Mikio Kakishita

Plasma Brain Natriuretic Peptide Levels Increase in Proportion to the Extent of Right Ventricular Dysfunction in Pulmonary Hypertension

OBJECTIVES This study sought to investigate the influence of right ventricular (RV) hemodynamic variables and function on the secretion of brain natriuretic peptide (BNP) in patients with isolated RV overload. BACKGROUND Plasma BNP is known to increase in proportion to the degree of left ventricular (LV) overload. However, whether BNP secretion is also regulated in the presence of RV overload remains unknown. METHODS Plasma BNP and atrial natriuretic peptide (ANP) levels in the pulmonary artery were measured in 44 patients with RV overload: 18 with RV volume overload (RVVO) due to atrial septal defect and 26 with RV pressure overload (RVPO) due to primary or thromboembolic pulmonary hypertension. Right heart catheterization was performed in all patients. RV and LV ejection fraction, myocardial mass and volume of the four chambers were determined by using electron beam computed tomography. RESULTS Although both plasma BNP and ANP levels were significantly elevated in patients with RV overload compared with values in control subjects, plasma BNP and the BNP/ANP ratio were significantly higher in patients with RVPO than with RVVO (BNP 294 +/- 72 vs. 48 +/- 14 pg/ml; BNP/ANP 1.6 +/- 0.2 vs. 0.8 +/- 0.2, both p < 0.05). Plasma BNP correlated positively with mean pulmonary artery pressure (r = 0.73), total pulmonary resistance (r = 0.79), mean right atrial pressure (r = 0.79), RV end-diastolic pressure (r = 0.76) and RV myocardial mass (r = 0.71); it correlated negatively with cardiac output (r = -0.33) and RV ejection fraction (r = -0.71). Plasma BNP significantly decreased from 315 +/- 120 to 144 +/- 54 pg/ml with long-term vasodilator therapy (total pulmonary resistance decreased from 23 +/- 4 to 15 +/- 3 Wood U). CONCLUSIONS Plasma BNP increases in proportion to the extent of RV dysfunction in pulmonary hypertension.

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.

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.

Mode of onset of ventricular fibrillation in patients with Brugada syndrome detected by implantable cardioverter defibrillator therapy

OBJECTIVES We sought to demonstrate the mode of spontaneous onset of ventricular fibrillation (VF) in patients with Brugada syndrome. BACKGROUND The electrophysiologic mechanisms of VF in Brugada syndrome have not been fully investigated. METHODS Nineteen patients (all male, mean age 47 +/- 12 years) with Brugada syndrome were treated with an implantable cardioverter defibrillator (ICD). The implanted devices were capable of storing electrograms during an arrhythmic event. We investigated the mode of spontaneous onset of VF according to the electrocardiographic features during the episode of VF, which were obtained from stored electrograms of ICDs and/or electrocardiographic (ECG) monitoring. RESULTS During a follow-up of 34.7 +/- 19.4 months (range 14 to 81 months), 46 episodes of spontaneous VF attacks were documented in 7/19 (37%) patients. The event-free period between ICD implantation and the first spontaneous occurrence of VF was 14.6 +/- 12.1 months (range 3.7 to 27.4 months). We investigated 33/46 episodes of VF, for which electrocardiographic features (10 to 20 s before and during VF) were obtained from ICDs and/or ECG monitoring in five patients. A total of 22/33 episodes of VF were preceded by premature ventricular contractions (PVCs), which were almost identical to the initiating PVCs of VF. Furthermore, in three patients who had multiple VF episodes, VF attacks were always initiated by the same respective PVC. The coupling interval of the initiating PVCs of VF was 388 +/- 28 ms. CONCLUSIONS Spontaneous episodes of VF in patients with Brugada syndrome were triggered by specific PVCs. These findings may provide important insights into the pathophysiological mechanisms causing VF in Brugada syndrome.

A case of takotsubo cardiomyopathy associated with epileptic seizure: reversible left ventricular wall motion abnormality and ST-segment elevation

A 59-year-old woman was admitted for consciousness disturbance. She had a history of endocranial operation for astrocytoma. Her electrocardiogram showed ST-segment elevation indicative of acute myocardial infarction. Emergency coronary angiography showed normal coronary arteries, whereas left ventriculography showed extensive severe hypokinesis in the anteroseptal and apical segments. Electroencephalography showed slow sharp wave activity from the left frontal lobe to the temporal lobe, and she was diagnosed as having status epilepticus. This is a rare case of takotsubo cardiomyopathy associated with epileptic seizure. Acute myocardial ischemia caused by impaired coronary microcirculation induced by abnormal catecholamine release is a possible cause of cardiac wall motion abnormality, as in our case.

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.

Aortic stiffness is an independent determinant of B-type natriuretic peptide in patients with coronary artery disease.

Previous studies demonstrated that the B-type natriuretic peptide (BNP) level is high in some patients with coronary artery disease (CAD) despite a preserved left ventricular function, although the mechanism underlying this increase in patients with CAD has not been fully elucidated. Because aortic stiffness is greater in patients with CAD and increases with CAD severity, there is a possibility that an increased aortic stiffness in turn increases the elevation of the BNP level in patients with CAD. In this study, we measured BNP level and brachial-ankle pulse wave velocity (baPWV) in 134 patients with CAD, and evaluated the relationship between BNP and baPWV. The patients were classified on the basis of the quartiles of BNP level to identify the characteristics of patients with a high BNP level. baPWV was significantly greater in patients classified into the highest quartile of BNP level than in those classified into the other quartiles. Multivariate analysis demonstrated that baPWV and left ventricular ejection fraction independently correlated with BNP level. Logistic regression analysis demonstrated that the odds ratio for the highest quartile of BNP level increased with baPWV quartile. This association remained significant after adjustment for systolic and diastolic function. In conclusion, increased aortic stiffness possibly underlies the increase in the BNP level in patients with CAD.

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.

Pseudoxanthoma elasticum with carotid rete mirabile.

We describe a case of Pseudoxanthoma elasticum (PXE) in a 14-year-old girl. This case is especially rare because of its association with carotid rete mirabile (CRM). Only three cases have been reported previously in the literature. Although the relation between P. elasticum and carotid rete mirabile is unclear, both disorders are believed to be major risk factors for cerebrovascular disease.