Tetsuro Emori

Carvedilol decreases elevated oxidative stress in human failing myocardium

Background—Oxidative stress has been implicated in the pathogenesis of heart failure. However, direct evidence of oxidative stress generation in the human failing myocardium has not been obtained. Furthermore, the effect of carvedilol, a vasodilating &bgr;-blocker with antioxidant activity, on oxidative stress in human failing hearts has not been assessed. This study was therefore designed to determine whether levels of lipid peroxides are elevated in myocardia of patients with dilated cardiomyopathy (DCM) and whether carvedilol reduces the lipid peroxidation level. Methods and Results—Endomyocardial biopsy samples obtained from 23 patients with DCM and 13 control subjects with normal cardiac function were studied immunohistochemically for the expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Expression of HNE-modified protein was found in all myocardial biopsy samples from patients with DCM. Expression was distinct in the cytosol of cardiac myocytes. Myocardial HNE-modified protein levels in patients with DCM were significantly increased compared with the levels in control subjects (P <0.0001). Endomyocardial biopsy samples from 11 patients with DCM were examined before and after treatment (mean, 9±4 months) with carvedilol (5 to 30 mg/d; mean dosage, 22±8 mg/d). After treatment with carvedilol, myocardial HNE-modified protein levels decreased by 40% (P <0.005) along with amelioration of heart failure. Conclusions—Oxidative stress is elevated in myocardia of patients with heart failure. Administration of carvedilol resulted in a decrease in the oxidative stress level together with amelioration of cardiac function.

Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome

OBJECTIVES We sought to study atrial vulnerability in patients with Brugada syndrome. BACKGROUND Atrial fibrillation (AF) often occurs in patients with Brugada syndrome, but atrial vulnerability in Brugada syndrome has not been evaluated. METHODS The patient group consisted of 18 patients with Brugada syndrome. The control group consisted of 12 age- and gender-matched subjects who had neither organic heart disease nor AF episodes. The incidence and clinical characteristics of AF were evaluated in all 18 patients with Brugada syndrome, and an electrophysiologic study was performed in all 12 control subjects and in 14 of the 18 patients with Brugada syndrome. The atrial effective refractory period of the right atrium (RA-ERP), intra-atrial conduction time (conduction time from the stimulus at the right atrium to atrial deflection at the distal portion of the coronary sinus), duration of local atrial potential, and repetitive atrial firing (occurrence of two or more premature atrial complexes after atrial stimulation) were studied. RESULTS Spontaneous AF occurred in 7 of the 18 patients with Brugada syndrome but in none of the control subjects. The RA-ERP was not different between the two groups. The intra-atrial conduction time was increased in the Brugada syndrome group versus the control group (168.4 +/- 17.5 vs. 131.8 +/- 13.0 ms, p < 0.001). The duration of atrial potential at the RA-ERP was prolonged in the Brugada syndrome group versus the control group (80.3 +/- 18.0 vs. 59.3 +/- 9.2 ms, p < 0.001). Repetitive atrial firing was induced in nine patients with Brugada syndrome and in six control subjects. Atrial fibrillation was induced in eight patients with Brugada syndrome but in none of the control subjects. In patients with Brugada syndrome without spontaneous AF, the intra-atrial conduction time and duration of atrial potential were also increased. CONCLUSIONS Atrial vulnerability is increased in patients with Brugada syndrome. Abnormal atrial conduction may be an electrophysiologic basis for induction of AF in patients with Brugada syndrome.

Epicardial electrogram of the right ventricular outflow tract in patients with the brugada syndrome: Using the epicardial lead

OBJECTIVES We tried to record an epicardial electrogram directly, and we examined local electrograms before and after administration of a class IC anti-arrhythmic drug in patients with the Brugada syndrome. BACKGROUND Electrical heterogeneity of the epicardium in the right ventricular outflow tract (RVOT) has been thought to be related to the Brugada syndrome. However, an epicardial abnormality has not been demonstrated in patients with the Brugada syndrome. METHODS In five patients with a Brugada-type electrocardiogram (ECG), local unipolar electrograms were recorded at the epicardium and endocardium of the RVOT. To record the epicardial electrogram directly, we introduced an electrical guidewire into the conus branch (CB) of the right coronary artery. The duration of the local electrogram after termination of the QRS complex (DP) was measured before and after class IC anti-arrhythmic drug administration. The signal-averaged electrocardiogram (SAECG) was also obtained in all patients. RESULTS A definite DP was observed at the epicardium, but not at the endocardium. After administration of a class IC anti-arrhythmic drug, the DP at the epicardium was prolonged from 38 +/- 10 ms to 67 +/- 24 ms. The late potential corresponding to the DP at the epicardium was observed in all patients on the SAECG. CONCLUSIONS An epicardial electrogram can be recorded from the CB. Recording from the CB enables identification of an epicardial abnormality in patients with the Brugada syndrome. These abnormal electrograms may be related to a myocardial abnormality in the epicardium of patients with the Brugada syndrome.

Site-Specific Arrhythmogenesis in Patients with Brugada Syndrome

Introduction: It has been believed that electrophysiologic abnormality of the epicardial region of the right ventricular free wall may play an important role in arrhythmogenesis of phase 2 reentry in Brugada syndrome, but clinical evidence of the occurrence of ventricular arrhythmias at the right ventricular free wall has not been evaluated. In this study, we evaluated the site‐specific inducibility of ventricular fibrillation (VF) and the origin of spontaneous premature ventricular contractions (PVCs) in patients with Brugada syndrome.

Cellular Basis for Complex T Waves and Arrhythmic Activity Following Combined IKr and IKs Block

Combined Congenital and Acquired LQTS. Introduction: A growing number of cardiomyopathies have been shown to result in a reduction in both IKr and IKs, yet little is known about the electrophysiologic and ECG characteristics of combined IKr and IKs block.

Relatively benign clinical course in asymptomatic patients with brugada-type electrocardiogram without family history of sudden death

Asymptomatic Brugada‐Type ECG. Introduction: The incidence of sudden death or ventricular fibrillation (VF) in asymptomatic Brugada syndrome patients with a family history of sudden death is reported to be very high. However, there are few reports on the prognosis of asymptomatic Brugada syndrome patients without a family history of sudden death.

Dynamic Relationship Between the Q‐aT Interval and Heart Rate in Patients with Long QT Syndrome During 24‐Hour Holter ECG Monitoring

The purpose of this study was to investigate the dynamic relationship between heart rate and the Q‐aT interval (the interval from the Q wave to the T wave apex) in patients with long QT syndrome. The QT to heart rate relation is useful for evaluating abnormalities of the ventricular repolarization, but its clinical application to the long QT syndrome requires accurate computer aided measurement of the QT interval and the sampling of a large number of beats. Therefore, the Q‐aT interval was used on the basis of some reports that the heart rate dependency of the QT interval was concentrated in the Q‐aT interval. Recent advances in the computer technology have allowed analysis of the relationship between the Q‐aT and RR intervals on Holter ECG recordings. However, in addition to a prolonged QT interval, most patients with long QT syndrome have bizarre and variable T waves and the influence of this T wave morphology on the Q‐aT to heart rate relation has not been clarified. We investigated the dynamic relationship between the Q‐aT interval and heart rate in 10 patients with long QT syndrome and 11 control subjects using our original computer algorithm for the analysis of 24‐hour Holter ECG recordings. The patients showed morphological T wave changes associated with heart rate changes during Holter recordings and these affected the Q‐aT interval. The patients showed the following characteristics in the relationship between the major T wave peak and the RR interval: (1) a modestly decreased correlation between Q‐aT and RR than in the control subjects (a median r value of 0.87 vs 0.93; P = 0.001); and (2) a steeper Q‐aT/RR slope than in controls (a median slope of 0.24 vs 0.16; P < 0.05). Abnormal and variable T wave morphology in the long QT patients was closely related to a modestly decreased correlation between Q‐aT and RR than in the control subjects. The steep Q‐aT/RR slope might reflect unstable repolarization of the ventricle, which could act as a substrate for ventricular tachyarrhythmias.

Direct evidence for increased hydroxyl radicals in angiotensin II-induced cardiac hypertrophy through angiotensin II type 1a receptor.

Summary: Oxidative stress is known to contribute to numerous cardiac disease processes. However, the contribution of reactive oxygen species to cardiac hypertrophy has not yet been fully investigated. The aim of the present study was therefore to determine whether levels of reactive oxygen species were increased in angiotensin IIinduced cardiac hypertrophy. We continuously administered angiotensin II (1.1 mg/kg per day) into wild‐type and angiotensin II type‐1a receptor knockout mice for 2 weeks. The angiotensin II treatment increased blood pressure and heart weight/body weight ratio in wild‐type mice but not in knockout mice. The generation of hydroxyl radicals in heart tissue homogenate was directly assessed with electron spin resonance spectroscopy using a spin trapping agent, alphaphenyl‐ N‐tert butylnitrone. Angiotensin II significantly increased hydroxyl radical production 2.2‐fold (p < 0.01) in the hearts of wildtype mice but not in knockout mice. The present study provided direct evidence for increased production of hydroxyl radicals in angiotensin II‐induced cardiac hypertrophy through angiotensin II type‐1a receptor. These findings in this study may provide important insights into the development of hypertrophy and the transition of hypertrophy to heart failure.

Successful Catheter Ablation in a Patient with Polymorphic Ventricular Tachycardia

Ablation of Polymorphic VT. We describe a patient with polymorphic ventricular tachycardia (PVT)/ventricular fibrillation (VF) without organic heart disease who was cured by radiofrequency catheter ablation. The patient was a 65‐year‐old woman with a l0‐year history of recurrent syncope. There was no evidence of organic heart disease, and the QT interval during sinus rhythm was borderline normal (corrected QT interval = 0.45 sec1/2). ECG, recording during syncope showed PVT. On one occasion, PVT degenerated into VF. This PVT was always induced by a premature ventricular complex (PVC) originating from the right ventricular (RV) outflow tract. Rapid pacing (220 beats/min) at the site of PVC origin reproduced polymorphic change of the QRS wave on surface ECG that was similar to PV T. This suggests that the PVT originated from a single focus in the RV outflow tract. Catheter ablation was performed at the site of PVC origin. During 18‐month follow‐up, PVT/VF was not documented.

Effect of regional myocardial perfusion abnormalities on regional myocardial early diastolic function in patients with hypertrophic cardiomyopathy

SummaryNonuniform hypertrophy of the left ventricle is an important factor in regional diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). However, the effect of myocardial perfusion abnormalities on regional diastolic dysfunction has not been established in patients with HCM. We investigated the relationship between regional myocardial perfusion abnormalities and regional early diastolic function in 31 patients with HCM and 8 control patients. Short-axis images of the left ventricle recorded by cine magnetic resonance imaging were divided into ten blocks. The time-to-peak-wall-thickness-thinning rate (TPWR) and the wall thickness were measured in each block. Of the 310 blocks from the patients with HCM, 242 (78%) showed normal thallium-201 uptake (group 1), 40 (13%) showed slightly decreased uptake (group 2), and 28 (9%) showed markedly decreased uptake (group 3). There was no difference in the regional wall thickness among the three groups. The TPWR was longer in patients with HCM than in control patients. It was significantly longer in group 3 (190±45ms) than in group 1 (167±36ms) and group 2 (160±31ms). (P<0.01). The linear regression slope of the relationship between the TPWR and the regional wall thickness was significantly steeper in group 3 than in groups 1 and 2 (P<0.05). In conclusion, abnormalities in regional myocardial perfusion, in addition to regional hypertrophy, contributed to the regional early diastolic dysfunction in patients with HCM.