Acute effects of angiotensin II receptor blocker on ventricular repolarization alternans in chronic heart failure.

Repolarization alternans, which can be detected clinically as microvolt-level T-wave alternans (TWA), is considered an important mechanism underlying the initiation of ventricular tachycardia/ventricular fibrillation (VT/VF) linked to sudden cardiac death (SCD). Recently, the rennin-angiotensin system (RAS) inhibitors have been suggested to have potential benefits in reducing SCD as well as heart failure death with chronic heart failure (CHF). In this study, we tested the acute effects of an angiotensin II receptor blocker (ARB), valsartan, on the development of TWA and the heart rate at which TWA appeared (onset heart rate; OHR). Fifty consecutive patients with CHF underwent TWA measurement. Patients with positive TWA were administered valsartan (80 mg/day) orally for 3 days. Alternans voltage in the vector magnitude lead (Valt) and the OHR were compared before and after the drug exposure. TWA was positive in 19 patients (38%), negative in 16 (32%), and indeterminate in 15 (30%). Nineteen patients with positive TWA received valsartan. However, 3 patients were withdrawn due to adverse drug reactions. In all the remaining 16 patients, markedly reduced Valt (6.1 +/- 3.8 microV to 2.5 +/- 1.9 microV; P = 0.002) and increased OHR (94 +/- 9 beats/min to 102 +/- 9 beats/min; p = 0.002) were observed. In particular, 3 patients became TWA negative. These results suggest that the RAS inhibitors prevent SCD by the improvement of repolarization abnormality.

Hepatic failure and enhanced oxidative stress in mitochondrial diabetes.

Mitochondrial diabetes is characterized by diabetes and hearing loss in maternal transmission with a heteroplasmic A3243G mutation in the mitochondrial gene. In patients with the mutation, it has been reported that hepatic involvement is rarely observed. We demonstrated a case of hypertrophic cardiomyopathy and hepatic failure with mitochondrial diabetes. To clarify the pathogenesis we analyzed the mitochondrial ultrastructure in the myocytes, the reactive oxygen species (ROS) production in the liver and the status of heteroplasmy of the mitochondrial A3243G mutation in the organs involved. In cardiomyocytes and skeletal muscle, electron microscopic analysis demonstrated typical morphological mitochondrial abnormalities. Immunohistochemical analysis demonstrated enhanced ROS production associated with marked steatosis in the liver, which is often associated with mitochondrial dysfunction. Analysis of the A3243G mutation revealed a substantial ratio of heteroplasmy in these organs including the liver. The presence of steatosis and enhanced oxidative stress in the liver suggested that hepatic failure was associated with mitochondrial dysfunction.

Correlation of connexin43 expression and late ventricular potentials in nonischemic dilated cardiomyopathy.

Nonischemic dilated cardiomyopathy (DCM) is associated with a high risk of sudden cardiac death. Signal-averaged electrocardiography (SAECG) is a useful clinical tool for detecting late ventricular potentials (LP). Gap junction alterations have recently been shown to be involved in the pathogenesis of ventricular arrhythmias in DCM; however, the possible relationship between gap junctional connexin43 (C x 43) expression and SAECG has not yet been evaluated. In the present study 16 patients (47+/-13 years) with DCM who had undergone SAECG testing were evaluated. In each patient, the expression of C x 43 proteins was qualitatively and quantitatively determined using immunoconfocal microscopy and right ventricular biopsy specimens. The level of expression of C x 43 protein was defined as the proportion of tissue area occupied by C x 43 (percent tissue area) in each test area. The abundance and distribution of the C x 43 signal was assessed in relation to LP. Late ventricular potentials were positive in 5 patients (LP (+) group) and negative in 11 patients (LP (-) group). The incidence of sustained ventricular tachycardia in the LP (+) group was higher than that in the LP (-) group (80% vs 18%, p=0.04). The percent tissue area of C x 43 in the LP (+) group was significantly lower than that in the LP (-) group (p=0.02). Furthermore, C x 43 protein in the LP (+) group was distributed more heterogeneously than that in the LP (-) group (p=0.001). The heterogeneous expression of C x 43 protein may contribute to impaired ventricular conduction, which may be related to the LP detected on SAECG.

Identification of functional block line in atrial flutter using three-dimensional intracardiac echocardiography.

The crista terminalis (CT) is reportedly a critical barrier for maintaining typical atrial flutter (AFL), but recent observations have suggested the presence of posteromedial functional block, as well as crista conduction. Therefore, this study was designed to identify the correlation between the posterior boundary of AFL and anatomical architecture in the human right atrium (RA) using 3-dimensional (D) intracardiac echocardiography (ICE). In 11 patients with AFL (typical 9, reverse typical 2), mapping with a 10-pole (n=5) or 32-pole (n=6) catheter was performed during AFL. ICE was used to determine the catheter's position relative to the intra-atrial structures. In all patients, double potentials were recorded at the posteromedial RA and the catheter positions were recognized as posterior to the CT by 3-D ICE. Double potentials were not recorded on the CT, and the activation sequence revealed a craniocaudal direction in the 9 patients with typical AFL and caudocranial direction in the 2 patients with reverse typical AFL. These findings demonstrate that the posterior boundary of the AFL circuit is in the sinus venosa region posterior to the CT, which may provide an important insight into the mechanism of maintaining AFL.

Alternancia de la onda T a nivel de microvoltaje: identificador de riesgo de arritmias ventriculares en pacientes con cardiopatía orgánica de base / T wave alternants at the microvolt level: risk marker for ventricular arrhythmias in patients with basal organic cardiopathy

La muerte súbita de origen cadíaco es una de las principales causas de muerte en los países occidentales. Recientemente, la alternancia de la onda T a nivel de micro-voltaje ha emergido como un método muy promisorio para la estratificación de riesgos de arritmias ventriculares. Varios estudios han demostrado la habilidad de este método para predecir inducibilidad de arritmias ventriculares con estimulación ventricular programada y también para episodios espontáneos de arritmias ventriculares con una alta sensibilidad y valor predictivo negativo. En este contexto, la alternancia de la onda T podría jugar un papel muy importante en el manejo de estos pacientes, pues nos permitiría direccionar mejor los pacientes hacia determinados estudios o tratamientos, y de esa forma guiar los recursos hacia los grupos en mayor riesgo

Comparative usefulness of beat-to-beat QT dispersion and QT interval fluctuations for identifying patients with organic heart disease at risk for ventricular arrhythmias.

The comparative usefulness of 10 min of beat-to-beat 12-lead QT dispersion (QTd) and QT interval variability index (QTVI) analysis for identifying patients with organic heart disease (OHD) at risk for ventricular arrhythmias was assessed in 86 subjects: 54 had OHD without a history of ventricular arrhythmias, 15 had OHD with documented ventricular tachycardia, and there were 17 controls. The following parameters were analyzed among the groups: (1) the average QTd (mean QTd), (2) the difference between the maximum and minimum QTd observed over the recording time (QTd variation), (3) the maximum difference of QTd between consecutive beats (QTd maximum), (4) the QTd standard deviation (QTd variability), and (5) QTVI, calculated in lead I or II according to an established formula: log 10 [(QTv/QTm2) / (HRv/HRm2)]. All the analyzed parameters were significantly increased in the patients with and without ventricular tachycardia when compared with the controls. QTd variation, QTd maximum and QTd variability were the only variables that remained significantly increased in the group of patients with documented ventricular tachycardia, compared with those without arrhythmia. Thus, beat-to-beat fluctuations of both the QT interval and QTd may be markers of temporal electrical instability in patients with OHD.

Heterogeneous loss of connexin43 protein in nonischemic dilated cardiomyopathy with ventricular tachycardia.

INTRODUCTION: Gap junction alterations recently have been implicated in chronic heart failure, but direct evidence between gap junction manifestation in nonischemic dilated cardiomyopathy (DCM) is lacking. The current study examines whether qualitative changes or altered distribution of gap junctional connexin43 (Cx43) are related to global ventricular function and ventricular arrhythmia in DCM. METHODS AND RESULTS: We investigated 31 DCM patients (52 +/- 15 years) and 5 control subjects (55 +/- 10 years). Expression of Cx43 proteins was qualitatively and quantitatively determined using immunoconfocal microscopy in right ventricular biopsy specimens from each patient. The expression level of Cx43 protein was defined as the proportion of tissue area occupied by Cx43 (percent tissue area) in each test area. Cx43 immunoreactive signal expressed as percent tissue area was not correlated with the change in left ventricular ejection fraction (P = 0.17). Of 31 DCM patients, 23% subsequently developed sustained ventricular tachycardia (VT), which allowed retrospective division of the samples into two groups: non-VT and VT. Left ventricular ejection fraction was comparable in both groups, but the percent tissue area in the VT groups was significantly decreased compared with that of the non-VT groups (P = 0.03). Furthermore, Cx43 protein was distributed heterogeneously in the VT groups (P < 0.0001). CONCLUSION: Heterogeneous reduction of Cx43 protein may result in development of malignant ventricular arrhythmia in DCM.

Onset heart rate of microvolt-level T-wave alternans provides clinical and prognostic value in nonischemic dilated cardiomyopathy.

OBJECTIVES: This study was designed to determine the prognostic value of onset heart rate (OHR) in T-wave alternans (TWA) in patients with nonischemic dilated cardiomyopathy (DCM). BACKGROUND: One of the current major issues in DCM is to prevent sudden cardiac death (SCD). However, the value of the OHR of TWA as a prognostic indicator in DCM remains to be elucidated. METHODS: We prospectively investigated 104 patients with DCM undergoing TWA testing. The end point of this study was defined as SCD, documented sustained ventricular tachycardia/ventricular fibrillation. Relations between clinical parameters and subsequent outcome were evaluated. RESULTS: Forty-six patients presenting with TWA were assigned to one of the following two subgroups according to OHR for TWA of < or = 100 beats/min: group A (n = 24) with OHR < or = 100 beats/min and group B (n = 22) with 100 < OHR < or = 110 beats/min. T-wave alternans was negative in 37 patients (group C) and indeterminate in 21 patients. The follow-up result comprised 83 patients with determined TWA. During a follow-up duration of 21 +/- 14 months, there was a total of 12 arrhythmic events, nine of which included three SCDs in group A, two in group B and one in group C. The forward stepwise multivariate Cox hazard analysis revealed that TWA with an OHR < or = 100 beats/min and left ventricular ejection fraction were independent predictors of these arrhythmic events (p = 0.0001 and p = 0.0152, respectively). CONCLUSIONS: The OHR of TWA is of additional prognostic value in DCM.