Hiroshige Yamabe

Pancreatic B-cell function is altered by oxidative stress induced by acute hyperglycaemia

Aims  Type 2 diabetes is preceded by a symptom‐free period of impaired glucose tolerance (IGT). Pancreatic B‐cell function decreases as glucose intolerance develops. In many patients with IGT, fasting blood glucose is within normal limits and hyperglycaemia occurs only postprandially. We examined whether pancreatic B‐cell function changes during acute hyperglycaemia induced by oral glucose loading.

Coronary Vasomotor Response to Intracoronary Acetylcholine Injection, Clinical Features, and Long-term Prognosis in 873 Consecutive Patients With Coronary Spasm: Analysis of a Single-Center Study Over 20 Years

Background The aim of this study was to elucidate the correlation between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection, clinical features, and long‐term prognosis in patients with vasospastic angina (VSA). Methods and Results This is a retrospective, observational, single‐center study of 1877 consecutive patients who underwent ACh‐provocation test between January 1991 and December 2010. ACh‐provoked coronary spasm was observed in 873 of 1637 patients included in the present analysis. ACh‐positive patients were more likely to be older male smokers with dyslipidemia, to have a family history of ischemic heart disease, and to have a comorbidity of coronary epicardial stenosis than were ACh‐negative patients. ACh‐positive patients were divided into 2 groups: those with focal (total or subtotal obstruction, n=511) and those with diffuse (severe diffuse vasoconstriction, n=362) spasm patterns. Multivariable logistic regression analysis identified female sex and low comorbidity of coronary epicardial stenosis to correlate with the ACh‐provoked diffuse spasm pattern in patients with VSA. Kaplan–Meier survival curve indicated better 5‐year survival rates free from major adverse cardiovascular events in patients with diffuse spasm pattern compared with those with focal spasm pattern (P=0.019). Multivariable Cox hazard regression analysis identified diffuse spasm pattern as a negative predictor of major adverse cardiovascular events in patients with VSA. Conclusions ACh‐induced diffuse coronary spasm was frequently observed in female VSA patients free of severe coronary epicardial stenosis and was associated with better prognosis than focal spasm. These results suggest the need to identify the ACh‐provoked coronary spasm subtypes in patients with VSA.

Mechanisms of the maintenance of atrial fibrillation: Role of the complex fractionated atrial electrogram assessed by noncontact mapping

BACKGROUND The role of complex fractionated atrial electrograms (CFAEs) in the maintenance of atrial fibrillation (AF) has not been well clarified. OBJECTIVE The purpose of this study was to examine the mechanisms of AF maintenance, especially in relation to CFAE. METHODS Endocardial mapping of the left atrium was performed during AF using a three-dimensional noncontact mapping system in 16 patients with paroxysmal AF. RESULTS During AF, focal discharges were found at the pulmonary vein and sites within the CFAE region (3.0 +/- 1.9 vs. 2.8 +/- 1.5 times/s; P = NS) but not in the non-CFAE region. One to four meandering waves propagated over various pathways during AF. The frequency of the wave break and pivoting activation in the CFAE region were significantly higher than in the non-CFAE region (5.6 +/- 3.6 vs. 0 +/- 0 times/s, P <.0001 and 5.0 +/- 2.1 vs. 0.3 +/- 0.8 times/s; P <.0001). Wave fusion in the CFAE region was more frequently observed than in the non-CFAE region (6.5 +/- 5.8 vs. 3.6 +/- 3.1 times/s; P <.05). Conduction velocity in the CFAE region was slower than in the non-CFAE region (0.7 +/- 0.4 vs. 1.9 +/- 0.5 m/s; P <.0001). The generation of a new wave was associated with the wave break, fusion, and focal discharge. Furthermore, perpetuation of these waves accompanied by slow conduction and pivoting activation was mostly observed in the CFAE region. CONCLUSION The CFAE region plays an important role in the perpetuation of AF. In addition to focal discharge, wave break and fusion associated with slow conduction and pivoting activation in the CFAE region sustained wave propagation, resulting in the maintenance of AF.

Electrophysiological Delineation of the Tachycardia Circuit in Atrioventricular Nodal Reentrant Tachycardia

BACKGROUND The exact boundaries of the reentry circuit in atrioventricular nodal reentrant tachycardia (AVNRT) have not been convincingly defined. METHODS AND RESULTS To define the tachycardia circuit, single extrastimuli were delivered during AVNRT to 8 sites of the right intra-atrial septum: 3 arbitrarily divided sites of the AV junction extending from the His bundle (HB) site to the coronary sinus ostium (CSOS) (sites S, M, and I) and the superior (S-CSOS), inferior (I-CSOS), posterior (P-CSOS), and posteroinferior (PI-CSOS) portions of the CSOS and the CSOS in 18 patients. The mean tachycardia cycle length (TCL) was 368+/-52 ms. Retrograde earliest atrial activation was observed at the HB site in all patients. The longest coupling intervals of single extrastimuli that reset AVNRT at sites S, M, I, I-CSOS, CSOS, S-CSOS, P-CSOS, and PI-CSOS were 356+/-51, 356+/-51, 355+/-52, 357+/-51, 318+/-47, 305+/-53, 311+/-56, and 312+/-56 ms, respectively, and the following return cycles at these sites were 368+/-52, 368+/-53, 367+/-53, 367+/-53, 407+/-66, 431+/-73, 415+/-55, and 412+/-56 ms, respectively. The longest coupling intervals at sites S, M, I, and I-CSOS did not differ from each other and were longer than those at CSOS and S-, P-, and PI-CSOS (P<0.0001). The return cycles at sites S, M, I, and I-CSOS did not differ from the TCL, whereas those at CSOS and S-, P-, and PI-CSOS were longer than the TCL (P<0.0001). CONCLUSIONS The perinodal atrium extending from the HB site to I-CSOS was involved in the tachycardia circuit. I-CSOS was thought to be the entrance of the slow pathway.

A study on coronary hemodynamics during acetylcholine-induced coronary spasm in patients with variant angina: Endothelium-dependent dilation in the resistance vessels.

The epicardial coronary artery of patients with variant angina is hyperreactive to the constrictive effect of acetylcholine, but it is not known whether the coronary microvasculature also constricts in response to acetylcholine. Incremental doses of acetylcholine were injected into the left coronary artery of 57 patients with variant angina and with spasm in this artery. By measuring coronary sinus blood flow, coronary hemodynamic status just before angiographic documentation of spasm was examined. Acetylcholine induced spasm in the left coronary artery in all patients. It also decreased the diameter of the nonspasm artery by 36 +/- 19% from baseline. For all patients, coronary sinus blood flow was 89 +/- 38 ml/min at baseline and increased to 104 +/- 61 ml/min during an acetylcholine-induced anginal attack (p less than 0.01). In 10 patients with spasm in both the left anterior descending and left circumflex arteries (that is, multivessel spasm), coronary sinus blood flow decreased from 84 +/- 21 to 52 +/- 26 ml/min (p less than 0.01). In the other 47 patients with spasm in only one of these two arteries (that is, single-vessel spasm), coronary sinus blood flow increased from 90 +/- 41 to 115 +/- 61 ml/min (p less than 0.01) without change in the rate-pressure product. It is concluded that in patients with variant angina, acetylcholine induces spasm and constriction in the epicardial coronary artery, whereas it dilates the resistance vessels presumably through the release of the endothelium-dependent relaxing factor.

Determination of cut-off levels for on-clopidogrel platelet aggregation based on functional CYP2C19 gene variants in patients undergoing elective percutaneous coronary intervention

INTRODUCTION Carriers of reduced-function CYP2C19 allele on antiplatelet therapy show diminished platelet inhibition and higher rate of clinical risk. The purpose of this study was to determine cut-off levels of VerifyNow P2Y12 system associated with effective inhibition of on-clopidogrel platelet aggregation to predict carriers of CYP2C19 reduced-function allele among patients undergoing percutaneous coronary intervention (PCI). MATERIALS AND METHODS We enrolled 202 consecutive patients with stable coronary artery disease (CAD) undergoing PCI and treated with clopidogrel. All patients underwent CYP2C19 genotyping and measurement of residual platelet aggregation by VerifyNow system. RESULTS Carriers of CYP2C19 reduced-function allele constituted 131 (65%) of 202 CAD patients. Platelet inhibition measured by P2Y12 reaction units (PRU) and %inhibition was diminished in carriers compared with noncarriers (PRU: 290.0±81.2 vs 217.6±82.4, p<0.001, %inhibition: 17.9±17.8 vs 35.5±22.8, p<0.001, respectively). Multiple logistic regression analysis identified PRU and %inhibition as significant predictors of carrier state [odds ratio (OR) 4.95; 95% confidence interval (95%CI): 2.49 to 9.85; p<0.001, OR 5.55; 95%CI: 2.80 to 10.99; p<0.001, respectively]. Receiver-operating characteristic analysis showed that PRU and %inhibition were significant predictors of carrier state [area under the curve (AUC) 0.736 (95%CI: 0.664 to 0.808; p<0.001), AUC 0.727 (95%CI: 0.651 to 0.803; p<0.001), respectively]. The cut-off levels of PRU and %inhibition were 256 and 26.5% for the identification of carriers. CONCLUSIONS Our results suggested that the cut-off levels of PRU and %inhibition to discriminate carriers of CYP2C19 reduced-function allele from noncarriers are potentially useful clinically to provide optimal clopidogrel therapy in patients with stable CAD undergoing PCI.

Improvement effect on endothelial function in patients with congestive heart failure treated with cardiac resynchronization therapy

BACKGROUND AND PURPOSE Cardiac resynchronization therapy (CRT) is a beneficial strategy to improve severe cardiac dysfunction in patients with congestive heart failure (CHF). The improvement of endothelial function in CHF patients treated with CRT is reflected in the mortality risk reduction. However the precise mechanisms of the relationship between CRT and vascular endothelial function have not been well discussed. METHODS AND SUBJECTS Twenty-two severe consecutive CHF patients associated with dilated cardiomyopathy [New York Heart Association (NYHA) class 3.3 ± 0.5, left ventricular ejection fraction (LVEF) 24.4 ± 5.9%] were included in this study. We evaluated endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), between optimal medical therapy alone group (medical therapy group: n = 10) and CRT group (n = 12) at the study enrolment and 12 weeks later. Furthermore we analyzed the association between the RH-PAT and cardiac function. ESSENTIAL RESULTS Both therapies significantly and equally improved NYHA class, LVEF, end-diastolic left ventricular dimension and plasma levels of brain natriuretic peptide (BNP). CRT significantly increased RH-PAT index (medical therapy group: 1.5 ± 0.2 to 1.5 ± 0.3, p = 0.824; CRT group: 1.4 ± 0.2 to 1.7 ± 0.4, p = 0.003) and cardiac output (medical therapy group: 3.3 ± 1.1 to 3.5 ± 1.0, p = 0.600; CRT group: 2.7 ± 0.6 to 4.3 ± 1.5, p = 0.001), compared to the medical therapy group. There was significant positive correlation between the change in RH-PAT index and cardiac output (r = 0.600, p = 0.003). CONCLUSIONS CRT significantly improved endothelial function through the improvement of cardiac output in CHF patients, compared to optimal medical therapy.

Conduction Properties of the Crista Terminalis and Its Influence on the Right Atrial Activation Sequence in Patients with Typical Atrial Flutter

YAMABE, H., et al.: Conduction Properties of the Crista Terminalis and Its Influence on the Right Atrial Activation Sequence in Patients with Typical Atrial Flutter. The conduction properties of the crista terminalis (CT) and its influence on the right atrial activation sequence were analyzed in 14 patients with typical atrial flutter (AF). Atrial mapping was performed with 35 points of the right atrium during typical AF and during atrial pacing performed after linear ablation of inferior vena cava‐tricuspid annulus (IVCTA) isthmus. Atrial pacing was delivered from the septal isthmus at cycle lengths of 600 ms and the tachycardia cycle length (TCL). The right atrial activation sequence and the conduction interval (CI) from the septal to lateral portion of the IVC‐TA isthmus were analyzed. During AF, the conduction block line (CBL) (detected by the appearance of double potentials along the CT and craniocaudal activation on the side anterior to CT) was observed along the CT in all patients. The TCL and CI during AF were 254 ± 19 and 207 ± 14 ms, respectively. During pacing at a cycle length of 600 ms, the CBL was observed along the CT in four patients, however, a short‐circuiting activation across the CT was observed in the remaining ten patients. The CI during pacing at 600 ms was 134 ± 38 ms, shorter than that during AF (P < .0001). During pacing at the TCL, the CBL was observed along the CT in all patients. The presence of the CBL along the CT prevented a short‐circuiting activation across the CT and resulted in the same right atrial activation as observed during AF. With the formation of the CBL, the CI significantly increased to 206 ± 17 ms and was not different from that during AF. These data suggest that the conduction block along the CT is functional. It was presumed that presence of conduction block at the CT has some relevance to the initiation of typical AF though it was not confirmed.

Endothelium-derived Nitric Oxide as a Mediator of Acetylcholine-induced Coronary Vasodilation in Dogs

To investigate the role of endothelium-derived nitric oxide (NO) in regulation of the tonus of the coronary artery system in vivo, the effect of NG-mono-methyl-L-arginine (L-NMMA), a specific inhibitor of the synthesis of NO from L-arginine, on acetylcholine (ACh)-induced coronary vasodilation was examined in open-chest, anesthetized dogs. At baseline, the infusion of ACh and adenosine into the left circumflex coronary artery (LCX) increased the LCX blood flow. Continuous infusion of L-NMMA (2 μmol/min, for 20 min) into LCX significantly attenuated ACh-induced increase in the LCX flow: percentage increases in the LCX flow by ACh (10 and 100 ng/kg) before L-NMMA were 42.0 ± 8.7 and 137.3 ± 12.5%, respectively, whereas those after L-NMMA were 14.0 ± 4.9 (p < 0.02) and 88.9 ± 10.9% (p < 0.005), respectively. L-NMMA showed no effect on adenosine-induced increase in the LCX flow. After the L-NMMA infusion was terminated, the effect of ACh partially returned to the baseline level. In other dogs, L-arginine (3 mg/min, for 20 min) was administered just after the L-NMMA infusion, which completely reversed the inhibitory effect of L-NMMA on ACh-induced vasodilation. Endothelium-derived NO is a mediator of ACh-induced vasodilation of the coronary resistance vessels in dogs.

Potential association of Helicobacter cinaedi with atrial arrhythmias and atherosclerosis

Helicobacter cinaedi has been increasingly recognized as an emerging pathogen. Reports of recurrent bacteremia and isolation of H. cinaedi organisms from a patient with myopericarditis led us to postulate that H. cinaedi is associated with chronic inflammatory cardiovascular diseases such as atrial arrhythmias and atherosclerosis. To assess any association of H. cinaedi with atrial arrhythmias, a retrospective case‐control study of patients attending Kumamoto University Hospital from 2005 to 2009 was performed. The arrhythmia status of these patients was determined from their electrocardiography and electrophysiological studies. Multiple logistic regression analysis was used to identify independent risk factors. In a comparison of case patients (n= 132) with control subjects (n= 137), H. cinaedi seropositivity was identified as an independent risk factor for atrial arrhythmia (odds ratio, 5.13; 95% confidence interval, 3.0–8.7; P < 0.001). There were no significant differences, however, between these two groups with respect to anti‐H. pylori IgG concentrations, anti‐Chlamydophila pneumoniae IgG concentrations, and other studied variables. IgG concentrations against H. cinaedi and H. pylori were inversely correlated, which suggests cross‐immunity between these two bacteria. Also, to explore any association of H. cinaedi with atherosclerosis, immunohistochemical analysis of atherosclerotic aortic tissues collected post mortem from nine patients was performed. Immunohistochemistry of atherosclerotic aortic tissues from all nine patients detected H. cinaedi antigens inside CD68+ macrophages. These findings provide the first evidence, to our knowledge, of a possible association of H. cinaedi with atrial arrhythmias and atherosclerosis.