Maurits A. Allessie

Atrial Fibrillation Begets Atrial Fibrillation A Study in Awake Chronically Instrumented Goats

BACKGROUND In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia. METHODS AND RESULTS Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF. Whereas during control episodes of AF were short lasting (6 +/- 3 seconds), artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (> 24 hours) after 7.1 +/- 4.8 days (10 of 11 goats). During the first 24 hours of AF the median fibrillation interval shortened from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%. The atrial effective refractory period (AERP) shortened from 146 +/- 19 to 95 +/- 20 ms (-35%) (S1S1, 400 ms). At high pacing rates the shortening was less (-12%), pointing to a reversion of the normal adaptation of the AERP to heart rate. In 5 goats, after 2 to 4 weeks of AF, sinus rhythm was restored and all electrophysiological changes were found to be reversible within 1 week. CONCLUSIONS Artificial maintenance of AF leads to a marked shortening of AERP, a reversion of its physiological rate adaptation, and an increase in rate, inducibility and stability of AF. All these changes were completely reversible within 1 week of sinus rhythm.

High-density mapping of electrically induced atrial fibrillation in humans.

BACKGROUND Mapping studies in animals have suggested that atrial fibrillation (AF) is based on multiple reentering wavelets. Little information is available about the patterns of activation during AF in humans. The objective of the present study was to reconstruct and classify the patterns of human right atrial (RA) activation during electrically induced AF. METHODS AND RESULTS AF was induced by rapid atrial pacing in 25 patients with Wolff-Parkinson-White syndrome undergoing surgery for interruption of their accessory pathway(s). The free wall of the RA was mapped using a spoon-shaped electrode containing 244 unipolar electrodes. The activation of the RA during AF showed large interindividual differences. Based on the complexity of atrial activation, three types of AF were defined. In type I (40% of patients), single broad wave fronts propagated uniformly across the RA. Type II (32%) was characterized by one or two nonuniformly conducting wavelets, whereas in type III (28%), activation of the RA was highly fragmented and showed three or more different wavelets that frequently changed their direction of propagation as a result of numerous arcs of functional conduction block. There were significant differences (P < .05) among the three types of AF in median intervals (174 +/- 28, 150 +/- 14, and 136 +/- 16 milliseconds), variation in AF intervals (P5-95) (54 +/- 25, 94 +/- 21, and 104 +/- 22 milliseconds), incidence of electrical inactivity (42 +/- 11%, 21 +/- 4%, and 8 +/- 4%) and reentry (3 +/- 7%, 36 +/- 28%, and 99 +/- 36%), and average conduction velocity during AF (61 +/- 6, 54 +/- 4, and 38 +/- 10 cm/s). CONCLUSIONS During pacing-induced AF in humans, the RA is activated by one or multiple wavelets propagating in different directions. Three types of RA activation during AF were identified. From type I to type III, the frequency and irregularity of AF increased, and the incidence of continuous electrical activity and reentry became higher. These various types of AF in humans appear to be characterized by different numbers and dimensions of the intra-atrial reentrant circuits.

Structural Changes of Atrial Myocardium due to Sustained Atrial Fibrillation in the Goat

BACKGROUND After cardioversion of sustained atrial fibrillation (AF), the electrical and contractile functions of the atria are impaired, and recurrences of AF frequently occur. Whether remodeling of the structure of atrial myocardium is the basis for this problem is not known. METHODS AND RESULTS Sustained AF was induced by electrical pacing in 13 goats instrumented long-term. The goats were killed after 9 to 23 weeks, and the atrial myocardium was examined by light and electron microscopy. The changes were quantified in left and right atrial free walls, appendages, trabeculae, the interatrial septum, and the bundle of Bachmann. A substantial proportion of the atrial myocytes (up to 92%) revealed marked changes in their cellular substructures, such as loss of myofibrils, accumulation of glycogen, changes in mitochondrial shape and size, fragmentation of sarcoplasmic reticulum, and dispersion of nuclear chromatin. These changes were accompanied by an increase in size of the myocytes (up to 195%). There were virtually no signs of cellular degeneration, and the interstitial space remained unaltered. The duration of sustained AF did not significantly affect the degree of myolytic cell changes. CONCLUSIONS Sustained AF in goats leads to predominantly structural changes in the atrial myocytes similar to those seen in ventricular myocytes from chronic hibernating myocardium. These structural changes may explain the depressed contractile function of atrial myocardium after cardioversion. This goat model of AF offers a new approach to study the cascade of events leading to sustained AF and its maintenance.

Pathophysiology and Prevention of Atrial Fibrillation

Atrial fibrillation (AF) is a ubiquitous yet diverse cardiac arrhythmia whose incidence increases with age; with most forms of cardiac and some pulmonary diseases; and with a number of metabolic, toxic, endocrine, or genetic abnormalities.1 2 Classification of clinical AF subtypes can be achieved on the basis of the ease by which episodes of the arrhythmia terminate as follows3 : “Paroxysmal” AF refers to episodes that generally stop spontaneously after no more than a few days. “Persistent” AF occurs less frequently than paroxysmal AF and, rather than self-terminating, requires cardioversion to restore sinus rhythm. “Permanent” AF cannot be converted to sinus rhythm. These terms apply strictly to chronic AF, because a single episode of the arrhythmia cannot be fully categorized. Although there are some mixed patterns, they generally derive from physician impatience for early cardioversion or from pragmatic clinical considerations (eg, to avoid thrombus formation or hemodynamic decompensation). Patients initially presenting with paroxysmal AF often progress to longer, non–self-terminating bouts. An exception may be paroxysmal AF during intense vagotonia. Moreover, AF initially responsive to pharmacological or electrical cardioversion tends to become resistant and cannot then be converted to sinus rhythm. To some extent, the failure of the physician to suggest or the patient to accept further cardioversion attempts may lead to diagnosis of “permanent” AF. Thus, the “point of no return” may be determined by true pathophysiological abnormalities or may merely be an artifact of clinical pragmatism. Effective prevention is essential in managing this arrhythmia whose occurrence is widespread, progression is relentless, and morbidity and mortality are significant. To focus on means for prevention necessitates considering both clinical risk factors and pathophysiology. AF derives from a complex continuum predisposing factors, summarized in Table 1⇓. In the West, about 5% of the population >65 years of age …

Configuration of Unipolar Atrial Electrograms During Electrically Induced Atrial Fibrillation in Humans

BACKGROUND During atrial fibrillation (AF), the atrium is activated by multiple wavelets that continuously change in size and direction. The aim of this study was to correlate the temporal variation in AF electrogram configuration with the varying spatial patterns of activation. METHODS AND RESULTS In a group of 25 Wolff-Parkinson-White patients undergoing cardiac surgery, the free wall of the right atrium was mapped (244 points) during electrically induced AF. The unipolar electrograms recorded during 4 seconds of AF were classified into four categories: (1) single deflections, (2) short-double potentials, (3) long-double potentials, and (4) fragmented potentials. The proportion of these four types of electrograms during AF was as follows: singles, 77 +/- 12%; short-doubles, 7 +/- 3%; long-doubles, 10 +/- 7%; and fragmented, 6 +/- 4%. Electrogram morphology was an indicator for rapid uniform conduction (single potentials; positive predictive value [PPV] of 0.96), collision (short-double potentials; PPV of 0.33), conduction block (long-double potentials; PPV of 0.84), and pivoting points or slow conduction (fragmented potentials; PPV of 0.87). In type I, II, and III AF, the proportion of long-double potentials was 4 +/- 2%, 12 +/- 3%, and 18 +/- 7% (P < .05); the proportion of fragmented complexes was 2 +/- 2%, 6 +/- 3%, and 10 +/- 4% (P < .05), respectively. During electrically induced and self-terminating episodes of AF, no preferential anatomic sites for double or fragmented potentials were found in the right atrium. CONCLUSIONS The morphology of single unipolar electrograms during AF reflects the occurrence of various specific patterns of conduction. This might be used to differentiate between different types of AF and to identify regions with structural conduction disturbances involved in perpetuation of chronic AF.

Effects of Atrial Dilatation on Refractory Period and Vulnerability to Atrial Fibrillation in the Isolated Langendorff-Perfused Rabbit Heart

BACKGROUND Atrial fibrillation (AF) is frequently observed under conditions that are associated with atrial dilatation. The aim of this study was to investigate the effects of atrial dilatation on the substrate of AF. METHODS AND RESULTS In 15 Langendorff-perfused rabbit hearts, the interatrial septum was perforated, and after occlusion of the caval and pulmonary veins, biatrial pressure was increased by raising the level of an outflow cannula in the pulmonary artery. Right and left atrial effective refractory periods (AERPs), monophasic action potentials (MAPs), and inducibility of AF by single premature stimuli were measured as a function of atrial pressure. Increasing the atrial pressure from 0.5+/-0.7 to 16.2+/-2.2 cm H2O resulted in a progressive shortening of the right AERP from 82.2+/-9.8 to 48.0+/-5.1 ms. In the left atrium, an increase in pressure up to 7.4+/-0.3 cm H2O had no effect on the AERP. At higher pressures, however, the left AERP also shortened, from 67.5+/-7.5 to 49.3+/-2.0 ms. The duration of MAPs also decreased by an increase in atrial pressure, showing a high correlation with the shortening in AERP (r=.94, P<.01). All these changes were completely reversible within 3 minutes after release of the atrial stretch. Dilatation of the atria was a major determinant for the vulnerability to AF. The inducibility of AF increased from 0% at low pressures to 100% when the atrial pressure was >10 cm H2O. Release of the atrial wall stress resulted in prompt cardioversion of AF. The increased vulnerability for AF was highly correlated with the shortening in AERP (logistic regression r=.97). No correlation was found with the spatial dispersion between right and left AERPs. CONCLUSIONS Increased atrial pressure in the isolated rabbit heart resulted in a significant increase in vulnerability to AF that was closely correlated to shortening of the AERP. These changes were completely reversible within 3 minutes after release of the atrial stretch, resulting in prompt termination of AF.

Electrical Remodeling due to Atrial Fibrillation in Chronically Instrumented Conscious Goats Roles of Neurohumoral Changes, Ischemia, Atrial Stretch, and High Rate of Electrical Activation

BACKGROUND Recently, we developed a goat model of chronic atrial fibrillation (AF). Due to AF, the atrial effective refractory period (AERP) shortened and its physiological rate adaptation inversed, whereas the rate and stability of AF increased. The goal of the present study was to evaluate the role of (1) the autonomic nervous system, (2) ischemia, (3) stretch, (4) atrial natriuretic factor (ANF), and (5) rapid atrial pacing in this process of electrical remodeling. METHODS AND RESULTS Twenty-five goats were chronically instrumented with multiple epicardial atrial electrodes. Infusion of atropine (1.0 mg/kg; n=6) or propranolol (0.6 mg/kg; n=6) did not abolish the AF-induced shortening of AERP or interval (AFI). Blockade of K+(ATP) channels by glibenclamide (10 micromol/kg; n=6) slightly increased the AFI from 95+/-4 to 101+/-5 ms, but AFI remained considerably shorter than during acute AF (145 ms). Glibenclamide had no significant effect on AERP after electrical cardioversion of AF (69+/-14 versus 75+/-15 ms). Volume loading by 0.5 to 1.0 L of Hemaccel (n=12) did not shorten AERP. The median plasma level of ANF increased from 42 to 99 pg/mL after 1 to 4 weeks of AF (n=6), but ANF infusion (0.1 to 3.1 microg/min, n=4) did not shorten AERP. Rapid atrial pacing (24 to 48 hours; n=10) progressively shortened AERP from 134+/-10 to 105+/-6 ms and inversed its physiological rate adaptation. CONCLUSIONS Electrical remodeling by AF is not mediated by changes in autonomic tone, ischemia, stretch, or ANF. The high rate of electrical activation itself provides the stimulus for the AF-induced changes in AERP.

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.

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.