Nobuhisa Hagiwara

Novel Mechanism Associated With an Inherited Cardiac Arrhythmia Defective Protein Trafficking by the Mutant HERG (G601S) Potassium Channel

BACKGROUNDnThe congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go-related gene (HERG), which encodes the rapidly activating component of the delayed rectifier current (IKr), cause chromosome 7-linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work.nnnMETHODS AND RESULTSnTo elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane.nnnCONCLUSIONSnOur results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2.

Creation of human cardiac cell sheets using pluripotent stem cells

Although we previously reported the development of cell-dense thickened cardiac tissue by repeated transplantation-based vascularization of neonatal rat cardiac cell sheets, the cell sources for human cardiac cells sheets and their functions have not been fully elucidated. In this study, we developed a bioreactor to expand and induce cardiac differentiation of human induced pluripotent stem cells (hiPSCs). Bioreactor culture for 14 days produced around 8×10(7) cells/100 ml vessel and about 80% of cells were positive for cardiac troponin T. After cardiac differentiation, cardiomyocytes were cultured on temperature-responsive culture dishes and showed spontaneous and synchronous beating, even after cell sheets were detached from culture dishes. Furthermore, extracellular action potential propagation was observed between cell sheets when two cardiac cell sheets were partially overlaid. These findings suggest that cardiac cell sheets formed by hiPSC-derived cardiomyocytes might have sufficient properties for the creation of thickened cardiac tissue.

Late gadolinium enhancement in cardiac sarcoidosis: characteristic magnetic resonance findings and relationship with left ventricular function.

Purpose: Cardiac involvement is an important prognostic factor in sarcoidosis, and cardiovascular magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE) can facilitate the identification of cardiac sarcoidosis (CS). In patients with CS, we investigated LGE characteristics and their relationship with left ventricular (LV) function to identify those characteristics unique to severely reduced LV function. We also investigated the relationship between LGE and duration of sarcoidosis. Materials and Methods: We retrospectively evaluated 19 patients with CS diagnosed according to the 2006 revised guidelines of the Japanese Ministry of Health and Welfare who underwent CMR imaging. We analyzed LGE location using 17-segment and subsegment (subepicardial, midwall, subendocardial, and transmural) models and evaluated the relationship between the characteristics of LGE and LV ejection fraction (LVEF) and duration of sarcoidosis. Results: Images of 17 of the 19 patients showed LGE most frequently in the subepicardial layer. The total number of affected segments with LGE correlated significantly with LVEF (r=−0.84, P<0.0001) and LV-diastolic volumes (r=0.88, P<0.0001). Transmural lesions were significantly more common in patients with LVEF of 35% or lower than in those with LVEF exceeding 35% (P=0.0004). All patients with LVEF of 35% or lower had both subepicardial and transmural lesions. The total number of affected segments with LGE correlated with the duration of sarcoidosis in patients with onset in an extracardiac organ (r=0.76, P=0.005). Conclusions: Demonstration of a characteristic LGE pattern and location allows diagnosis of CS, and CMR imaging with LGE aids in prediction of LV function.

Clinical outcome in Japanese elderly patients with non-valvular atrial fibrillation taking warfarin: A single-center observational study

BACKGROUNDnAlthough a lower target prothrombin time-international normalized ratio (PT-INR) with warfarin therapy is recommended in Japan for atrial fibrillation (AF) patients ≥70 years of age, few studies have provided supporting data. The current study aimed to evaluate the clinical outcome in elderly Japanese patients with non-valvular AF who were taking warfarin.nnnMETHODSnWe conducted a cohort study of 845 consecutive non-valvular AF patients ≥70 years of age who were taking warfarin (median age, 74 years; 30.5% women) with a median follow-up period of 27 months (4-69 months). Of these patients, 29.7% had a history of stoke/transient ischemic attack (TIA), and 73.1% of the patients had a CHADS(2) score ≥2. The occurrence of thromboembolic events, including ischemic stroke, TIA and other systemic embolisms, and major bleeding events were validated through a review of medical records.nnnRESULTSnThe incidence of thromboembolic and major bleeding events were 3.8 and 2.1% per year, respectively. A higher incidence of both events was observed in patients with a CHADS(2) score ≥3. The multivariate analysis showed that prior stroke/TIA (odds ratio 1.7, 95% CI 1.0-2.7) and diabetes (odds ratio 1.7, 95% CI 1.0-2.8) were independent risks of thromoembolic events. A HAS-BLED score ≥3 represented a risk for major bleeding (hazard ratio 2.8, 95% CI 1.7-4.6). A PT-INR of 1.5-2.5 indicated a low incidence of thromboembolic and major bleeding events in patients with a CHADS(2) score ≥2.nnnCONCLUSIONSnOur results demonstrate that a target PT-INR of 2.0 and a range of 1.5-2.5 may be safe for elderly Japanese patients with non-valvular AF.

Impact of diastolic dysfunction on the outcome of catheter ablation in patients with atrial fibrillation.

OBJECTIVEnTo evaluate the impact of diastolic dysfunction on the outcome of atrial fibrillation (AF) ablation.nnnMETHODSnEighty consecutive patients with drug-refractory symptomatic AF who underwent AF ablation were enrolled (65 males, 58 ± 10 years, 65 paroxysmal AF, 15 persistent AF). All patients underwent extensive pulmonary vein isolation with a double lasso technique using CARTO MERGE. Diastolic dysfunction was defined as a ratio of the mitral inflow early filling velocity to the velocity of the early medial mitral annular ascent of >10. The clinical and echocardiographic data were compared between the patients with and without diastolic dysfunction, and between the patients with and without AF recurrences after the AF ablation.nnnRESULTSnTwenty-nine out of all the patients (36.3%) had diastolic dysfunction. Compared with the patients without diastolic dysfunction, the patients with diastolic dysfunction had higher brain natriuretic peptide (p=0.001) and C-reactive protein (p=0.023) levels, and a larger left atrial diameter (P=0.019). The AF-free rate after a single or repeat AF ablation procedure in the patients with diastolic dysfunction was lower than that in those without diastolic dysfunction (p=0.005 and p=0.013 by the log-rank test, respectively). In the univariate analysis, the patients with persistent AF and diastolic dysfunction were likely to have AF recurrences after a single AF ablation. The multivariate analysis indicated diastolic dysfunction as the only independent predictor of an AF recurrence after a single AF ablation (P=0.023).nnnCONCLUSIONnThe patients with diastolic dysfunction had a worse outcome of the AF ablation not only for a single procedure but also a repeat procedure.

Long-term prognosis of patients with acute myocardial infarction in the era of acute revascularization (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] registry)☆

BACKGROUNDnThe long-term prognosis of patients with acute myocardial infarction (AMI) in the contemporary acute revascularization era is not fully understood.nnnMETHODSnTo clarify long-term prognosis and prognostic factors of AMI patients in a real-world setting, we consecutively registered 3021 patients with AMI (mean age 69 years, 70.7% male) who were admitted to 17 participating medical institutions and followed up prospectively. The outcome measure was death from any cause.nnnRESULTSnAmong 3021 patients, 629 patients had non-ST elevation MI (non-STEMI). During the index hospitalization, coronary angioplasty and thrombolytic therapy were performed in 58.1% and 16.3% of patients, respectively. During hospitalization, 285 patients (9.4%) died. Among 2736 patients (90.6%) who were discharged alive and followed for a median of 4.3 years (follow-up rate, 97.1%), 434 patients (15.9%) died. Among them, 250 (57.6%) died from non-cardiac causes. Compared with STEMI patients, non-STEMI patients suffered significantly more adverse outcomes. Advanced age and non-STEMI disease were associated with poorer outcomes. Multivariate analysis revealed that diabetes mellitus, acute-phase heart failure (Killip functional class ≥ 2), higher serum creatinine level (≥ 1.2 mg/dl), and advanced age (≥ 70 years and ≥ 80 years) at the onset of the AMI were independent poor prognostic factors (hazard ratios, 1.07, 2.53, 1.89, 2.50, and 6.80 respectively).nnnCONCLUSIONSnAMI patients in the era of acute revascularization have favorable long-term prognoses, and a large proportion of late deaths are non-cardiac in nature. The establishment of an optimal management strategy for elderly AMI patients, AMI patients with diabetes, and non-ST elevation AMI patients are essential.

Long-term results of a cardiovascular implantable electronic device wrapped with an expanded polytetrafluoroethylene sheet

The use of an expanded polytetrafluoroethylene (ePTFE) sheet wrapping device for patients with pacemaker contact dermatitis is still controversial. This study aimed to retrospectively investigate the occurrence rate of allergies and other complications after implantation of a cardiovascular implantable electronic device (CIED) wrapped with an ePTFE sheet. A total of 4,497 procedures of CIED implantation were performed at our institution between January 1993 and April 2010. Among 19 patients who underwent implantation of an electronic cardiac device wrapped with an ePTFE sheet, device implantation was performed in 11 patients for secondary prevention of device contact sensitivity, in 7 patients for primary prevention of device contact sensitivity, and in 1 patient for avoiding over-sensing of myopotentials. During follow-up periods (mean 46xa0±xa034xa0months), there were no allergic or inflammatory reactions to components of the device or ePTFE itself. Among 11 patients with a device wrapped with an ePTFE sheet for secondary prevention, 5 patients completed device replacement due to battery depletion and 3 patients had infections from the device. Wrapping implantable devices with an ePTFE sheet is an effective way of preventing device sensitivity in patients who require CIED therapy. However, the risk of infection from the device should be taken into consideration.

Lipid-lowering and anti-inflammatory effect of ezetimibe in hyperlipidemic patients with coronary artery disease

We evaluated the effects of adding ezetimibe to statin therapy in hypercholesterolemic patients with coronary artery disease (CAD) who could not achieve the target cholesterol levels recommended in the 2007 Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases on statin monotherapy. Ezetimibe (10 mg) was added to basal statin therapy for 12 weeks in 35 patients with hypercholesterolemia and a history of CAD who had not achieved their target cholesterol level with statin monotherapy. Changes in serum lipids, obesity markers, an oxidative stress marker, inflammatory markers, and laboratory values were investigated. Total cholesterol (from 200.6 ± 30.4 mg/dL in week 0 to 173.4 ± 33.3 mg/dL in week 12, P < 0.001), low-density lipoprotein cholesterol (LDL-C) (121.3 ± 29.4 vs. 94.6 ± 30.4 mg/dL, P < 0.001), and remnant lipoprotein cholesterol (6.4 ± 3.5 vs. 5.3 ± 3.0 mg/dL, P < 0.05) all decreased significantly after addition of ezetimibe. The LDL-C/high-density lipoprotein cholesterol ratio also decreased significantly (2.5 ± 0.8 in week 0 vs. 1.9 ± 0.7 in week 12, P < 0.001). The percentage of patients achieving the target LDL-C level (<100 mg/dL) increased significantly (70.8xa0% in week 4 and 65.4xa0% in week 12, P < 0.001). There were no significant changes in the obesity or oxidative stress markers and high-sensitivity C-reactive protein (an inflammatory marker). However, another inflammatory marker (tumor necrosis factor-α) was decreased significantly by ezetimibe (1.36 ± 1.06 in week 0 vs. 0.96 ± 0.24 in week 12, P = 0.042). In conclusion, when ezetimibe was added to basal statin therapy, serum lipids improved significantly and the rate of achieving the target cholesterol level increased. Thus, ezetimibe efficiently decreases LDL-C and might prevent arteriosclerosis in hypercholesterolemic patients with CAD when added to basal statin therapy.

Usefulness of tissue Doppler echocardiography to predict perioperative cardiac events in patients undergoing noncardiac surgery

Guidelines have not recommended routine echocardiography to predict perioperative cardiac events (PCE). We aimed to evaluate the prognostic significance of tissue Doppler echocardiography-derived E/E′ for risk stratification before noncardiac surgery. We reviewed 445 consecutive patients with cardiovascular diseases who had undergone tissue Doppler echocardiography before noncardiac surgery. The revised cardiac risk index (RCRI) was assessed from clinical records. After excluding patients who could not have E/E′ measurements, 200 patients were further analyzed. PCEs included death, arrhythmia, myocardial infarction, heart failure and deferred surgery. Eleven patients developed PCEs. E/E′ was significantly higher in patients with PCE (18.4xa0±xa05.8 vs. 12.2xa0±xa04.5, pxa0<xa00.0005). Multivariate analysis showed E/E′ (odds ratio 1.2, pxa0<xa00.007) and RCRI (OR 4.8; 95%, pxa0<xa00.006) were independent predictors of PCE. E/E′ appeared to be useful in perioperative risk stratification among patients with cardiovascular diseases undergoing noncardiac surgery.

Localized reentrant tachycardia in the aorta contiguity region mimicking perimitral atrial flutter in the context of atrial fibrillation ablation

We describe a case with a focal atrial tachycardia (AT) masquerading as perimitral atrial flutter revealed after circumferential pulmonary vein antral isolation for atrial fibrillation. It was successfully terminated and became noninducible by a point ablation on the left atrial anterior wall (LAAW) near the mitral annulus in contact with the aortic root and on the left superior pulmonary vein–left atrial appendage ridge, without any linear ablation, using electroanatomical mapping and conventional precise mapping with a maximum amplified gain within the low-voltage area. The AT revealed in our case was an LAAW–aorta contiguity area-related AT.