data from 24 patients whose endothelial function was assessed as described above.Our findings show that levels of uric acid significantly decreased, whereas those of HMW adiponectin and the RHI have significantly increased after treatment with benzbromarone. Meanwhile, in patients administered with febuxostat, uric acid levels tended to decrease and RHI significantly decreased. Neither of the two agents altered ADMA levels. The changes in RHI (P = 0.026) and HMW adiponectin levels (P = 0.001) were found to be significantly greater in patients treated with benzbromarone than febuxostat. Changes in the levels of HMW adiponectin and of uric acid were significantly correlated (r = -0.424, P = 0.039).Benzbromarone has increased adiponectin besides reducing uric acid levels, and thus, this might confer more benefits on endothelial function than febuxostat.

Reduced expressions of plakoglobin and connexin 43 have been reported in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, the relationships between these expression abnormalities and the clinical features of ARVC remain unknown. The expressions of plakoglobin and connexin 43 in myocardial biopsy specimens from 10 patients with confirmed ARVC, and 13 control patients without ARVC (non-ARVC; hypertrophic cardiomyopathy, n = 7; dilated cardiomyopathy, n = 6), were examined by immunostaining to evaluate the relationships between these expressions and the clinical characteristics of ARVC. The ratios of plakoglobin/N-cadherin and of plakoglobin/connexin 43 expressions were significantly lower in the ARVC group than in the control group. Significantly more patients had decreased plakoglobin expression in the ARVC group than in the control group (9/10 versus 7/13; P = 0.0376). Sustained ventricular tachycardia occurred more frequently in patients with ARVC and with decreased expressions of both plakoglobin and connexin 43 than in those with decreased expression of plakoglobin alone (5/5 versus 1/4, P = 0.048). Decreased expressions of both connexin 43 and plakoglobin in the myocardium might be associated with the development of arrhythmia in ARVC., International Heart Journal, 56(6), pp.626-631; 2015

24-year-old Japanese man with type 2 diabetes mellitus and diabetic neuropathy was admitted to our ward to evaluate the cause of orthostatic intolerance. During a head-up tilt test, his heart rate increased from 105 to 155 beats/minute within 3 minutes, and chest discomfort began. He was diagnosed with postural orthostatic tachycardia syndrome (POTS), and orthostatic intolerance disappeared after β-blocker treatment. Scintigraphy using123I-metaiodobenzylguanidine showed decreased cardiac uptake. Power spectral analysis of heart rate variability for 24 hours in Holter electrocardiography demonstrated decreases in both sympathetic and parasympathetic nervous system activities, with a greater decrease in parasympathetic activity than sympathetic activity. The relative sympathetic hyperactivity in the present patient with diabetic neuropathy seemed to be related to POTS., International Heart Journal, 59(6), pp.1488-1490; 2018

Background Although ventricular premature contraction (VPC) commonly arises in subjects with and without heart diseases, the prognosis of VPC has remained controversial and the effect of their morphology on mortality has not been fully determined in subjects without obvious heart diseases. The objective of this study was to assess the morphologic effect of VPC on mortality. Methods Japanese atomic bomb survivors (n = 6685) underwent baseline health examinations and standard 12-lead electrocardiogram (ECG) between January 1990 and December 1991. Of these, we extracted data from 5,685 (67.1% women) subjects who had neither heart diseases nor electrocardiographic abnormalities at baseline. Among them, we identified 131 VPC cases using standard 12-lead ECG and classified them into left bundle branch block (LBBB) type (n = 74), right bundle branch block (RBBB) type (n = 21), and undetermined type (n = 36) according to their morphology. These subjects were followed up until December 2008; we compared all-cause, cardiac and coronary heart disease (CHD) mortality rates using multivariate Cox regression analysis between those with and without VPC. Results No VPCs were associated with all-cause and cardiac mortality, but the LBBB type was significantly associated with CHD mortality (hazard ratio, 2.73; 95% confidence interval, 1.11–6.73) after controlling for age, sex, smoking status, alcohol consumption, and underlying diseases. Conclusions Among Japanese atomic bomb survivors without obvious heart diseases, LBBB-type VPC was associated with increased CHD mortality. Larger studies are needed to confirm the effect of morphology as it might help to predict the risk.

A 68-year-old man with sick sinus syndrome (SSS) was referred to our department for pacemaker implantation. After implantation of a pacemaker with rate-responsive dual chamber (DDDR) mode and minimized ventricular pacing (MVP) functions, paroxysmal atrial fibrillation (PAF) repeatedly developed. Pacemaker memory showed that the intrinsic atrioventricular (AV) (atrial pacing-ventricular sensing [Ap-Vs]) interval was paradoxically prolonged during rate-responsive atrial single-chamber (AAIR) mode rapid pacing because of MVP. Accordingly, to eliminate the paradoxical prolongation of the AV interval during rapid atrial pacing, we changed MVP to medium AV hysteresis and conducted DDDR mode pacing with rate-dependent AV delay. PAF then sharply decreased without antiarrhythmic drugs.

A 72-year-old man with non-valvular atrial fibrillation and metastatic liver and lung cancer after surgery for colon cancer developed thrombosis in the right atrium one month after decreasing the dose of warfarin due to the introduction of double anti-platelet therapy for coronary stent implantation. Restoring the warfarin dose with ordinary control for two months did not result in any changes in the size of the thrombus; however, the subsequent substitution of rivaroxaban (oral treatment with a direct Factor Xa inhibitor) for warfarin ultimately resolved the thrombosis., Internal Medicine, 54(6), pp.601-604; 2015