Kiyotaka Matsuo

Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG

Background—Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. Methods and Results—Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers. Conclusions—We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.

Incidence and Prognostic Value of Early Repolarization Pattern in the 12-Lead Electrocardiogram

Background— Early repolarization pattern is a common ECG finding characterized by J-point elevation and QRS notching or slurring in the inferior and/or lateral leads, yet little is known about its incidence and long-term prognosis in Asian populations. Methods and Results— We reviewed all the ECG records of the 5976 atomic-bomb survivors who were examined at least once during our biennial health examination in Nagasaki, Japan, between July 1958 and December 2004. We defined early repolarization pattern as ≥0.1-mV elevation of the J point or ST segment, with notching or slurring in at least 2 inferior and/or lateral leads. We assessed unexpected, cardiac, and all-cause death risk by Cox analysis. We identified 1429 early repolarization pattern cases (779 incident cases) during follow-up, yielding a positive rate of 23.9% and an incidence rate of 715 per 100 000 person-years. Early repolarization pattern had an elevated risk of unexpected death (hazard ratio, 1.83; 95% confidence interval, 1.12 to 2.97; P=0.02) and a decreased risk of cardiac (hazard ratio, 0.75; 95% confidence interval, 0.60 to 0.93; P<0.01) and all-cause (hazard ratio, 0.85; 95% confidence interval, 0.78 to 0.93; P<0.01) death. In addition, both slurring and notching were related to higher risk of unexpected death (hazard ratio, 2.09; 95% confidence interval, 1.06 to 4.12; P=0.03), as was early repolarization pattern manifestation in both inferior and lateral leads (hazard ratio, 2.50; 95% confidence interval, 1.29 to 4.83; P<0.01). Conclusions— Early repolarization pattern is associated with an elevated risk of unexpected death and a decreased risk of cardiac and all-cause death. Specific early repolarization pattern morphologies and location are associated with an adverse prognosis.

Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome.

Dynamic ECG Changes in Brugada Syndrome. We present a patient with Brugada syndrome in whom 12‐lead ECXis were recorded just before and after an episode of ventricular fibrillation (VF). A progressive elevation of both the RS‐T segment and J waves just preceding and following the VF, and a close relationship between the amplitude of the RS‐T segment and the preceding R‐R intervals during atrial fibrillation, were documented. These findings support the hypothesis that RS‐T elevation and a subsequent VF are related to a transient outward current‐mediated spike‐and‐dome morphology of the epicardial action potential.

Electrophysiologic characteristics andimplications of induced ventricular fibrillationin symptomatic patients with brugada syndrome

OBJECTIVES: The study examined the electrocardiographic and electrophysiologic characteristics in relation to programmed ventricular stimulation (PVS)-induced ventricular fibrillation (VF), as well as the implications of PVS-induced VF on the recurrence of cardiac events in symptomatic Brugada syndrome. BACKGROUND: Brugada syndrome is characterized by ST-segment elevation in the right precordial leads (V(1)-V(3)) and an episode of VF. METHODS: Thirty-four symptomatic patients with Brugada syndrome (33 men and 1 woman; 44 +/- 12 years old) were classified into two groups according to the inducibility of VF with PVS: 22 patients with induced VF requiring direct cardioversion for termination (Induced VF group) and 12 patients without induced VF (Noninduced VF group). RESULTS: The induced VF group showed a longer QRS duration, a higher incidence of right bundle branch block and late potentials detected on the signal-averaged electrocardiogram, longer His-ventricular intervals and a longer conduction time from the RVOT to the left ventricle at extrastimulation than those in the non-induced VF group. However, there was no significant difference in the recurrence of cardiac events (VF documented by an implantable cardioverter-defibrillator and sudden cardiac death) between the two groups (8 [36%] of 22 patients vs. 7 [58%] of 12 patients) during long-term follow-up (range 1 to 149 months; mean 38). CONCLUSIONS: Our data suggest that induction of VF by PVS depends on the severity of depolarization abnormalities but does not predict the recurrence of cardiac events in symptomatic Brugada syndrome, indicating that both depolarization and repolarization abnormalities are important in the development of VF.

Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations.

Background—The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease. However, the value of the test remains controversial. Methods and Results—We studied 147 individuals representing 4 large families with SCN5A mutations. Of these, 104 were determined to be at possible risk for Brugada syndrome and underwent both electrocardiographic and genetic evaluation. Twenty-four individuals displayed an ECG diagnostic of Brugada syndrome at baseline. Of the remaining, 71 received intravenous ajmaline. Of the 35 genetic carriers who received ajmaline, 28 had a positive test and 7 a negative ajmaline test. The sensitivity, specificity, and positive and negative predictive values of the drug challenge were 80% (28:35), 94.4% (34:36), 93.3% (28:30), and 82.9% (34:41), respectively. Penetrance of the disease phenotype increased from 32.7% to 78.6% with the use of sodium channel blockers. In the absence of ST-segment elevation under baseline conditions, a prolonged P-R interval, but not incomplete right bundle-branch block or early repolarization patterns, indicates a high probability of an SCN5A mutation carrier. Conclusions—In families with Brugada syndrome, the data suggest that ajmaline testing is valuable in the diagnosis of SCN5A carriers. In the absence of ST-segment elevation at baseline, family members with first-degree atrioventricular block should be suspected of carrying the mutation. An ajmaline test is often the key to making the proper diagnosis in these patients.

Sex Hormone and Gender Difference—Role of Testosterone on Male Predominance in Brugada Syndrome

Introduction: The clinical phenotype is 8 to 10 times more prevalent in males than in females in patients with Brugada syndrome. Brugada syndrome has been reported to be thinner than asymptomatic normal controls. We tested the hypothesis that higher testosterone level associated with lower visceral fat may relate to Brugada phenotype and male predominance.

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.

Disappearance of the Brugada-type electrocardiogram after surgical castration: a role for testosterone and an explanation for the male preponderance.

We describe two cases of asymptomatic Brugada syndrome that displayed a persistent ECG manifestation, but in which the typical ECG pattern disappeared following surgical castration for prostate cancer. These facts suggest a possible association between manifestation of the Brugada‐type ECG pattern and testosterone. (PACE 2003; 26[Pt. I]:1551–1553)

Diagnostic Value of Plasma Levels of Brain Natriuretic Peptide in Arrhythmogenic Right Ventricular Dysplasia

BACKGROUND Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by local or diffuse wall motion abnormalities in the right ventricle (RV), associated with recurrent ventricular tachycardia (VT) of RV origin. Brain natriuretic peptide (BNP) was first isolated from a porcine brain extract. In humans, BNP is expressed predominantly in the ventricles of failing hearts, and its expression has been observed primarily in myocytes in the interstitial fibrous area in dilated cardiomyopathy. We hypothesized that BNP is increasingly secreted from the residual myocytes within the atrophic tissue in patients with ARVD. METHODS AND RESULTS Plasma BNP levels were measured in 17 patients with ARVD, 12 patients with idiopathic RV outflow tract tachycardia (RVOT), and 120 control subjects. We performed cardiac catheterization, RV endomyocardial biopsy, electron- beam CT, and biventricular endomyocardial mapping in the ARVD patients. There was a significant increase in plasma BNP levels in the ARVD patients compared with the RVOT patients and control subjects (61.4+/-59.6 pg/mL versus 8.3+/-5. 5 pg/mL and 9.3+/-5.8 pg/mL; P<0.0001, respectively). The plasma BNP levels had no correlation with any of the hemodynamic data, but they had a significant correlation with the RV ejection fraction (r=-0. 588, P=0.025) and with the fractionated-area scores (r=0.705, P=0. 005). Light microscopic immunohistochemistry showed strong BNP immunoreactivity in residual myocytes with fibrofatty replacement. CONCLUSIONS These results suggest that plasma BNP levels were not increased in RVOT patients but were increased in ARVD patients, and that the increased BNP levels indicate the severity of both the RV dysfunction and the arrhythmogenic substrate.

Increased Dispersion of Repolarization Time Determined by Monophasic Action Potentials in Two Patients with Familial Idiopathic Ventricular Fibrillation

Increased Dispersion of RT in Familial Idiopathic VF. Introduction: The role of increased dispersion of repolarization in the genesis of torsades de pointes in patients with long QT syndrome has been clarified, but its role in the genesis of idiopathic ventricular fibrillation (VF) is not yet known. To investigate the pathogenesis of VF, we recorded monophasic action potentials (MAPs) from two siblings (48‐ and 36‐year‐old males) with familial idiopathic VF.