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Background: Heart rate turbulence (HRT) has recently been described as a strong, independent risk stratifier in postinfarct patients. To date, however, the incidence of false positive HRT findings in adults is unknown. Therefore, we performed a blinded, retrospective analysis of HRT in a prospectively collected database of 110 apparently healthy persons to determine the prevalence and clinical significance of abnormal HRT findings in healthy controls using previously published cut-off values.Methods and Results: The study included 43 out of 110 apparently healthy adults, in whom a sufficient number of ventricular premature beats were available for HRT analysis on 24-hour Holter recordings. The HRT slope was dichotomized at 2.5 ms per R-R interval and HRT onset was dichotomized at 0% using previously established criteria to define an abnormal HRT analysis in postinfarct patients. Using these definitions, abnormal HRT results were found in 2 out of 43 controls (5%) for HRT slope and in 8 out of 43 controls (19%) for HRT onset without any cardiac deaths during 32 +/- 15 months follow-up.Conclusions: The incidence of false positive HRT results in healthy middle-aged volunteers is low for HRT slope (5%), but not for HRT onset (19%) when previously published cut-off values are used to define abnormal HRT results. Thus, HRT slope dichotomized at 2.5 ms per R-R interval, but not HRT onset dichotomized at 0%, may be used as a relatively specific tool for risk stratification in middle-aged persons. [ABSTRACT FROM AUTHOR]

Background: To date, prevalence and clinical significance of noninvasive arrhythmia risk predictors in apparently healthy, middle-aged persons are largely unknown.Methods: A total of 110 apparently healthy persons 20-75 years old were enrolled in this prospective observational monocenter study and followed up for 32 +/- 15 months. Baseline investigations included symptom-limited bicycle ergometry, echocardiography, time-domain analysis, and spectral turbulence analysis of the signal-averaged electrocardiogram (ECG), ventricular arrhythmias, and heart rate variability on 24-hour Holter ECG, baroreflex sensitivity, and t-wave alternans in all persons.Results: The prevalence of an abnormal signal-averaged ECG was 1% for spectral turbulence analysis and varied between 1% and 37% for time-domain analysis depending upon the definition used for an abnormal time-domain analysis. A reduced heart rate variability defined as a standard deviation of normal-to-normal intervals < or =105 ms, <100 ms and <70 ms was found in 12%, 9%, and 1% of persons. A baroreflex sensitivity <6 ms/mmHg and <3 ms/mmHg was present in 15% and 2% of persons. Microvolt t-wave alternans was found to be positive in 5%, negative in 88%, and indeterminate in 7% of persons, respectively. During the 32 +/- 15 months follow-up, no arrhythmic events and no cardiovascular mortality were observed in this population.Conclusions: Abnormal findings of noninvasive arrhythmia risk stratification can be found in 1-37% of healthy, middle-aged persons when previously reported cut-off values are used. [ABSTRACT FROM AUTHOR]

During World War II two researchers from the Department of Education of the Deaf, University of Manchester, England developed a technique for auditorily screening infants and pre-school children. The technique has been referred to as the distraction technique, wherein the mother holds the infant on her lap while an observer sits in front of the baby and attracts the infant's attention visually. The tester, standing behind the infant, presents stimuli to the right or left side of the infant and notes whether or not the baby turns his head toward the source of the sound. The Ohio Department of Health has used the test as modified for testing children eight to 14 months of age. The procedure was used with some success. However, training of nurses to administer the test required at least one week, and changing personnel made the testing program difficult to maintain. Other shortcomings of the procedure were the number of personnel needed and the tack of stimulus control, such as training testers to speak at 30db levels.

Background: Data on the prevalence and predictors for the development of pacing-dependency in patients with cardiovascular implantable electronic devices (CIEDs) are sparse., Methods: Pacing-dependency defined as an absence of intrinsic rhythm of ≥ 30 bpm was determined in 802 consecutive patients with CIEDs who visited the documented pacemaker or implantable cardioverter- defibrillator outpatient clinic for routine follow-up., Results: A total of 131 (16%) patients were found to be pacing-dependent 67 ± 70 months after CIED implant. Multivariate analysis revealed a significant association between pacing-dependency and the following clinical variables: second or third-degree atrioventricular (AV) block at implant (OR = 19.9; 95% CI: 10.9-38.5, p < 0.01), atrial fibrillation at implant (OR = 2.15; 95% CI: 1.16-4.05, p = 0.02), left ventricular ejection fraction (LVEF) ≤ 30% (OR = 2.06; 95% CI: 1.03-4.15, p = 0.04), B-type natriuretic peptide (BNP) > 150 pg/mL (OR = 2.12; 95% CI: 1.16-3.97, p = 0.02), chronic kidney disease (OR = 1.86; 95% CI: 1.08-3.26, p = 0.03), and follow-up duration after implantation > 5 years (OR = 3.29; 95% CI: 1.96-5.64, p < 0.01). None of the remaining clinical variables including age, gender, diabetes mellitus, underlying heart disease, prior cardiac surgery or medication during follow-up including betablockers and amiodarone predicted pacing-dependency., Conclusions: Pacing-dependency is associated with second or third-degree AV-block at implant, atrial fibrillation before implant, low LVEF, elevated BNP, chronic kidney disease and follow-up duration after implant.

Background: Cardiac-specific JDP2 overexpression provokes ventricular dysfunction and atrial dilatation in mice. We performed in vivo studies on JDP2-overexpressing mice to investigate the impact of JDP2 on the predisposition to spontaneous atrial fibrillation (AF)., Methods: JDP2-overexpression was started by withdrawal of a doxycycline diet in 4-week-old mice. The spontaneous onset of AF was documented by ECG within 4 to 5 weeks of JDP2 overexpression. Gene expression was analyzed by real-time RT-PCR and Western blots., Results: In atrial tissue of JDP2 mice, besides the 3.6-fold increase of JDP2 mRNA, no changes could be detected within one week of JDP2 overexpression. Atrial dilatation and hypertrophy, combined with elongated cardiomyocytes and fibrosis, became evident after 5 weeks of JDP2 overexpression. Electrocardiogram (ECG) recordings revealed prolonged PQ-intervals and broadened P-waves and QRS-complexes, as well as AV-blocks and paroxysmal AF. Furthermore, reductions were found in the atrial mRNA and protein level of the calcium-handling proteins NCX, Cav1.2 and RyR2, as well as of connexin40 mRNA. mRNA of the hypertrophic marker gene ANP, pro-inflammatory MCP1, as well as markers of immune cell infiltration (CD68, CD20) were increased in JDP2 mice., Conclusion: JDP2 is an important regulator of atrial calcium and immune homeostasis and is involved in the development of atrial conduction defects and arrhythmogenic substrates preceding paroxysmal AF.

The relationship between heart failure (HF), sleep-disordered breathing and cardiac arrhythmias is complex and poorly understood. Whereas the frequency of predominantly obstructive sleep apnea in HF patients is low and similar or moderately higher to that observed in the general population, central sleep apnea (CSA) has been observed in approximately 50% of HF patients, depending on the methods used to detect CSA and patient selection. Despite this high prevalence, it is still unclear whether CSA is merely a marker or an independent risk factor for an adverse prognosis in HF patients and whether CSA is associated with an increased risk for supraventricular as well as ventricular arrhythmias in HF patients. The current review focuses on the relationship between CSA and atrial fibrillation as the most common atrial arrhythmia in HF patients, and on the relationship between CSA and ventricular tachycardia and ventricular fibrillation as the most frequent cause of sudden cardiac death in HF patients.

Aims: To assess the prognostic significance of screening for sleep-disordered breathing in patients with implantable cardioverter-defibrillator (ICD) with regard to appropriate ICD therapy and total mortality., Methods and Results: Overnight sleep studies were performed in 204 ICD recipients not known to have sleep apnoea and with no history of daytime sleepiness. Sleep-disordered breathing was diagnosed in the presence of an apnoea-hypopnea index of five or more events per hour. Seventy patients (34%) had no sleep apnoea, 105 patients (51%) had central sleep apnoea, and 29 patients (14%) had obstructive sleep apnoea. During 38 ± 26 months follow-up, 80 patients (39%) received appropriate ICD therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF), and 54 patients (26%) died. On multivariate Cox regression analysis, age, left ventricular (LV) end-diastolic diameter, secondary prevention ICD indication, use of diuretics, and absence of aldosterone antagonist therapy but not sleep apnoea were associated with appropriate ICD therapy for VT or VF. In addition, multivariate Cox analysis identified age and LV ejection fraction but not sleep apnoea as predictors of total mortality., Conclusion: Undiagnosed sleep-disordered breathing is common in ICD recipients. The presence and severity of previously unknown sleep apnoea in ICD recipients, however, does not appear to be an independent predictor of appropriate ICD therapy or morality during follow-up.

Objective: Expression profile analysis using endomyocardial biopsy specimens from patients with cardiomyopathies promises to improve the differential diagnosis of heart failure., Methods: In this study, left ventricular endomyocardial biopsy specimens were obtained from 50 patients and histopathologically classified according to the World Heart Federation Task Force criteria as having dilated cardiomyopathy (n = 17), inflammatory cardiomyopathy (n = 11), myocarditis (n = 15), or pericarditis (n = 7). Microarrays were performed by hybridization of synthesized complementary DNA against a Lab-Arraytor60-combi microarray (SIRS-Lab, Jena, Switzerland). Differentially expressed genes were clustered hierarchically according to their variation in hybridization signals., Results: In samples from patients with dilated cardiomyopathy, two different types of gene expression profiles were distinguishable. One pattern was unique for dilated cardiomyopathy and inflammatory cardiomyopathy, respectively, and the other more closely resembled that seen in samples from inflammatory heart disease. Additionally, we confirmed the microarray data by showing that dilated cardiomyopathy is associated with a reduced myocardial toll-like receptor 9 expression that resulted from progressive loss of functional cardiomyocytes. Taken together, our data demonstrate the utility and validity of microarrays from endomyocardial biopsy specimens in detecting subentities of dilated cardiomyopathy that do not differ histopathologically, but transcriptionally, from each other. The gene expression profile observed in one subgroup of patients with dilated cardiomyopathy is indicative of ongoing immune activation, albeit infiltrating immunocompetent cells were not detected histopathologically., Conclusion: Thus, our transcriptional data indicate that dilated cardiomyopathy constitutes a heterogeneous disease with an broad overlap to inflammatory heart disease.

Introduction: We examined whether B-type natriuretic peptide (BNP) levels predict outcome in heart failure patients with implantable cardioverter defibrillators (ICD) using a combined endpoint of malignant tachyarrhythmias, death or heart transplantation., Methods and Results: BNP levels were measured in 123 ICD patients with chronic heart failure (age: 63+/-12 years, ejection fraction: 29+/-10%). After a median follow-up of 25 months, the combined endpoint was reached in 28 patients (first tachyarrhythmic event, n=16; death, n=11; heart transplantation, n=1). BNP levels were significantly lower in patients with event-free survival compared to patients reaching the combined endpoint of this study (median: 140 vs. 373 pg/ml; p<0.001). Multivariable Cox regression analysis revealed that BNP levels predict adverse outcome (RR 1.002 per pg/ml increment; 95% CI: 1.001-1.003; p<0.001) and use of beta-blockers was associated with favourable outcome (RR 0.319; 95% CI 0.151-0.670; p=0.004). LV ejection fraction (p=0.66) did not significantly predict event-free survival in multivariable analysis., Conclusions: BNP plasma levels are useful markers to predict event-free survival in ICD patients with heart failure. Of note, malignant tachyarrhythmias appear responsible for about 50% of fatal outcomes. Our findings suggest that determination of BNP plasma levels is more valuable than determining LV ejection fraction to anticipate event-free survival in this population.

Aims: Previous studies indicate that low cholesterol levels are associated with adverse prognosis in heart failure patients, because elevated lipoprotein levels may negate bacterial endotoxin load induced by gastrointestinal congestion., Methods and Results: We examined the prognostic significance of lipid levels in a cohort of 422 patients with idiopathic dilated cardiomyopathy (iDCM) [50+/-12 years, 342 males, 80 females, left ventricular ejection fraction (LV-EF): 31.6+/-10.6%]. During 42 months of follow-up, 86 patients (20.3%) died or received a heart transplant. In univariate Cox regression analysis, reduced LV-EF, high New York Heart Association (NYHA) class, and increased LV end-diastolic diameter (LVEDD) were strong risk factors associated with that endpoint, whereas decreased total cholesterol, HDL-cholesterol, and apoprotein I levels were identified as weak risk predictors. After step-wise multivariable analysis, only LVEDD, NYHA class, and LV-EF emerged as parameters independently contributing to the model predicting risk for death or heart transplantation (P<0.05). Cholesterol levels were positively associated with LV-EF and negatively associated with LVEDD (P<0.05). Circulating sCD14 levels, a marker of endotoxin exposure, were related to cholesterol levels (P<0.05) and LV-EF (P<0.05)., Conclusion: Decreased cholesterol levels do not independently predict adverse prognosis in patients with iDCM. Our findings indicate that low cholesterol levels are dependent on the severity of cardiac disease.

Objectives: This study investigated the incidence of appropriate implantable cardioverter defibrillator (ICD) interventions for ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients with idiopathic dilated cardiomyopathy (IDC) and nonsustained VT in the presence of a left ventricular ejection fraction below 30%, versus in patients with syncope and patients with a history of VT or VF., Background: To date, only limited information is available about the prophylactic use of ICDs in patients with IDC., Methods: From January 1993 to July 2000, 101 patients with IDC underwent implantation of ICDs with electrogram storage capability at our institution. Patients were placed into one of three groups according to their clinical presentation: asymptomatic or mildly symptomatic nonsustained VT in the presence of a left ventricular ejection fraction < or = 30% (49 patients, prophylactic group), unexplained syncope or near syncope (26 patients, syncope group) and a history of sustained VT or VF (26 patients, VT/VF group)., Results: During 36 +/- 22 months follow-up, 18 of 49 patients (37%) in the prophylactic group received appropriate shocks for VT or VF, compared with 8 of 26 patients (31%) in the syncope group and with 9 of 26 patients (35%) of the VT/VF group. Multivariate Cox analysis of baseline clinical variables identified left ventricular ejection fraction, atrial fibrillation and a history of sustained VT or VF as predictors for appropriate ICD interventions during follow-up., Conclusions: Patients with IDC and prophylactic ICD implantation for nonsustained VT in the presence of a left ventricular ejection fraction < or = 30% had an incidence of appropriate ICD interventions similar to that of patients with a history of syncope or sustained VT or VF. These findings indicate that ICDs may have a role in not only secondary but also primary prevention of sudden death in IDC.

The radionuclides (131)I and (99m)Tc are frequently used for therapy of benign and malignant thyroid disease ((131)I) and for diagnosis of thyroid and other diseases ((99m)Tc). However, the levels of DNA single-strand breaks (SSBs) induced in cells of patients after administration of (131)I and (99m)Tc are not known. In this study, we measured the number of SSBs per cell induced by (131)I and (99m)Tc in vitro, extrapolated the results to the clinical situation, and assessed their biological relevance by comparing levels of SSBs induced after therapeutic administration of (131)I and (99m)Tc to those induced by endogenous processes or by occupational exposure to genotoxic substances. A linear dose-response relationship between the radioactivity concentrations of (131)I and (99m)Tc and SSBs in human mononuclear blood cells (determined by alkaline elution) was obtained after incubation at 4 and 37 degrees C. At 4 degrees C, where almost no repair of SSBs takes place, (131)I and (99m)Tc induced 81 and 7 SSBs per cell per hour/(MBq/ml), respectively. At 37 degrees C, only 20 and 1.6 SSBs per cell per hour/(MBq/ml) were observed after incubation with (131)I and (99m)Tc. To estimate the induction of SSBs in vivo in cells of patients after administration of 3700 MBq (131)I (oral) or 60 MBq (99m)Tc (i.v.), the rates of induction of SSBs obtained in vitro were extrapolated to the concentrations of (131)I and (99m)Tc measured in blood of patients. The total number of SSBs (mean +/- standard deviation) accumulated after oral administration of 3700 MBq (131)I up to 70 h after administration was calculated as 200 +/- 59 SSBs/cell. After administration of 60 MBq (99m)Tc (i.v.), 0.032 +/- 0.009 SSBs per cell (total SSBs up to 2 h after administration) were cumulated. The induction of SSBs by endogenous processes (estimated 2,000 SSBs per cell per hour) and by occupational exposure to genotoxic substances (125-430 SSBs per cell) has been estimated in earlier studies. In conclusion, the frequency of SSBs induced by thyroid diagnosis with 60 MBq (99m)Tc is approximately 5 orders of magnitude smaller than the frequency of spontaneous SSBs and thus is most probably without biological relevance. Since the frequency of induction of SSBs by therapy with (131)I (3700 MBq) is about 6000-fold higher compared to thyroid diagnosis by (99m)Tc, its biological relevance is more difficult to assess. Nevertheless, the number of SSBs induced by therapy with (131)I is substantially lower than that induced by endogenous processes.