Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: The primary objective of the present study was to assess the efficacy of metoprolol CR/XL to reduce the risk of relapse after cardioversion of persistent atrial fibrillation to sinus rhythm. BACKGROUND: Indirect data from studies with d,l sotalol provide evidence that the beta-blocking effects of the compound are important in maintaining sinus rhythm after cardioversion of atrial fibrillation. METHODS: After successful conversion to sinus rhythm, 394 patients with a history of persistent atrial fibrillation were randomly assigned to treatment with metoprolol CR/XL or placebo. The two treatment groups were similar with respect to all pretreatment characteristics. Patients were seen on an outpatient basis for recording of resting electrocardiogram (ECG) after one week, one, three and six months of follow-up or whenever they felt that they had a relapse into atrial fibrillation or experienced an adverse event. RESULTS: In the metoprolol CR/XL group, 96 patients (48.7%) had a relapse into atrial fibrillation compared with 118 patients (59.9%) in the placebo group (p = 0.005). Heart rate in patients after a relapse into atrial fibrillation was significantly lower in the metoprolol group (98 +/- 23 beats/min) than in the placebo group (107 +/- 27 beats/min). The rate of adverse events reported was similar in both groups when the difference in follow-up time was taken into account. CONCLUSIONS: The results of this double-blind, placebo-controlled study in patients after cardioversion of persistent atrial fibrillation showed that metoprolol CR/XL was effective in preventing relapse into atrial fibrillation or flutter.

QT variability improves risk stratification in patients with dilated cardiomyopathy.

Recently it could be demonstrated that systolic and diastolic blood pressure variability (BPV) as well as segmented Poincare plot analysis (SPPA) contribute to risk stratification in patients suffering from dilated cardiomyopathy (DCM). The aim of this study was to improve the risk stratification applying a multivariate technique including QT variability (QTV). We enrolled and significantly separated 56 low risk and 13 high risk DCM patients by nearly all applied BPV and QTV methods, but not with traditional heart rate variability analysis. The optimum set of two indices calculating the multivariate discriminate analysis (DA) included one BPV index calculated by symbolic dynamics method (DBP(Shannon)) and one index calculated from QTV (QTV(log)) achieving an area under the receiver operating characteristics curve (AUC) of 92%, sensitivity of 92.3% and specificity of 89.3%. Performing only electrocardiogram analysis, the optimum multivariate approach including indices from segmented Poincaré plot analysis and QTV still achieved a remarkable AUC of 88.3%. Increasing the number of indices for multivariate DA up to three, we achieved an AUC of 95.7%, sensitivity of 100% and specificity of 85.7% including one clinical, one BPV and one QTV index. Summarizing, we identified DCM patients with an increased risk of sudden cardiac death applying QTV analysis in a multivariate approach.

Forecasting of life threatening arrhythmias using the compression entropy of heart rate.

OBJECTIVES: Ventricular tachycardia (VT) provoking sudden cardiac death (SCD) are a major cause of mortality in the developed countries. The most efficient therapy for SCD prevention are implantable cardioverter defibrillators (ICD). In this study heart rate variability (HRV) measures were analyzed for short-term forecasting of VT in order to improve VT sensing and to enable a patient warning of forth-coming shocks. METHODS: The last 1000 normal beat-to-beat intervals before 50 VT episodes stored by the ICD were analyzed and compared to individually acquired control time series (CON). HRV analysis was performed with standard parameters of time and frequency domain as suggested by the HRV Task Force and furthermore with a newly developed and optimized nonlinear parameter that assesses the compression entropy of heart rate (Hc). RESULTS: Except of meanNN (p = 0.02) we found no significant differences in standard HRV parameters. In contrast, Hc revealed highly significant (p = 0.007) alterations in VT compared with CON suggesting a decreased complexity before the onset of VT. CONCLUSION: Compression entropy might be a suitable parameter for short-term forecasting of life-threatening tachycardia in ICD.

Evaluation of renormalised entropy for risk stratification using heart rate variability data.

Standard time and frequency parameters of heart rate variability (HRV) describe only linear and periodic behaviour, whereas more complex relationships cannot be recognised. A method that may be capable of assessing more complex properties is the non-linear measure of 'renormalised entropy.' A new concept of the method, RE(AR), has been developed, based on a non-linear renormalisation of autoregressive spectral distributions. To test the hypothesis that renormalised entropy may improve the result of high-risk stratification after myocardial infarction, it is applied to a clinical pilot study (41 subjects) and to prospective data of the St George's Hospital post-infarction database (572 patients). The study shows that the new RE(AR) method is more reproducible and more stable in time than a previously introduced method (p<0.001). Moreover, the results of the study confirm the hypothesis that on average, the survivors have negative values of RE(AR) (-0.11+/-0.18), whereas the non-survivors have positive values (0.03+/-0.22, p<0.01). Further, the study shows that the combination of an HRV triangular index and RE(AR) leads to a better prediction of sudden arrhythmic death than standard measurements of HRV. In summary, the new RE(AR) method is an independent measure in HRV analysis that may be suitable for risk stratification in patients after myocardial infarction.

Model based analysis of the heart rate and blood pressure relationship.

The main intention of this contribution is to measure the coupling between bivariate time series using the dual sequence method to estimate the baroreflex as well as a nonlinear regression approach, namely the maximal correlation method, to get a better understanding of the underlying processes. The data we analyse are heart rate and blood pressure variability time series from 27 patients with dilated cardiomyopathy as well as from a control group of 27 age- and sex-matched healthy subjects. The results strongly indicate and confirm the mechanisms of respiratory sinus arrhythmia in heart rate. Revealing the coupling direction and the strength of coupling between heart rate and blood pressure via optimal transformations in addition to the baroreflex estimation seems to be a very promising approach.

[Modified interaction of blood pressure and heart rate in idiopathic dilated cardiomyopathy]. / Veränderte Interaktion von Blutdruck und Herzfrequenz bei idiopathischer dilatativer Kardiomyopathie.

BACKGROUND: Neurovegetative and haemodynamic changes impact on the regulation pattern of blood pressure and heart rate in patients with heart failure. We studied these patterns and their interactions in patients with idiopathic dilated cardiomyopathy (IDC) and in healthy subjects (REF). METHODS: We continually measured the heart rate and blood pressure (Portapres device) in twenty-five supine IDC patients (age: 51 +/- 13 y; left ventricular end-diastolic diameter 67 +/- 11 mm; ejection fraction 30 +/- 11%) and in twenty-seven REF (age: 50 +/- 11 y) Recording time was 30 minutes. The heart rate (HR) of each beat and the systolic blood pressure (SYS) of the subsequent beat were measured. Code numbers (symbols) were assigned to the beat-to-beat changes in HR and SYS (increase: 1; decrease: 0). The frequencies of the symbols sequences of three successive beats were counted. In this way we obtained a matrix consisting of eight (two to the power of three) HR and SYS combinations: 000, 100, 010, 001, 111, 110, 011 and 101. We then counted the frequencies of the different combinations of the symbol sequences in HR and SYS (2(3) x 2(3) = 64 combinations). The relative frequencies of symbol patterns appearing in HR, SYS and in the combined analysis of HR and SYS, were compared for IDC and REF using the T-test for independent samples. RESULTS: Significant differences were seen between IDC and REF. The HR patterns 101 and 010 were more frequent in IDC than in REF patients (11.1 +/- 4.7 vs. 7.7 +/- 2.9%, p = 0.003, and 16.1 +/- 6.3 vs. 11.7 +/- 4.9%, p = 0.008). This finding was even more marked in the analysis of the SYS patterns 101 and 010 (11.0 +/- 7.4 vs. 8.2 +/- 2.9%, p < 0.001, and 11.6 +/- 7.4 vs. 5.4 +/- 2.7%, p < 0.001). Non-alternating patterns were more frequent in REF (e.g. 000HR & 111SYS: 4.6 +/- 3.3 vs. 2.9 +/- 2.4%, p = 0.03). CONCLUSIONS: We demonstrated significant interaction of the regulation patterns of blood pressure and heart rate, as also their interactions in IDC. Opposed changes in HR and SYS mediated by the baroreflex, became superimposed by alternans phenomena in IDC. The pattern analysis of changes in HR and SYS detects these disturbances of neurovegetative short-term control.

Classifying cardiac biosignals using ordinal pattern statistics and symbolic dynamics.

The performance of (bio-)signal classification strongly depends on the choice of suitable features (also called parameters or biomarkers). In this article we evaluate the discriminative power of ordinal pattern statistics and symbolic dynamics in comparison with established heart rate variability parameters applied to beat-to-beat intervals. As an illustrative example we distinguish patients suffering from congestive heart failure from a (healthy) control group using beat-to-beat time series. We assess the discriminative power of individual features as well as pairs of features. These comparisons show that ordinal patterns sampled with an additional time lag are promising features for efficient classification.

Cardiac magnetic field mapping quantified by Kullback-Leibler entropy detects patients with coronary artery disease.

Cardiac magnetic field mapping (CMFM) is a noninvasive method to determine cardiac electrical activity. We analysed the utility of CMFM for the detection of patients with coronary artery disease (CAD) without subjecting them to stress. We studied 59 healthy control subjects and 101 patients with CAD without previous myocardial infarction (MI). The heart's magnetic field was recorded over the anterior chest wall using a multichannel magnetic measurement system with axial second-order gradiometers. The evaluation of CMFM was based on comparison of the 'ideal' group mean maps of young healthy subjects and maps of examined individuals. Three measures of similarity were considered: Kullback-Leibler (KL) entropy, normalized residual magnetic field strength and deviations in the magnetic field map orientation. The mean values of these parameters during the depolarization and repolarization were used for further classification with the help of logistic regression. The feature set based on the KL-entropy demonstrated the best classification results (sensitivity/specificity of 85/80%), followed by the residual feature (85/75%) and the magnetic field orientation feature (80/73%) sets. The forward stepwise technique was applied to select the best set of features from the combined feature set. Two parameters were selected, namely the KL-entropy for the repolarization period and the residual parameter for the depolarization period. The classification based on these parameters demonstrated a sensitivity of 88% and a specificity of 88% for the distinction of CAD patients from the control subjects. The area under the receiver operator curve was 94%. Hence, we suggest that CMFM evaluation based on KL-entropy is a promising technique to identify patients with CAD.

Cardiac magnetic field map topology quantified by Kullback-Leibler entropy identifies patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common primary inherited cardiac muscle disorder, defined clinically by the presence of unexplained left ventricular hypertrophy. The detection of affected patients remains challenging. Genetic testing is limited because only in 50%-60% of all HCM diagnoses an underlying mutation can be found. Furthermore, the disease has a varied clinical course and outcome, with many patients having little or no discernible cardiovascular symptoms, whereas others develop profound exercise limitation and recurrent arrhythmias or sudden cardiac death. Therefore prospective screening of HCM family members is strongly recommended. According to the current guidelines this includes serial echocardiographic and electrocardiographic examinations. In this study we investigated the capability of cardiac magnetic field mapping (CMFM) to detect patients suffering from HCM. We introduce for the first time a combined diagnostic approach based on map topology quantification using Kullback-Leibler (KL) entropy and regional magnetic field strength parameters. The cardiac magnetic field was recorded over the anterior chest wall using a multichannel-LT-SQUID system. CMFM was calculated based on a regular 36 point grid. We analyzed CMFM in patients with confirmed diagnosis of HCM (HCM, n=33, 43.8+/-13 years, 13 women, 20 men), a control group of healthy subjects (NORMAL, n=57, 39.6+/-8.9 years; 22 women and 35 men), and patients with confirmed cardiac hypertrophy due to arterial hypertension (HYP, n=42, 49.7+/-7.9 years, 15 women and 27 men). A subgroup analysis was performed between HCM patients suffering from the obstructive (HOCM, n=19) and nonobstructive (HNCM, n=14) form of the disease. KL entropy based map topology quantification alone identified HCM patients with a sensitivity of 78.8% and specificity of 86.9% (overall classification rate 84.8%). The combination of the KL parameters with a regional field strength parameter improved the overall classification rate to 87.9% (sensitivity: 84.8%, specificity: 88.9%, area under ROC curve: 0.94). KL measures applied to discriminate between HOCM and HNCM patients showed a correct classification of 78.8%. The combination of one KL and one regional parameter again improved the overall classification rate to 97%. A preliminary prospective analysis in two HCM families showed the feasibility of this diagnostic approach with a correct diagnosis of all 22 screened family members (1 HOCM, 4 HNCM, 17 normal). In conclusion, Cardiac Magnetic Field Mapping including KL entropy based topology quantifications is a suitable tool for HCM screening.

Spontaneous heart rate turbulence in patients with dilated cardiomyopathy.

Parameters of heart rate turbulence (HRT) and blood pressure turbulence (BPT) reflect the baroreflex mediated transient acceleration-deceleration response of the sinus node triggered by a premature ventricular complex (PVC) and are known to be useful risk markers in different cardiac diseases. However, the analyses of HRT and BPT are based on the prevalence of PVC. In this study the spontaneous HRT and BPT after most premature normal beats (MPNB) was investigated in comparison to HRT and BPT after PVC. ECG and blood pressure were recorded from 91 patients with dilated cardiomyopathy (DCM) and 45 healthy subjects (REF). In 69% of DCM and 33% of REF data sets PVCs were present. HRT and BPT were determined for all patients with PVC as well as in all patients triggered by MPNB. Univariate statistical analysis of the comparison between DCM and REF revealed similar results for HRT/BPT after PVC and MPNB. In conclusion, HRT and BPT triggered by PVC might be substituted by spontaneous HRT and BPT after MPNB. In contrast to the HRT and BPT after PVC, an increased number of data sets can be included in the analysis and may lead to an enhancement in risk stratification in different cardiac diseases.

[Importance of PQ time in the evaluation of bifascicular block]. / Zur Bedeutung der PQ-Zeit bei der Beurteilung bifaszikulärer Blockbilder.

In 103 patients with bifascicular block was tested by means of the His bundle electrography, whether with the help of the PQ-time an indirect estimation of the conduction capacity of the still conducting fascicle (HV-interval) is possible. In 70% of the cases with bifascicular blocking and AV-block of first degree the HV-interval was prolonged. However, also 45% of the patients with bifascicular block showed a prolonged HV-interval despite normal PQ-time. Of 21 patients with syncopes due to an intermitting trifascicular block 10 had a normal PQ-time in phases of the transduction. Thus a normal PQ-time in patients with bifascicular block is no guarantee for a good transduction via the still conducting fascicle. If in patients with bifascicular block additionally an AV-block of first degree is existing, the place of the primary retardation of the conduction should more exactly be analysed. For this purpose offer themselves an atropine test or the His bundle electrography.

[Short-term heart rate turbulence analysis versus variability and baroreceptor sensitivity in patients with dilated cardiomyopathy]. / Kurzzeit-Analyse der Herzfrequenzturbulenz versus Variabilitätsparameter und Barorezeptorsensitivität bei Patienten mit dilatativer Kardiomyopathie.

New methods for the analysis of arrhythmias and their hemodynamic consequences have been applied in risk stratification, particularly to patients after myocardial infarction. This study investigates the suitability of shortterm heart rate turbulence (HRT) in comparison to heart rate and blood pressure variability as well as baroreceptor sensitivity analyses to characterize the regulatory differences in patients with dilated cardiomyopathy (DCM) and healthy controls. In this study, 30 minutes data from noninvasive continuous blood pressure and ECG of 37 DCM patients and 167 controls under standard resting conditions were analyzed. The results showed highly significant differences between DCM patients and controls in heart rate and blood pressure variability as well as baroreceptor sensitivity parameters. Applying a combined heart rate-blood pressure trigger, in 24.3% (9) of the DCM patients and in 11.3% (19) of the controls ventricular premature beats were detected. This fact demonstrates the constricted applicability of short-term HRT analyses. However, the HRT parameters showed significant differences in this subgroup with ventricular premature beats (Turbulence Onset: DCM: 1.80+/-2.72, CONTROLS: -4.34+/-3.10, p<0.001; Turbulence Slope: DCM: 6.75+/-5.50, CONTROLS: 21.30+/-17.72, p = 0.021). Considering all (including HRT) parameters in the subgroup with ventricular beats, a discrimination rate between DCM patients and controls of 88.0% was obtained (max. 6 parameters). In comparison, in the total group this rate was 86.3% (without HRT parameters). The comparable classification rates and the high correlations between heart rate turbulence and variability and baroreflex parameters point to a more universal applicability of the last-mentioned methods.

[Dual sequence method for analysis of spontaneous baroreceptor reflex sensitivity in patients with dilated cardiomyopathy]. / Duale Sequenzmethode zur Analyse der spontanen Baroreflexsensitivität bei Patienten mit dilatativer Kardiomyopathie.

The analysis of heart rate variability (HRV) and blood pressure variability (BPV) improves the characterization of patients with dilated cardiomyopathy (DCM). In this study we tested the hypothesis that patients with DCM and controls show a different behavior in the baroreflex (BR) regulation. In contrast to other methods, the new dual sequence method (DSM) analyzes the baroreflex sensitivity (BRS) as a response of the heart rate (interbeat interval, IBI) on dual spontaneous fluctuations of blood pressure (BP). The DSM includes the analysis of bradycardiac fluctuations (an increase of BP causes an increase of IBI) and tachycardiac fluctuations (decrease of BP causes a decrease of IBI) to obtain enhanced information about the sympathetic-vagal regulation. DCM patients show a 40-50% lower number of correlated blood pressure-heart rate fluctuations (DCM patients: male 154 +/- 93, female 93 +/- 40 vs. control group: m 245 +/- 112, f 150 +/- 55, p < 0.05). The BRS in DCM patients is significantly lower than in controls (5.2 +/- 1.9 vs. 8.0 +/- 5.4 (ms/mm Hg), p < 0.05). Using the DSM the discriminant function analysis (6 parameters) classifies correctly 84% of DCM patients and the control group. Using the classical sequence method, only 76% were correctly classified. The DSM is a useful method for analyzing the BRS based on the spontaneous BR to obtain an increased classification of patients with DCM. BRS in patients with DCM is significantly reduced and apparently more ineffective.

[Arrhythmogenic effects of anti-arrhythmia agents]. / Arrhythmogene Effekte von Antiarrhythmika.

Arrhythmogenic effects appear in 5-22% of all patients. On the basis of a literary investigation on 11,547 patients with 1,114 proarrhythmic effects and of 21 own observations mechanisms, risks and diagnostics of this dangerous side effect are demonstrated. In most cases patients with severe functional disturbances of the heart and known ventricular tachyarrhythmias are affected. Not infrequently a prolonged QT-internal is found. An accumulation of the known arrhythmias or an appearance of new disturbed rhythms, frequently Torsade de pointes, may occur. Holter-ECG and programmed stimulation are suited for recognition, which are together to be applied in malignant tachyarrhythmias. The prophylaxis deals with a careful indication, aimed selection of the antiarrhythmic drugs and a subtile control of therapy in the first days after the beginning of the therapy and after every increase of dosage.

Short-term forecasting of life-threatening cardiac arrhythmias based on symbolic dynamics and finite-time growth rates.

Ventricular tachycardia or fibrillation (VT-VF) as fatal cardiac arrhythmias are the main factors triggering sudden cardiac death. The objective of this study is to find early signs of sustained VT-VF in patients with an implanted cardioverter-defibrillator (ICD). These devices are able to safeguard patients by returning their hearts to a normal rhythm via strong defibrillatory shocks; additionally, they store the 1000 beat-to-beat intervals immediately before the onset of a life-threatening arrhythmia. We study these 1000 beat-to-beat intervals of 17 chronic heart failure ICD patients before the onset of a life-threatening arrhythmia and at a control time, i.e., without a VT-VF event. To characterize these rather short data sets, we calculate heart rate variability parameters from the time and frequency domain, from symbolic dynamics as well as the finite-time growth rates. We find that neither the time nor the frequency domain parameters show significant differences between the VT-VF and the control time series. However, two parameters from symbolic dynamics as well as the finite-time growth rates discriminate significantly both groups. These findings could be of importance in algorithms for next generation ICD's to improve the diagnostics and therapy of VT-VF.

The mode of onset of ventricular tachycardia. A patient-specific phenomenon.

AIMS: The purpose of our study was to investigate the electrical trigger modes of monomorphic ventricular tachycardia, by analysing stored intracardiac electrograms, and to identify haemodynamic or electrocardiographic predictors in patients with cardioverter-defribrillators. METHODS: We recorded 286 episodes of monomorphic ventricular tachycardia in 38 patients with at least three events. The electrical triggers were characterized by the morphology number, complexity, and coupling interval of premature depolarizations preceding the ventricular tachycardia. We also evaluated clinical and electrocardiographic data. RESULTS: We found two basic electrical trigger modes. Two hundred and sixteen events (75%) were observed to have no RR-interval variations before onset, while 70 episodes (25%) had a short-long-short sequence. These episodes invariably featured increased QT disperson. In 31 of 38 patients (82%), the ventricular tachycardias were always initiated by the same mode of onset. In eight patients, the monomorphic ventricular tachycardias were always triggered by short-long-short sequences. In seven patients, more than one onset mechanism was observed. CONCLUSIONS: Two basic modes of onset were responsible for monomorphic ventricular tachycardia: one without RR-interval variations immediately prior to onset and another characterized by short-long-short sequences and increased QT dispersion. The mechanisms were largely patient-specific and not related to cardiac diagnosis or left ventricular function.

Multiparametric analysis of heart rate variability used for risk stratification among survivors of acute myocardial infarction.

A multiparametric heart rate variability analysis was performed to prove if combined heart rate variability (HRV) measures of different domains improve the result of risk stratification in patients after myocardial infarction. In this study, standard time domain, frequency domain and non-linear dynamics measures of HRV assessment were applied to 572 survivors of acute myocardial infarction. Three parameter sets each consisting of 4 parameters were applied and compared with the standard measurement of global heart rate variability HRVi. Discriminant analysis technique and t-test were performed to separate the high risk groups from the survivors. The predictive value of this approach was evaluated with receiver operator (ROC) and positive predictive accuracy (PPA) curves. Results--The discriminant analysis shows a separation of patients suffered by all cause mortality in 80% (best single parameter 74%) and sudden arrhythmic death in 86% (73%). All parameters of set 1 show a high significant difference (p < 0.001) between survivors and non-survivors based on two-tailed t-test. The specificity level of the multivariate parameter sets is at the 70% sensitivity level (ROC) about 85-90%, whereas HRVi shows maximum levels of 70%. The PPA in the all cause mortality group is at the 70% sensitivity level twice as high as the univariate HRV measure and increases to more than fourfold as high within the VT/VF group. In conclusion, in this population, the multiparametric approach with the combination of four parameters from all domains especially from NLD seems to be a better predictor of high arrhythmia risk than the standard measurement of global heart rate variability.