Circadian variation of variability and irregularity of heart rate in patients with permanent atrial fibrillation: relation to symptoms and rate control drugs.

The aim of the present study was to evaluate diurnal variations of the variability and irregularity of heart rate (HR) in patients with permanent atrial fibrillation (AF) with and without rate control drugs. Thirty-eight patients with permanent AF were part of an investigator-blind crossover study comparing diltiazem, verapamil, metoprolol, and carvedilol. We analyzed five Holter recordings per patient: at baseline (no rate control drug) and with each of the four drug regimens. HR, variability (SD; percentages of interval differences of successive RR intervals of >20, 50, and 80 ms; and root of the mean squared differences of successive RR intervals), and irregularity (approximate and sample entropy) parameters were computed in 20-min long nonoverlapping segments. Circadian rhythmicity was evaluated using cosinor analysis to each parameter series, which is characterized by the 24-h mean [midline statistic of rhythm (MESOR)] and excursion over the mean (amplitude). Arrhythmia-related symptoms were assessed by a questionnaire measuring symptom severity and frequency. HR and variability parameters showed a significant circadian variation in most patients, whereas only a small minority of the patients had circadian variations of irregularity parameters. Patients with circadian approximate entropy n at baseline had more severe symptoms (symptom severity: 9 ± 4 vs. 6 ± 5, P < 0.05, circadian vs. noncircadian variations). All drugs decreased the MESOR of HR and increased the MESOR of variability parameters. Only carvedilol and metoprolol decreased the normalized amplitude over 24 h of all parameters and HR. In conclusion, HR and RR variability parameters present a circadian variation in patients with permanent AF, whereas few patients demonstrated circadian fluctuations in irregularity parameters, suggesting different physiological mechanisms.

Rate-control drugs affect variability and irregularity measures of RR intervals in patients with permanent atrial fibrillation.

INTRODUCTION: Irregularity measures have been suggested as risk indicators in patients with atrial fibrillation (AF); however, it is not known to what extent they are affected by commonly used rate-control drugs. We aimed at evaluating the effect of metoprolol, carvedilol, diltiazem, and verapamil on the variability and irregularity of the ventricular response in patients with permanent AF. METHODS AND RESULTS: Sixty patients with permanent AF were part of an investigator-blind cross-over study, comparing 4 rate-control drugs (diltiazem, verapamil, metoprolol, and carvedilol). We analyzed five 20-minute segments per patient: baseline and the 4 drug regimens. On every segment, heart rate (HR) variability and irregularity of RR series were computed. The variability was assessed as standard deviation, pNN20, pNN50, pNN80, and rMSSD. The irregularity was assessed by regularity index, approximate (ApEn), and sample entropy. A significantly lower HR was obtained with all drugs, the HR was lowest using the calcium channel blockers. All drugs increased the variability of ventricular response in respect to baseline (as an example, rMSSD: baseline 171 ± 47 milliseconds, carvedilol 229 ± 58 milliseconds; P < 0.05 vs. baseline, metoprolol 226 ± 66 milliseconds; P < 0.05 vs. baseline, verapamil 228 ± 84; P < 0.05 vs. baseline, diltiazem 256 ± 87 milliseconds; P < 0.05 vs. baseline and all other drugs). Only ß-blockers significantly increased the irregularity of the RR series (as an example, ApEn: baseline 1.86 ± 0.13, carvedilol 1.92 ± 0.09; P < 0.05 vs. baseline, metoprolol 1.93 ± 0.08; P < 0.05 vs. baseline, verapamil 1.86 ± 0.22 ns, diltiazem 1.88 ± 0.16 ns). CONCLUSION: Modification of AV node conduction by rate-control drugs increase RR variability, while only ß-blockers affect irregularity.

Impact of atrial fibrillation on levels of high-sensitivity troponin I in a 75-year-old population.

PURPOSE: Atrial fibrillation (AF) has been associated with elevated levels of cardiac troponins; however, it is not clear if this association is independent of underlying cardiovascular disease. The aim of this study was to investigate the impact of AF on cardiac troponin I levels in a 75-year-old cohort from the general population, using a recently introduced, highly sensitive assay. METHODS: All 75-year-old citizens in Asker and Baerum counties were invited to participate in a prevalence study of AF. High-sensitive troponin I (hs-TnI) levels were measured (Abbott Diagnostics) in serum samples collected from 62 subjects with AF and a gender-matched control group of 126 subjects in sinus rhythm. RESULTS: Hs-TnI was detectable in all subjects (median 7.3 ng/L [range 3.0-88.7]). Patients with AF had higher levels than subjects in sinus rhythm (8.3 ng/L [3.7-88.7] vs. 6.8 ng/L [3.0-77.5]; p = 0.011). Male gender (p = 0.002), hypertension (p = 0.001), coronary heart disease (p < 0.001), heart failure (p < 0.001), prior stroke or transient ischemic attack (p = 0.013) and serum creatinine (p < 0.001) were all associated with higher levels of hs-TnI in univariate analysis. Heart failure and coronary heart disease remained significantly associated with hs-TnI in multivariate analysis, whereas the relation between AF and hs-TnI was no longer statistically significant. CONCLUSION: All subjects had detectable levels of hs-TnI. AF patients had higher hs-TnI levels than subjects in sinus rhythm; however, this difference was not statistically significant after adjustment for heart failure and coronary heart disease.

Non-invasive assessment of the effect of beta blockers and calcium channel blockers on the AV node during permanent atrial fibrillation.

AIM: We aimed at assessing changes in AV nodal properties during administration of the beta blockers metoprolol and carvedilol, and the calcium channel blockers diltiazem and verapamil from electrocardiographic data. METHODS: Parameters accounting for the functional refractory periods of the slow and fast pathways (aRPs and aRPf) were estimated using atrial fibrillatory rate (AFR) and ventricular response assessed from 15-min ECG segments recorded at baseline and on drug treatment from sixty patients with permanent AF. RESULTS: The results showed that AFR and HR were significantly reduced for all drugs, and that aRPs and aRPf were significantly prolonged in both pathways. The prolongation in aRP was significantly larger for the calcium channel blockers than for the beta blockers. CONCLUSIONS: The changes observed in the AV node parameters are in line with the results of previous electrophysiological studies performed in patients during sinus rhythm, therefore supporting the clinical value of the method.

Calcium channel blockers improve exercise capacity and reduce N-terminal Pro-B-type natriuretic peptide levels compared with beta-blockers in patients with permanent atrial fibrillation.

AIMS: Rate control of atrial fibrillation (AF) has become a main treatment modality, but we need more knowledge regarding the different drugs used for this purpose. In this study, we aimed to compare the effect of four common rate-reducing drugs on exercise capacity and levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with permanent AF. METHODS AND RESULTS: We included 60 patients (mean age 71 ± 9 years, 18 women) with permanent AF and normal left ventricular function in a randomized, cross-over, investigator-blind study. Diltiazem 360 mg, verapamil 240 mg, metoprolol 100 mg, and carvedilol 25 mg were administered o.d. for 3 weeks. At baseline and on the last day of each treatment period, the patients underwent a maximal cardiopulmonary exercise test and blood samples were obtained at rest and at peak exercise. The exercise capacity (peak VO2) was significantly lower during treatment with metoprolol and carvedilol compared with baseline (no treatment) or treatment with diltiazem and verapamil (P < 0.001 for all). Compared with baseline, treatment with diltiazem and verapamil significantly reduced the NT-proBNP levels both at rest and at peak exercise, whereas treatment with metoprolol and carvedilol increased the levels (P < 0.05 for all). CONCLUSION: Rate-reducing treatment with diltiazem or verapamil preserved exercise capacity and reduced levels of NT-proBNP compared with baseline, whereas treatment with metoprolol or carvedilol reduced the exercise capacity and increased levels of NT-proBNP.

Non-invasive evaluation of the effect of metoprolol on the atrioventricular node during permanent atrial fibrillation.

AIMS: During atrial fibrillation (AF), conventional electrophysiological techniques for assessment of refractory period or conduction velocity of the atrioventricular (AV) node cannot be used. We aimed at evaluating changes in AV nodal properties during administration of metoprolol from electrocardiogram data, and to support our findings with simulated data based on results from an electrophysiological study. METHODS AND RESULTS: Sixty patients (age 71 ± 9 years, 42 men) with permanent AF were included in the RATe control in Atrial Fibrillation (RATAF) study. Two 15 min segments, during baseline and metoprolol administration, starting at 2 pm were analysed in this study. Atrial fibrillatory rate (AFR), heart rate (HR), and AV nodal parameters were assessed. The AV nodal parameters account for the probability of an impulse not taking the fast pathway, the absolute refractory periods of the slow and fast pathways (aRPs and aRPf), representing the functional refractory period, and their respective prolongation in refractory period. In addition, simulated RR series were generated that mimic metoprolol administration through prolonged AV conduction interval and AV node effective refractory period. During metoprolol administration, AFR and HR were significantly decreased and aRP was significantly prolonged in both pathways (aRPs: 337 ± 60 vs. 398 ± 79 ms, P < 0.01; aRPf: 430 ± 91 vs. 517 ± 100 ms, P < 0.01). Similar results were found for the simulated RR series, both aRPs and aRPf being prolonged with metoprolol (aRPs: 413 ± 33 vs. 437 ± 43 ms, P = 0.01; aRPf: 465 ± 40 vs. 502 ± 69 ms, P = 0.02). CONCLUSION: The AV nodal parameters reflect expected changes after metoprolol administration, i.e. a prolongation in functional refractory period. The simulations confirmed that aRPs and aRPf may serve as an estimate of the functional refractory period.

Impact of atrial fibrillation on inflammatory and fibrinolytic variables in the elderly.

PURPOSE: Atrial fibrillation (AF) is associated with inflammation and a prothrombotic state; however, it is still unclear whether this is independent of ageing and comorbidity. The objective of this study was to investigate the impact of AF on circulating levels of inflammatory and fibrinolytic markers in a 75-year-old general population. METHODS: All 75-year-old citizens in Asker and Baerum counties in Norway were invited to participate in a prevalence study of AF. Blood samples were collected from 63 subjects with AF and a gender-matched control group of 126 subjects in sinus rhythm. C-reactive protein (CRP), tumour necrosis factor α (TNFα), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), P-selectin, CD40 ligand, tissue plasminogen activator antigen (tPA ag), plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase inhibitor 1 (TIMP-1) activity were analyzed using commercially available assays. RESULTS: Subjects with AF had higher levels of IL-6 (median 3.07 pg/mL (interquartile range 2.11, 4.36) vs. 2.26 (1.70, 3.26); p = 0.002) and PAI-1 activity (12.9 U/mL (6.6, 17.1) vs. 9.0 (4.6, 14.0); p = 0.005). No difference was found for the other markers. The presence of AF was still significantly associated with higher levels of IL-6 and PAI-1 activity after adjusting for confounders (p = 0.028 and p = 0.007, respectively). CONCLUSION: AF was independently associated with higher levels of IL-6 and PAI-1 activity. Thus, there is evidence of a proinflammatory state and reduced fibrinolysis also in this stable, out-of-hospital group of 75-year-old AF patients.

Model-based estimation of AV-nodal refractory period and conduction delay trends from ECG.

Introduction: Atrial fibrillation (AF) is the most common arrhythmia, associated with significant burdens to patients and the healthcare system. The atrioventricular (AV) node plays a vital role in regulating heart rate during AF by filtering electrical impulses from the atria. However, it is often insufficient in regards to maintaining a healthy heart rate, thus the AV node properties are modified using rate-control drugs. Moreover, treatment selection during permanent AF is currently done empirically. Quantifying individual differences in diurnal and short-term variability of AV-nodal function could aid in personalized treatment selection. Methods: This study presents a novel methodology for estimating the refractory period (RP) and conduction delay (CD) trends, and their uncertainty in the two pathways of the AV node during 24 h using non-invasive data. This was achieved by utilizing a network model together with a problem-specific genetic algorithm and an approximate Bayesian computation algorithm. Diurnal variability in the estimated RP and CD was quantified by the difference between the daytime and nighttime estimates, and short-term variability was quantified by the Kolmogorov-Smirnov distance between adjacent 10-min segments in the 24-h trends. Additionally, the predictive value of the derived parameter trends regarding drug outcome was investigated using several machine learning tools. Results: Holter electrocardiograms from 51 patients with permanent AF during baseline were analyzed, and the predictive power of variations in RP and CD on the resulting heart rate reduction after treatment with four rate control drugs was investigated. Diurnal variability yielded no correlation to treatment outcome, and no prediction of drug outcome was possible using the machine learning tools. However, a correlation between the short-term variability for the RP and CD in the fast pathway and resulting heart rate reduction during treatment with metoprolol (ρ = 0.48, p < 0.005 in RP, ρ = 0.35, p < 0.05 in CD) were found. Discussion: The proposed methodology enables non-invasive estimation of the AV node properties during 24 h, which-indicated by the correlation between the short-term variability and heart rate reduction-may have the potential to assist in treatment selection.

ECG based assessment of circadian variation in AV-nodal conduction during AF-Influence of rate control drugs.

The heart rate during atrial fibrillation (AF) is highly dependent on the conduction properties of the atrioventricular (AV) node. These properties can be affected using ß-blockers or calcium channel blockers, mainly chosen empirically. Characterization of individual AV-nodal conduction could assist in personalized treatment selection during AF. Individual AV nodal refractory periods and conduction delays were characterized based on 24-hour ambulatory ECGs from 60 patients with permanent AF. This was done by estimating model parameters from a previously created mathematical network model of the AV node using a problem-specific genetic algorithm. Based on the estimated model parameters, the circadian variation and its drug-dependent difference between treatment with two ß-blockers and two calcium channel blockers were quantified on a population level by means of cosinor analysis using a linear mixed-effect approach. The mixed-effects analysis indicated increased refractoriness relative to baseline for all drugs. An additional decrease in circadian variation for parameters representing conduction delay was observed for the ß-blockers. This indicates that the two drug types have quantifiable differences in their effects on AV-nodal conduction properties. These differences could be important in treatment outcome, and thus quantifying them could assist in treatment selection.

Non-invasive Characterization of Human AV-Nodal Conduction Delay and Refractory Period During Atrial Fibrillation.

During atrial fibrillation (AF), the heart relies heavily on the atrio-ventricular (AV) node to regulate the heart rate. Thus, characterization of AV-nodal properties may provide valuable information for patient monitoring and prediction of rate control drug effects. In this work we present a network model consisting of the AV node, the bundle of His, and the Purkinje fibers, together with an associated workflow, for robust estimation of the model parameters from ECG. The model consists of two pathways, referred to as the slow and the fast pathway, interconnected at one end. Both pathways are composed of interacting nodes, with separate refractory periods and conduction delays determined by the stimulation history of each node. Together with this model, a fitness function based on the Poincaré plot accounting for dynamics in RR interval series and a problem specific genetic algorithm, are also presented. The robustness of the parameter estimates is evaluated using simulated data, based on clinical measurements from five AF patients. Results show that the proposed model and workflow could estimate the slow pathway parameters for the refractory period, R m i n S P and ΔR SP , with an error (mean ± std) of 10.3 ± 22 and -12.6 ± 26 ms, respectively, and the parameters for the conduction delay, D m i n , t o t S P and Δ D t o t S P , with an error of 7 ± 35 and 4 ± 36 ms. Corresponding results for the fast pathway were 31.7 ± 65, -0.3 ± 77, 17 ± 29, and 43 ± 109 ms. These results suggest that both conduction delay and refractory period can be robustly estimated from non-invasive data with the proposed methodology. Furthermore, as an application example, the methodology was used to analyze ECG data from one patient at baseline and during treatment with Diltiazem, illustrating its potential to assess the effect of rate control drugs.

Improved rate control reduces cardiac troponin T levels in permanent atrial fibrillation.

BACKGROUND: Detectable levels of troponins are often found in serum of patients with atrial fibrillation (AF), and recent reports suggest that Tn concentrations are independently related to patient prognosis. HYPOTHESIS: We hypothesized that treatment with common rate-reducing drugs might lower the levels of cardiac troponin T (TnT) in patients with permanent AF. We also wanted to investigate whether the different drugs would impact the Tn levels differently. METHODS: Sixty patients were included (mean age 71 ± 9 years, 18 women) in this randomized crossover study. All patients had stable, permanent AF without ischemic heart disease or congestive heart failure. Diltiazem 360 mg, verapamil 240 mg, metoprolol 100 mg, and carvedilol 25 mg were administered once daily for 3 weeks, in a randomized sequence. At baseline and on the last day of each treatment period, TnT concentrations were measured at rest and after a maximal exercise test. RESULTS: TnT was detectable in all patients. In 22% of the patients, TnT concentrations were above the threshold normally used for diagnosing myocardial infarction. All drugs reduced the levels of TnT significantly compared with baseline (P < 0.001 for all), but there were no significant differences between the treatments. Levels of TnT increased significantly in response to exercise testing (P < 0.001 for all). CONCLUSIONS: Elevated TnT was demonstrated in a large proportion of stable patients with permanent AF without ischemic heart disease. A moderate reduction of heart rate by the study drugs was associated with a significant reduction in levels of TnT.

Comparison of four single-drug regimens on ventricular rate and arrhythmia-related symptoms in patients with permanent atrial fibrillation.

Rate control of atrial fibrillation (AF) is a main treatment modality. However, data are scarce on the relative efficacy of calcium channel blockers and ß blockers or between drugs within each class. The purpose of the present study was to compare the effect of 4 rate-reducing, once-daily drug regimens on the ventricular heart rate and arrhythmia-related symptoms in patients with permanent AF. We included 60 patients (mean age 71 ± 9 years, 18 women) with permanent AF in an investigator-blind cross-over study. Diltiazem 360 mg/day, verapamil 240 mg/day, metoprolol 100 mg/day, and carvedilol 25 mg/day were administered for 3 weeks in a randomized sequence. The 24-hour heart rate was measured using Holter monitoring, and arrhythmia-related symptoms were assessed using the Symptom Checklist questionnaire before randomization and on the last day of each treatment period. The 24-hour mean heart rate was 96 ± 12 beats/min at baseline (no treatment), 75 ± 10 beats/min with diltiazem, 81 ± 11 beats/min with verapamil, 82 ± 11 beats/min with metoprolol, and 84 ± 11 beats/min with carvedilol. All drugs reduced the heart rate compared to baseline (p <0.001 for all). The 24-hour heart rate was significantly lower with diltiazem than with any other drug tested (p <0.001 for all). Compared to baseline, diltiazem significantly reduced both the frequency (p <0.001) and the severity (p = 0.005) of symptoms. In contrast, verapamil reduced symptom frequency only (p = 0.012). In conclusion, diltiazem 360 mg/day was the most effective drug regimen for reducing the heart rate in patients with permanent AF. Arrhythmia-related symptoms were reduced by treatment with the calcium channel blockers diltiazem and verapamil, but not by the ß blockers.