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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.

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

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

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

Background-Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identifcation of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. Methods and Results-We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identifed 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was signifcantly less (mean±SE, 12.4±4.6 years; n=5) than in SCN5A-negative probands (47.0±4.6 years; n=10; P, Circulation: Arrhythmia and Electrophysiology, 7(3), pp.511-517; 2014

A 67-year-old woman was referred to our hospital with a sudden syncopal attack. She suffered from cardiogenic shock due to left ventricular (LV) outflow stenosis with simultaneous complete atrioventricular (AV) block. An endomyocardial biopsy of the left ventricle demonstrated myocardial disarray and myocardial fibrous and edematous tissue with infiltration of mononuclear cells. Cardiac magnetic resonance imaging (cMRI) detected a damaged septal area that was likely associated with the conduction disturbance. The diagnosis was hypertrophic cardiomyopathy accompanied by acute myocarditis. Although the LV outflow stenosis was transient, the complete AV block was persistent, thus requiring permanent pacemaker implantation., Internal Medicine, 51(18), pp.2565-2571; 2012

Introduction: Although prolonged and fractionated right atrial electrograms have been reported as predictors of the development of chronic atrial fibrillation in patients with paroxysmal atrial fibrillation (PAF), the effects of angiotensin-converting enzyme inhibitor (ACEI) on these electrophysiologic abnormalities remain unknown. The purpose of this study was to evaluate whether ACEI influences these electrophysiologic abnormalities of atrial muscle in patients with PAF. Methods: While taking oral ACEI for hypertension, 12 patients (ACEI group) with PAF underwent electrophysiologic study (EPS). Catheter mapping of 12 right atrial sites and right atrial extrastimulation were performed during sinus rhythm. Twenty-four age-matched patients with PAF but not taking oral ACEI were included as a control group. Results: The longest duration of the right atrial electrogram was significantly shorter and the maximum number of fragmented deflections per patient was significantly lower in the ACEI group than in the control group (79 ± 15 ms vs 100 ± 15 ms, P < 0.005; 5.5 ± 1.9 vs 7.9 ± 2.4, P < 0.001, respectively). The number of abnormal atrial electrograms per patient was significantly lower in the ACEI group than in the control group (0.5 ± 1.4 vs 2.1 ± 1.8, P < 0.05). The percentage of patients with at least one abnormal atrial electrogram was significantly lower in the ACEI group than in the control group (16.7% vs 79.2%, P < 0.0005). Conclusions: ACEI use is associated with a decrease in the incidence of prolonged and fractionated right atrial electrograms in patients with PAF. In addition, we suggest that ACEI may help prevent PAF from becoming chronic.

A 24-year-old pregnant woman with Marfans syndrome delivered by cesarean section during the 38th week of gestation. Although aortic root dilatation did not increase during pregnancy, three months after delivery, the patient noticed a pulsatile abdominal mass. Aortic aneurysm was diagnosed and surgical replacement of the infrarenal abdominal aorta to the common iliac arteries and reconstruction of the inferior mesenteric artery were performed. Moreover, the patient subsequently developed a Stanford type B thoracic aortic dissection, even after more than four months of β-blockade., Internal Medicine, vol.45(22), pp.1285-1289; 2006

Although electrophysiological abnormalities of atrial muscle have been evaluated in patients with paroxysmal atrial fibrillation (PAF), no prior study has determined the contribution of the patient's history of PAF to electrophysiological abnormalities. The study population consisted of 108 patients (71 men; mean age, 57 +/- 14 years) with symptomatic and idiopathic PAF who underwent electrophysiological study. Before electrophysiological study, histories of frequency, number of PAF episodes per month, and duration, a time interval from the first episode of PAF to electrophysiological study, were examined. At electrophysiological study, endocardial electrograms from 12 right atrial sites were recorded during sinus rhythm, and the right atrial effective refractory period was determined. Longest duration of atrial electrograms, maximal number of fragmented deflections, and number of abnormal atrial electrograms recorded at the right atrial sites were significantly greater in the frequent group (> 1 PAF episode per month, n = 57) than in the infrequent group (< 1 PAF episode per month, n = 51) (98 +/- 18 ms vs 88 +/- 16 ms, P < 0.005; 8.7 +/- 2.6 vs 7.5 +/- 2.6, P < 0.05; and 2.2 +/- 2.2 vs 1.4 +/- 1.6, P < 0.05, respectively). Indices of atrial vulnerability were also greater in the frequent group. Duration of PAF history was significantly correlated with longest duration r = 0.52, P < 0.0001), maximal number of fragmented deflections r = 0.51, P < 0.0001), and number of abnormal atrial electrograms r = 0.58, P < 0.0001). More frequent episodes and longer history of PAF significantly increased the electrophysiological abnormalities of the atrial muscle, suggesting that PAF results in gradual electrical remodeling of the atrial muscle.

Insulin resistance is known as an important risk factor for coronary artery disease (CAD). However, CAD-related mortality in Japanese type 2 diabetics is lower than in Caucasians. To investigate whether insulin resistance is related to CAD in Japanese type 2 diabetics, we measured insulin sensitivity and several coronary risk factors in Japanese patients with type 2 diabetes with and without CAD. Thirty-three patients with definite CAD and 33 age- and sex-matched patients without CAD (control) were studied. Insulin sensitivity was assessed by the K index of insulin tolerance test (KITT). Clinical characteristics, classical risk factors, lipoprotein (a), and insulin sensitivity were compared between the two groups. Patients with CAD had a significantly longer duration of diabetes (9.0 +/- 1.4 vs. 5.5 +/- 0.9 years, P0.05, respectively), were mostly hypertensive (69.7 vs. 39.4%, P0.05), and more likely to be treated with insulin (45.5 vs. 18.2%, P0.05) compared with the control. Concerning the metabolic parameters, patients with CAD had a significantly higher insulin resistance than control (2.40 +/- 0.15 vs. 3.23 +/- 0.17%/min, P0.01, respectively), higher triglyceride (1.39 +/- 0.10 vs. 1.05 +/- 0.05 mmol/l, P0.05), lower HDL cholesterol (1.05 +/- 0.05 vs. 1.28 +/- 0.06 mmol/l, P0.05), and higher lipoprotein (a) (27.5 +/- 4.3 vs. 17.4 +/- 2.0 mg/dl, P0.05). Multiple logistic regression analysis indicated that hypertension, insulin resistance, high lipoprotein (a) and triglyceride, and low HDL cholesterol were independently related to CAD. Our results suggest that insulin resistance per se is a significant risk factor for CAD in Japanese patients with type 2 diabetes.

We report a patient with a complex nonreentrant supraventricular tachycardia because of double ventricular response resulting from antegrade dual atrioventricular (AV) nodal pathways. We could induce double ventricular response and confirm dual AV nodal pathways by AV simultaneous pacing during basic stimulation proceeding with programmed atrial single extrastimulation. As far as we know, it is the first report about the application of the AV simultaneous basic stimulation to prove the sustained nonreentrant tachycardia because of simultaneous conduction over dual AV nodal pathways. This was also confirmed by absence of the arrhythmia immediately after the elimination of the slow pathway conduction by radiofrequency ablation.

We appreciated hearing from Casado-Arroyo et al regarding our recently published article, “Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated With Early Repolarization,” showing that SCN5A is a novel causative gene of early repolarization syndrome.1 In this study, we identified 3 SCN5A mutations in 3 unrelated patients with idiopathic ventricular fibrillation associated with early repolarization (or early repolarization syndrome). Because all of the patients had J-point elevation in the right precordial lead(s) in addition to J-point elevation in the inferior/lateral leads, Casado-Arroyo et al suggested that all of our patients have Brugada syndrome based on their recent findings that the risk of arrhythmia events is similar between patients with the Type 1 Brugada electrocardiographic pattern in 1 of the right precordial leads and patients with the Type 1 electrocardiographic pattern in >1 lead.2 However, we respectfully disagree because our patients never met the diagnostic criteria for Brugada syndrome.3 The diagnosis of Brugada syndrome is made when patients have a Type 1 Brugada electrocardiographic pattern, which is characterized by a prominent coved ST-segment elevation displaying a J-wave amplitude or ST-segment elevation ≥0.2 mV followed by a negative T-wave in ≥2 of the right precordial leads in the absence or presence of sodium channel blockers.3 Although the J-point elevation was ≥0.2 mV in 1 (Patients 2 and 3) or 2 (Patient 1) of the right …

Background— Recently, we and others reported that early repolarization (J wave) is associated with idiopathic ventricular fibrillation. However, its clinical and genetic characteristics are unclear. Methods and Results— This study included 50 patients (44 men; age, 45±17 years) with idiopathic ventricular fibrillation associated with early repolarization, and 250 age- and sex-matched healthy controls. All of the patients had experienced arrhythmia events, and 8 (16%) had a family history of sudden death. Ventricular fibrillation was inducible by programmed electric stimulation in 15 of 29 patients (52%). The heart rate was slower and the PR interval and QRS duration were longer in patients with idiopathic ventricular fibrillation than in controls. We identified nonsynonymous variants in SCN5A (resulting in A226D, L846R, and R367H) in 3 unrelated patients. These variants occur at residues that are highly conserved across mammals. His-ventricular interval was prolonged in all of the patients carrying an SCN5A mutation. Sodium channel blocker challenge resulted in an augmentation of early repolarization or development of ventricular fibrillation in all of 3 patients, but none was diagnosed with Brugada syndrome. In heterologous expression studies, all of the mutant channels failed to generate any currents. Immunostaining revealed a trafficking defect in A226D channels and normal trafficking in R367H and L846R channels. Conclusions— We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.

A 31-year-old woman underwent radiofrequency catheter ablation of a concealed left posteroseptal accessory pathway associated with a coronary sinus diverticulum. The patient had previously undergone unsuccessful catheter ablation of the posteroseptal region of the mitral annulus. Coronary sinus venography revealed the presence of the diverticulum near the ostium. An electrogram in the neck of the diverticulum showed the shortest ventriculoatrial conduction time and a large accessory pathway potential during atrioventricular reciprocating tachycardia. The pathway was successfully ablated within the neck of the diverticulum. The findings in this case underscore the importance of coronary sinus venography before ablation.

We describe the case of a 39-year-old man who experienced a ventricular fibrillation storm related to a prominent J wave in the inferior and lateral electrocardiographic leads on the day after gastrostomy. The J wave slowly decreased after amiodarone therapy (400 mg/day) was started, and ventricular fibrillation disappeared.

It is sometimes very difficult to diagnose dissecting aortic aneurysms in the early stage. We report an autopsy case in which an acute myocardial infarction and cerebral infarction simultaneously occurred and the symptoms were transiently ameliorated in a patient with an acute aortic dissection., Internal Medicine, vol.45(16), pp.957-962; 2006

A 21-year-old woman with long QT syndrome and missense mutation in HERG (T613M), suffered from repeated attacks of pause dependent torsade de pointes, even though she was given β-blockers and underwent stellate ganglion block twice at the age of eight. After she received permanent pacemaker implantation and administration of verapamil, no premature beats or pause dependent torsade de pointes was observed. (PACE 2004; 27:123–124)