Robert G. Tieleman

Verapamil Reduces Tachycardia-Induced Electrical Remodeling of the Atria

BACKGROUND Prolonged periods of atrial fibrillation or rapid atrial pacing induce shortening of the atrial effective refractory period (AERP), which is thought to be related to the lower success rates of various antifibrillatory treatments when the arrhythmia has lasted for a longer period of time. METHODS AND RESULTS To investigate whether an increase in intracellular calcium could be the stimulus for electrical remodeling, the effects of verapamil on shortening of the AERP in response to 24 hours of rapid atrial pacing (300 bpm) were studied in five chronically instrumented conscious goats during infusion of saline or verapamil. During rapid atrial pacing, the ventricular rate was kept constant by ventricular pacing (150 bpm). The AERP was measured by programmed electrical stimulation at basic cycle lengths of 430, 300, and 200 ms. Verapamil had no effects on the AERP before rapid atrial pacing. However, in the course of 24 hours of rapid atrial pacing, the AERP shortened significantly less (27% to 58%) in the presence of verapamil compared with control (at 430, 300, and 200 ms, P < .001, P < .01, and P < .01, respectively). Also, after cessation of pacing, complete recovery of the AERP during verapamil infusion occurred much sooner than in the control experiments. Despite a significant reduction in electrical remodeling, there was only a minimal reduction in inducibility of atrial fibrillation by verapamil (34% versus 39% in the control experiments, P = .03). CONCLUSIONS Electrical remodeling of the atrium during rapid atrial pacing was significantly attenuated by verapamil. This suggests that electrical remodeling of the atrium is triggered by the high calcium influx during rapid atrial pacing rates.

Progression From Paroxysmal to Persistent Atrial Fibrillation: Clinical Correlates and Prognosis

OBJECTIVES We investigated clinical correlates of atrial fibrillation (AF) progression and evaluated the prognosis of patients demonstrating AF progression in a large population. BACKGROUND Progression of paroxysmal AF to more sustained forms is frequently seen. However, not all patients will progress to persistent AF. METHODS We included 1,219 patients with paroxysmal AF who participated in the Euro Heart Survey on AF and had a known rhythm status at follow-up. Patients who experienced AF progression after 1 year of follow-up were identified. RESULTS Progression of AF occurred in 178 (15%) patients. Multivariate analysis showed that heart failure, age, previous transient ischemic attack or stroke, chronic obstructive pulmonary disease, and hypertension were the only independent predictors of AF progression. Using the regression coefficient as a benchmark, we calculated the HATCH score. Nearly 50% of the patients with a HATCH score >5 progressed to persistent AF compared with only 6% of the patients with a HATCH score of 0. During follow-up, patients with AF progression were more often admitted to the hospital and had more major adverse cardiovascular events. CONCLUSIONS A substantial number of patients progress to sustained AF within 1 year. The clinical outcome of these patients regarding hospital admissions and major adverse cardiovascular events was worse compared with patients demonstrating no AF progression. Factors known to cause atrial structural remodeling (age and underlying heart disease) were independent predictors of AF progression. The HATCH score may help to identify patients who are likely to progress to sustained forms of AF in the near future.

Early recurrences of atrial fibrillation after electrical cardioversion: A result of fibrillation-induced electrical remodeling of the atria?

OBJECTIVES We sought to investigate whether, in humans, the timing and incidence of a relapse of atrial fibrillation (AF) during the first month after cardioversion indicates the presence of electrical remodeling and whether this could be influenced by prevention of intracellular calcium overload during AF. BACKGROUND Animal experiments have shown that AF induces shortening of the atrial refractory period, resulting in an increased vulnerability for reinduction of AF. This electrical remodeling was completely reversible within 1 week after cardioversion of AF and was presumably related to intracellular calcium overload. METHODS Using transtelephonic monitoring in 61 patients cardioverted for chronic AF, we evaluated the daily incidence of recurrence of AF and determined, by Cox regression analysis, the influence of patient characteristics and medication on relapse of AF. RESULTS During 1 month of follow-up, 35 patients (57%) had a relapse of AF, with a peak incidence during the first 5 days after cardioversion. Furthermore, in patients with a recurrence of AF, there was a positive correlation between the duration of the shortest coupling interval of the premature atrial beats after cardioversion and the timing of the recurrence of AF (p = 0.0013). Multivariate analysis revealed that the use of intracellular calcium-lowering drugs during AF was the only significant variable related to maintenance of sinus rhythm after cardioversion (p = 0.03). CONCLUSIONS The daily distribution of recurrences of AF suggests a temporary vulnerable electrophysiologic state of the atria. Use of intracellular calcium-lowering medications during AF appeared to reduce recurrences, possibly due to a reduction of electrical remodeling during AF.

Quarterly Focus Issue: Heart Rhythm DisorderClinical Research: Atrial FibrillationProgression From Paroxysmal to Persistent Atrial Fibrillation: Clinical Correlates and Prognosis

OBJECTIVES We investigated clinical correlates of atrial fibrillation (AF) progression and evaluated the prognosis of patients demonstrating AF progression in a large population. BACKGROUND Progression of paroxysmal AF to more sustained forms is frequently seen. However, not all patients will progress to persistent AF. METHODS We included 1,219 patients with paroxysmal AF who participated in the Euro Heart Survey on AF and had a known rhythm status at follow-up. Patients who experienced AF progression after 1 year of follow-up were identified. RESULTS Progression of AF occurred in 178 (15%) patients. Multivariate analysis showed that heart failure, age, previous transient ischemic attack or stroke, chronic obstructive pulmonary disease, and hypertension were the only independent predictors of AF progression. Using the regression coefficient as a benchmark, we calculated the HATCH score. Nearly 50% of the patients with a HATCH score >5 progressed to persistent AF compared with only 6% of the patients with a HATCH score of 0. During follow-up, patients with AF progression were more often admitted to the hospital and had more major adverse cardiovascular events. CONCLUSIONS A substantial number of patients progress to sustained AF within 1 year. The clinical outcome of these patients regarding hospital admissions and major adverse cardiovascular events was worse compared with patients demonstrating no AF progression. Factors known to cause atrial structural remodeling (age and underlying heart disease) were independent predictors of AF progression. The HATCH score may help to identify patients who are likely to progress to sustained forms of AF in the near future.

Ion Channel Remodeling Is Related to Intraoperative Atrial Effective Refractory Periods in Patients With Paroxysmal and Persistent Atrial Fibrillation

Background —Sustained shortening of the atrial effective refractory period (AERP), probably due to reduction in the L-type calcium current, is a major factor in the initiation and maintenance of atrial fibrillation (AF). We investigated underlying molecular changes by studying the relation between gene expression of the L-type calcium channel and potassium channels and AERP in patients with AF. Methods and Results —mRNA and protein expression were determined in the left and right atrial appendages of patients with paroxysmal (n=13) or persistent (n=16) AF and of 13 controls in sinus rhythm using reverse transcription polymerase chain reaction and slot-blot, respectively. The mRNA content of almost all investigated ion channel genes was reduced in persistent but not in paroxysmal AF. Protein levels for the L-type Ca2+ channel and 5 potassium channels (Kv4.3, Kv1.5, HERG, minK, and Kir3.1) were significantly reduced in both persistent and paroxysmal AF. Furthermore, AERPs were determined intraoperatively at 5 basic cycle lengths between 250 and 600 ms. Patients with persistent and paroxysmal AF displayed significant shorter AERPs. Protein levels of all ion channels investigated correlated positively with the AERP and with the rate adaptation of AERP. Patients with reduced ion channel protein expression had a shorter AERP duration and poorer rate adaptation. Conclusions —AF is predominantly accompanied by decreased protein contents of the L-type Ca2+ channel and several potassium channels. Reductions in L-type Ca2+ channel correlated with AERP and rate adaptation, and they represent a probable explanation for the electrophysiological changes during AF.

Nurse-led care vs. usual care for patients with atrial fibrillation: results of a randomized trial of integrated chronic care vs. routine clinical care in ambulatory patients with atrial fibrillation

AIMS The management of patients with atrial fibrillation (AF) is often inadequate due to deficient adherence to the guidelines. A nurse-led AF clinic providing integrated chronic care to improve guideline adherence and activate patients in their role, may effectively reduce morbidity and mortality but such care has not been tested in a large randomized trial. Therefore, we performed a randomized clinical trial to compare the AF clinic with routine clinical care in patients with AF. METHODS AND RESULTS We randomly assigned 712 patients with AF to nurse-led care and usual care. Nurse-led care consisted of guidelines based, software supported integrated chronic care supervised by a cardiologist. The primary endpoint was a composite of cardiovascular hospitalization and cardiovascular death. Duration of follow-up was at least 12 months. Adherence to guideline recommendations was significantly better in the nurse-led care group. After a mean of 22 months, the primary endpoint occurred in 14.3% of 356 patients of the nurse-led care group compared with 20.8% of 356 patients receiving usual care [hazard ratio: 0.65; 95% confidence interval (CI) 0.45-0.93; P= 0.017]. Cardiovascular death occurred in 1.1% in the nurse-led care vs. 3.9% in the usual care group (hazard ratio: 0.28; 95% CI: 0.09-0.85; P= 0.025). Cardiovascular hospitalization amounted (13.5 vs. 19.1%, respectively, hazard ratio: 0.66; 95% CI: 0.46-0.96, P= 0.029). CONCLUSION Nurse-led care of patients with AF is superior to usual care provided by a cardiologist in terms of cardiovascular hospitalizations and cardiovascular mortality. Trial registration information: Clinicaltrials.gov identifier number: NCT00391872.

Efficacy, safety, and determinants of conversion of atrial fibrillation and flutter with oral amiodarone

Amiodarone is effective for long-term maintenance of sinus rhythm after electrical cardioversion of refractory atrial fibrillation or flutter. To examine its efficacy and safety for pharmacologic conversion of these arrhythmias, we studied 129 patients with refractory atrial fibrillation or flutter who had failed previous intensive conventional antiarrhythmic treatment. In anticipation of electrical cardioversion, patients were loaded with amiodarone, 600 mg/day during a 4-week period. The main outcome measure was pharmacologic conversion during this period. During the loading period, 23 patients (18%) converted to sinus rhythm. When analyzed in a multivariate model, conversion was related to desethylamiodarone plasma level (p = 0.0006), arrhythmia duration (p = 0.04), left atrial area (p = 0.02), and concomitant treatment with verapamil (p = 0.01). During ongoing atrial fibrillation after loading, the ventricular rate decreased from 100 +/- 25 to 87 +/- 27 beats/ min (p <0.001). Amiodarone appeared to be safe and did not have to be discontinued because of intolerable side effects. Thus, amiodarone loading is safe and is still able to convert refractory atrial fibrillation or flutter. Conversion is related to increased desethylamiodarone plasma levels and concomitant treatment with verapamil. Because prolonged loading may increase desethylamiodarone plasma concentrations, this may enhance efficacy and obviate the need for electrical cardioversion.

Atrial Tissue Doppler Imaging For Prediction Of New-Onset Atrial Fibrillation

Background: The total atrial conduction time (TACT) is an independent predictor of atrial fibrillation (AF). A new transthoracic echocardiographic tool to determine TACT by tissue Doppler imaging (PA-TDI (the time from the initiation of the P wave on the ECG (lead II) to the A′ wave on the lateral left atrial tissue Doppler tracing)) has been developed recently. Objective: To test the hypothesis that measurement of PA-TDI enables prediction of new-onset AF. Methods: 249 Patients without a history of AF were studied. All patients underwent an echocardiogram and the PA-TDI interval was measured. Patient characteristics and rhythm at follow-up were recorded. Results: During a mean (SD) follow-up of 680 (290) days, 15 patients (6%) developed new-onset AF. These patients had a longer PA-TDI interval than patients who remained in sinus rhythm (172 (25) ms vs 150 (20) ms, p = 0.001). Furthermore, the patients developing AF were older, more often had a history of heart failure or chronic obstructive pulmonary disease, more often used α blockers, had enlarged left atria and more frequently mitral incompetence on the echocardiogram. After adjusting for potential confounders, Cox regression showed that PA-TDI was independently associated with new-onset AF (OR = 1.375; 95% CI 1.037 to 1.823; p = 0.027). The 2-year incidence of AF was 33% in patients with a PA-TDI interval >190 ms versus 0% in patients with a PA-TDI interval <130 ms (p = 0.002). Conclusions: A prolonged PA-TDI interval may predict the development of new-onset AF. This measure may be used to identify patients at risk in future strategies to prevent the development or complications of AF.

Should we abandon the common practice of withholding oral anticoagulation in paroxysmal atrial fibrillation

AIMS To assess the relation between the atrial fibrillation (AF) subtype and thrombo-embolic events. METHODS AND RESULTS The observational Euro Heart Survey on AF (2003-04) enrolled 1509 paroxysmal, 1109 persistent, and 1515 permanent AF patients, according to the 2001 American College of Cardiology, American Heart Association, and the European Society of Cardiology guidelines definitions. A 1 year follow-up was performed. Permanent AF patients had at baseline a worse stroke risk profile than paroxysmal and persistent AF patients. In paroxysmal AF, the risk for stroke, any thrombo-embolism, major bleeding and the combined endpoint of cardiovascular mortality, any thrombo-embolism, and major bleeding was comparable with persistent and permanent AF, in both univariable and multivariable analyses. Compared with AF patients without stroke, patients suffering from a stroke had a comparable frequency and duration of AF attacks, but tended to have a worse stroke risk profile at baseline. During 1 year following cardioversion, paroxysmal AF patients had a higher risk for stroke (P = 0.029) and any thrombo-embolism (P = 0.001) than persistent AF patients. CONCLUSION In the Euro Heart Survey, paroxysmal AF had a comparable risk for thrombo-embolic events as persistent and permanent AF. This observation strengthens the guideline recommendation not to consider the clinical AF subtype when deciding on anticoagulation.

Heart Rate Variability in Patients With Atrial Fibrillation Is Related to Vagal Tone

BACKGROUND Analysis of heart rate variability (HRV) has thus far not been applied in patients with atrial fibrillation, probably because of the presumed absence of any form of patterning of the ventricular rhythm, particularly vagally mediated respiratory arrhythmia. However, such patterning is theoretically conceivable given the function of the atrioventricular node in atrial fibrillation and its susceptibility to autonomic influences. METHODS AND RESULTS Sixteen patients (mean age, 56+/-4 years) with long-term atrial fibrillation on fixed doses of digoxin or verapamil were studied; 12 healthy men in sinus rhythm were used as control subjects. HRV (standard deviation of RR intervals [SD], coefficient of variance [CV], the root-mean-square of successive difference [RMSSD], and low-frequency [LF] and high-frequency power [HF]) was analyzed during 500 RR intervals at baseline, after administration of propranolol (0.2 mg/kg I.V.), and after subsequent administration of methylatropine (0.02 mg/kg I.V.). HRV at baseline and changes in HRV after methylatropine were then related to vagal tone (vagal cardiac control), quantified as the decrease in mean RR after methylatropine. Baseline HRV was higher in the atrial fibrillation group than in the control group; after propranolol, HRV increased in both groups; after methylatropine, HRV neared zero in the control group, whereas it returned to baseline values in the atrial fibrillation group. SD, RMSSD, LF, and HF at baseline were significantly (P<.05) correlated with vagal tone in the control group but also in the atrial fibrillation group (correlation coefficients of .60, .61, .57, and .64, respectively). Even stronger correlations were observed between changes in these parameters after methylatropine and vagal tone, particularly in the atrial fibrillation group (correlation coefficients of .89, .87, .72, and .90, respectively). CONCLUSIONS This study shows that HRV in patients with atrial fibrillation is related to vagal tone.