Alexander Schirdewan

Recurrence-plot-based measures of complexity and their application to heart-rate-variability data

The knowledge of transitions between regular, laminar or chaotic behaviors is essential to understand the underlying mechanisms behind complex systems. While several linear approaches are often insufficient to describe such processes, there are several nonlinear methods that, however, require rather long time observations. To overcome these difficulties, we propose measures of complexity based on vertical structures in recurrence plots and apply them to the logistic map as well as to heart-rate-variability data. For the logistic map these measures enable us not only to detect transitions between chaotic and periodic states, but also to identify laminar states, i.e., chaos-chaos transitions. The traditional recurrence quantification analysis fails to detect the latter transitions. Applying our measures to the heart-rate-variability data, we are able to detect and quantify the laminar phases before a life-threatening cardiac arrhythmia occurs thereby facilitating a prediction of such an event. Our findings could be of importance for the therapy of malignant cardiac arrhythmias.

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.

Nonlinear analysis of complex phenomena in cardiological data

Zusammenfassung Das Hauptanliegen dieses Beitrages ist es, verschiedene Ansätze in der Herzfrequenz- und Blutdruckvariabilität zu diskutieren und damit das Verständnis der kardiovaskulären Regulation zu verbessern. Wir betrachten Komplexitätsmaße basierend auf der symbolischen Dynamik, die renormierte Entropie und die ,finite-time’ Wachstumsraten. Weiterhin werden die duale Sequenzmethode zur Bestimmung der Baroreflexsensitivität sowie die Maximalkorrelationsmethode zur Schätzung der nichtlinearen Kopplung in bivariaten Daten vorgestellt. Letztere stellt eine geeignete Methode zur Bestimmung der Kopplungsstärke und –richtung dar. Herzfrequenz- und Blutdruckvariabilitätsdaten einer klinischen Pilotstudie und einer großangelegten klinischen Studie werden analysiert. Wir demonstrieren in diesem Beitrag, dass Methoden der nichtlinearen Dynamik nützlich sind für die Risikostratifizierung nach Herzinfarkt, für die Vorhersage von lebensbedrohlichen Rhythmusstörungen sowie für die Modellierung der Herzfrequenz- und Blutdruckregulation. Diese Ergebnisse könnten in der klinischen Diagnostik sowie für therapeutische und präventive Zwecke von implantierbaren Defibrillatoren der nächsten Generation von Bedeutung sein.Summary The main intention of this contribution is to discuss different nonlinear approaches to heart rate and blood pressure variability analysis for a better understanding of the cardiovascular regulation. We investigate measures of complexity which are based on symbolic dynamics, renormalised entropy and the finite time growth rates. The dual sequence method to estimate the baroreflex sensitivity and the maximal correlation method to estimate the nonlinear coupling between time series are employed for analysing bivariate data. The latter appears to be a suitable method to estimate the strength of the nonlinear coupling and the coupling direction. Heart rate and blood pressure data from clinical pilot studies and from very large clinical studies are analysed. We demonstrate that parameters from nonlinear dynamics are useful for risk stratification after myocardial infarction, for the prediction of life-threatening cardiac events even in short time series, and for modelling the relationship between heart rate and blood pressure regulation. These findings could be of importance for clinical diagnostics, in algorithms for risk stratification, and for therapeutic and preventive tools of next generation implantable cardioverter defibrillators.

Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease

We aimed to identify genetic variants associated with heart failure by using a rat model of the human disease. We performed invasive cardiac hemodynamic measurements in F2 crosses between spontaneously hypertensive heart failure (SHHF) rats and reference strains. We combined linkage analyses with genome-wide expression profiling and identified Ephx2 as a heart failure susceptibility gene in SHHF rats. Specifically, we found that cis variation at Ephx2 segregated with heart failure and with increased transcript expression, protein expression and enzyme activity, leading to a more rapid hydrolysis of cardioprotective epoxyeicosatrienoic acids. To confirm our results, we tested the role of Ephx2 in heart failure using knockout mice. Ephx2 gene ablation protected from pressure overload–induced heart failure and cardiac arrhythmias. We further demonstrated differential regulation of EPHX2 in human heart failure, suggesting a cross-species role for Ephx2 in this complex disease.

Potential role of home monitoring to reduce inappropriate shocks in implantable cardioverter-defibrillator patients due to lead failure.

AIMS Lead dysfunctions in implantable cardioverter-defibrillator (ICD) patients can lead to inappropriate shocks or even complete loss of function of the device. Home monitoring (HM) systems are capable of daily data transmissions regarding the device and the lead integrity as well as information concerning anti-arrhythmic therapies. We therefore analysed the data from the Biotronik HM system whether it enables physicians to react quickly on serious ICD malfunctions and to avoid inappropriate shocks. METHODS AND RESULTS Fifty-four patients who had to undergo resurgery due to malfunctions of the ICD lead were included. Eleven of them were on HM interrogating the device every night at 3 am. If any adverse event was detected, a fax alert was sent to the clinic and the patients were asked for in-hospital ICD interrogation. The rate of inappropriate shocks and symptomatic pacemaker inhibition due to oversensing was compared with the 43 patients without remote surveillance. HM sent alert messages in 91% of all incidents. All lead failures became obvious because of oversensing of high frequency artefacts. Only in 18%, changes in the pacing impedance were noticed, in all cases preceded by oversensing. Eighty per cent of the patients were asymptomatic at the first onset of oversensing. Only one patient suffered an inappropriate shock as first manifestation of lead failure. Compared with the patients without HM, inappropriate shocks occurred in 27.3% in the HM group vs. 46.5% (P = n.s.). This trend gains statistical significance, if the compound endpoint of symptomatic lead failure consisting of inappropriate shocks and symptomatic pacemaker inhibition due to oversensing is focused: 27.3% event in the HM group vs. 53.4% in the group without HM (P = 0.04). Event messages were despatched in a mean of 54 days after the last ICD interrogation and 56 days before next scheduled visit. Thus, 56 days of reaction time are gained to avoid adverse events. CONCLUSION In 91% of all lead-related ICD complications, the diagnosis could be established correctly by an alert of the HM system. Mostly, the first incident sent was oversensing of artefacts, falsely detected as ventricular fibrillation-the VF zone. The automatic HM surveillance system enables physicians to detect severe lead problems early and to react quickly; thus, it might have a potential to avoid inappropriate shocks due to lead failure and T-wave oversensing.

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 I 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 univarihate 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.

Dietary n-3 Polyunsaturated Fatty Acids and Direct Renin Inhibition Improve Electrical Remodeling in a Model of High Human Renin Hypertension

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180±3 mm Hg) compared with dTGRs (208±5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110±3 and 119±6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QTc intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.

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.

Comparison of nonlinear methods symbolic dynamics, detrended fluctuation, and Poincaré plot analysis in risk stratification in patients with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) has an incidence of about 20100 000 new cases per annum and accounts for nearly 10 000 deaths per year in the United States. Approximately 36% of patients with dilated cardiomyopathy (DCM) suffer from cardiac death within five years after diagnosis. Currently applied methods for an early risk prediction in DCM patients are rather insufficient. The objective of this study was to investigate the suitability of short-term nonlinear methods symbolic dynamics (STSD), detrended fluctuation (DFA), and Poincare plot analysis (PPA) for risk stratification in these patients. From 91 DCM patients and 30 healthy subjects (REF), heart rate and blood pressure variability (HRV, BPV), STSD, DFA, and PPA were analyzed. Measures from BPV analysis, DFA, and PPA revealed highly significant differences (p<0.0011) discriminating REF and DCM. For risk stratification in DCM patients, four parameters from BPV analysis, STSD, and PPA revealed significant differences between low and high risk (maximum sensitivity: 90%, specificity: 90%). These results suggest that STSD and PPA are useful nonlinear methods for enhanced risk stratification in DCM patients.

Prediction of Life-Threatening Arrhythmic Events in Patients With Chronic Myocardial Infarction by Contrast-Enhanced CMR

OBJECTIVES We hypothesized that infarct transmurality assessed with late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) predicts arrhythmic events in patients with chronic myocardial infarction. BACKGROUND Patients with decreased left ventricular function due to chronic myocardial infarction are at increased risk for life-threatening arrhythmias related to infarcted tissue. LGE-CMR accurately detects infarct morphology. METHODS We prospectively enrolled 52 patients with chronic myocardial infarction referred for primary preventive implantable cardioverter-defibrillator (ICD) implantation following MADIT (Multicenter Automatic Defibrillator Implantation Trial) study criteria. Using LGE-CMR, left ventricular volumes, function, and infarct morphology were assessed including calculation of total and relative infarct mass, infarct border, infarct border zone, and infarct transmurality. RESULTS Patients were followed for 1,235 ± 341 days. The primary combined endpoint including appropriate device therapy (ICD discharge or antitachycardia pacing) or death from cardiac cause occurred in 16 individuals resulting in an annual event rate of 4.7%. Six patients received an appropriate shock, 7 patients received recurrent appropriate antitachycardia pacing for sustained ventricular tachycardia, and 3 patients died of cardiac cause. There was a significant association to relative infarct mass (38 ± 8% vs. 28 ± 14%, p = 0.02), infarct transmurality (24 ± 8 g vs. 16 ± 12 g, p = 0.02), and relative infarct transmurality (RIT) (63 ± 12% vs. 48 ± 23%, p = 0.01). In separate logistic regression models, no variable emerged as significant when combined with RIT. As a single effect, RIT emerged as a predictor of the primary endpoint (p = 0.02). A RIT cutoff at 43% resulted in a sensitivity of 88%, a specificity of 50%, a positive predictive value of 44%, and a negative predictive value of 90%. CONCLUSIONS In patients with chronic myocardial infarction scheduled for primary preventive ICD implantation, infarct transmurality as defined by LGE-CMR identifies a subgroup with increased risk for life-threatening arrhythmias and cardiac death.