Atrial fibrillation: the remodelling phenomenon

Transcription

1 European Heart Journal Supplements (2003) 5 (Supplement H), H1 H7 Atrial fibrillation: the phenomenon G.L. Botto, M. Luzi and A. Sagone Department of Cardiology, St Anna Hospital, Como, Italy KEYWORDS Antiarrhythmic drugs; Atrial fibrillation; Atrial ; Cardioversion of atrial fibrillation; Electrophysiological Introduction Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. 1 Epidemiological studies have shown that the natural history of AF tends to worsen with time. Paroxysmal AF can progress to persistent AF, 2 and pharmacological and electrical cardioversion (CV) achieve higher rates of success when AF is of short duration. 3,4 Furthermore, the likelihood of the recurrence of AF decreases a few weeks after CV. 5 These findings suggest that AF is a progressive disease and may be self-perpetuating. The Correspondence: Giovanni Luca Botto, MD, FESC, Divisione di Cardiologia, Ospedale Sant Anna, Via Napoleona 60, 22100, Como, Italy Atrial fibrillation (AF) is a progressive disease and may be self-sustaining. The processes that lead to the worsening of AF over time include electrical, contractile, neurohormonal, macroanatomical and ultrastructural changes, and these may occur over different periods of time. The term electrical indicates long-term changes in atrial electrophysiological parameters that result from prolonged changes in atrial rate. The mechanism of tachycardia-induced is associated with altered ion channel function, the most important of which is a reduction in L-type calcium current, which is responsible for a reduction in the duration of the action potential, atrial refractory period and refractory period adaptation to rate. Recovery from atrial electrical occurs within a few days, even in cases of very long-lasting AF, although clinically the atria remain vulnerable for weeks after cardioversion. A so-called second factor may play a role in this prolonged vulnerability to recurrent AF. In animals tachycardia-induced electrophysiological modification is reduced by verapamil and angiotensin II receptor antagonists, but the effect of these drugs in preventing atrial electrical in humans is disputed. Despite these findings, there is growing clinical evidence that verapamil and angiotensin II receptor antagonists could reduce the recurrence of AF after cardioversion. In this report current knowledge of the mechanisms and clinical consequences of AF-induced electrical is discussed The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved processes that lead to worsening of AF with time have been defined as domestication of AF. 6 Therefore, this definition should include electrical, contractile, neurohormonal, macroanatomical and ultrastructural changes. The time course of these alterations after the onset of AF differs profoundly. In this report studies on AF-induced electrophysiological are discussed. Time course and definition of electrical Although the term electrical is now frequently used, it is usually not defined very well. The term was first introduced by Allessie and coworkers 6 to indicate long-term changes in the X/03/0H $35.00/ The European Society of Cardiology, Published by Elsevier Science Ltd. All rights reserved.

2 H2 G.L. Botto et al. Table 1 Time domains in adaptation to rate Time domains Process Period of time Effects Short term Metabolic Seconds to minutes Ion concentration Ion pump activities Phosphorylation of ion channel Moderate term Electrical Hours to days Altered gene expression Synthesis/assembly Long term Contractile Weeks Hibernation Very long term Anatomical Months to years Irreversible structural damage (fibrosis, fatty degeneration, etc.) (Modified from Allessie. 7 ) refractory period resulting from prolonged changes in atrial rate. To distinguish between the different mechanisms, with their different time courses, it is important to define clearly the time domain of the adaptation process. Allessie 7 proposed that four time domains be distinguished for the different adaptation processes that occur in response to change in heart rate (Table 1). 7 The metabolic adaptation processes are operative during the early time domain and quickly lead to a new steady state in intracellular ion concentration, activity of ion pumps and phosphorylation of ion channels. These adaptation processes are the best studied mechanisms of rate adaptation, 8 but they should not be confused with the process of electrical. Only if the heart remains altered for hours or days do process other than metabolic adaptation come into play. Thus, the term should not be used for the processes that are associated with shortterm changes in the myocardium. Animal studies on electrical Animal studies have been conducted to investigate how atrial rate impacts on the electrophysiological properties of the atrium. Prolonged high-rate atrial pacing in goats 6 and dogs 9 caused reversible electrophysiological and structural changes in the atria. During control conditions, however, no sustained AF could be induced; after rapid pacing in these animals for several days, AF had become sustained. In the normal goat, Wijffels et al. 6 demonstrated that electrically induced AF lasted only for a short time and ceased promptly within a few seconds, whereas pacing-induced AF for up to 2 weeks induced a shortening of the atrial refractory period and a reverse adaptation of refractoriness to rate, leading to an increase in inducibility and stability of the arrhythmia with time (Fig. 1). 6 The reduction in refractoriness results in a shorter wavelength of the travelling impulses, which is a determinant for the induction and maintenance of these re-entrant arrhythmias; the shorter the wavelength, the easier that AF was induced and maintained. 10 Moreover, reverse adaptation to rate (in which the atrial refractory period is shorter at lower rates and longer at higher rates) could have great importance in AF induction and recurrence, because the short refractory period during sinus rhythm increases the ability of premature beats to induce AF. At the same time as the study by Wijffels et al. in goats, Morillo et al. 9 conducted a similar study in mongrel dogs. At baseline sustained AF could not be induced in any dog, but after 6 weeks of rapid atrial pacing at 400 beats/minute, programmed atrial stimulation induced AF in 50% of the animals. Marked bi-atrial enlargement was documented by echocardiography, and the atrial refractory period was significantly reduced. Moreover, atrial conduction velocity was also decreased, as indicated by an increase in duration of the P wave; this decreases the wavelength further and stabilizes AF. 10 These data suggest that the cascade of cause and effect leading to chronic AF starts with a progressive shortening of the atrial refractory period, leading to a more stable arrhythmia and an increase in the duration of AF. This in turn shortens the refractory period further, which prolongs the duration of AF again. This vicious cycle continues until interruptions in AF no longer occur. 7 The results of these experimental studies led to the concept that AF begets AF 6 and provide a good explanation for the observed domestication of AF. Human atrial electrical Clinically, AF tends to worsen with time; chronic AF is often preceded by a phase during which fibrillation is still paroxysmal, 2 and it has also been shown that pharmacological or electrical CV

3 Atrial H3 Fig. 1 Demonstration of the self-maintaining effect of atrial fibrillation (AF). Shown is the duration of AF, induced in chronically instrumented goats by a fibrillation pacemaker that automatically restarted the arrhythmia by a burst of stimuli every time sinus rhythm was detected, after AF had been maintained for the duration indicated to the left of each panel. (Reproduced with permission from Wijffels et al. 6 ) of AF becomes more difficult when the arrhythmia has continued for a longer period of time. 3,4 This suggests that AF may promote itself in humans by a process of electrical and/or anatomical. However, it is extremely difficult to study electrical in humans. Despite these limitations, all studies concerning the presence of electrical in humans have shown a shortening of the atrial refractory period or the duration of the monophasic action potential after CV of persistent AF, whereas conflicting results have been reported regarding adaptation to the rate of refractoriness. As early as the 1980s, Attuel et al. 11 established that sustained atrial tachyarrhythmias were correlated with short refractory periods and failure of the atrial refractory period to adapt to changes in pacing rate. However, the best available evidence for AF-induced in humans was provided more recently by Franz et al. 12 who, using monophasic action potentials, showed that patients with chronic AF or flutter that had been cardioverted to sinus rhythm had flattened rate adaptation in addition to shortening refractoriness early after conversion. Despite this, these data do not prove that AF produces shortening of refractoriness because short refractoriness might have been present before the onset of AF and might have been a cause of the arrhythmia. In patients with chronic AF, Yu et al. 13 showed that refractoriness increased significantly within 3 days after CV (Fig. 2). In addition, rate adaptation that diminished immediately after CV was restored only in the left atrium and not in the right atrial appendage, suggesting that, soon after CV, increased refractory period dispersion may play a role in the reinduction of AF. In contrast to this are the findings reported by Pandozi et al., 14 who studied atrial refractoriness after CV and repeated the measurements after 4 weeks of maintained sinus rhythm. The increase in atrial refractoriness was rather modest (about 10%), and they found a rather normal rate adaptation after CV. In addition, dispersion of refractoriness was modest. Ion channels and electrical The most important feature of electrophysiological is represented by the shortening of the duration of the action potential and refractory period. It is commonly thought that even minutes of rapid atrial rates can result in intracellular calcium overload, which decreases the L-type calcium current (I CaL ) because of a decreased trans-sarcolemmal calcium gradient and calcium-

4 H4 (a) ERP (ms) (b) ERP (ms) PCL: 300 ms Control D0 D1 D2 D3 D4 PCL: 700 ms Time (days) RAA DCS Control D0 D1 D2 D3 D4 Time (days) RAA DCS Fig. 2 Temporal changes in effective refractory periods (ERP) of the right atrial appendage (RAA ) and distal coronary sinus (DCS) at a pacing cycle length (PCL) of (a) 300 ms and (b) 700 ms, after conversion to sinus rhythm of chronic (>6 months) atrial fibrillation in humans. The ERPS both in the RAA and in the DCS gradually increase and reach a stable level on the third day after cardioversion. (Reproduced with permission from Yu et al. 13 ) induced inactivation of the L-type calcium channel, with consequent reduction in the I CaL. 15 This phenomenon, termed pseudo-, shortens the refractory period. In cases of persistent high atrial rate of longer duration, a subsequent downregulation in L-type calcium channels and reduction in I CaL will maintain the short atrial refractory period. 16 In atrial tissue (obtained during cardiac surgery) from patients with long-standing AF, a similar reduction in I CaL and inactivation of calcium channels was demonstrated. 17 Animal and human studies have shown that many other ionic currents are unchanged. 16 Only the transient outward current carried by potassium and the sustained component of the ultrarapid delayed rectifier potassium current were modified by rapid pacing but, surprisingly, they appear to be reduced, rather than elevated as expected. 16 The results of these studies suggest that the reduction in I CaL is likely to play a central role in electrophysiological changes caused by rapid atrial rates, whereas modification of other currents are probably of much less importance, at least at the atrial level. 18 The changes in ionic currents are the result of molecular modifications involving ion channel proteins in cardiac sarcolemma. The mechanisms of modification of ion channel density and function are induced by altered gene expression, and take place over hours or days, last for a long period of time and represent the basis of true electrophysiological. 15,18 Figure 3 illustrates the way in which rapid atrial activation results in modification of the calcium current. Recovery from atrial electrical G.L. Botto et al. In their study in goats, Wijffels et al. 6 demonstrated that after CV of persistent AF, which had lasted 2 4 weeks, the atrial refractory period and AF vulnerability normalized within 1 week. After episodes of AF that last a few minutes to several hours, the duration of recovery of the atrial refractory period in animals and humans occurs within 3 30 min. However, in cases in which the duration of AF ranges from 1 day to 6 years, recovery takes place within a few days. 19 Apparently, the atrial cell can upregulate its downregulated ion channels quite rapidly after restoration of sinus rhythm. In contrast, the daily incidence of recurrence of AF suggests that the atria remain highly vulnerable during the first 2 weeks after CV. It is probable that a so-called second factor of electrical may play a role in this prolonged vulnerability to recurrent AF. 19,20 Preventing atrial electrical with drugs In patients with AF long-term maintenance of sinus rhythm after successful CV is difficult, mainly because of a high rate of recurrence of AF within the first week after CV. 5 The increased vulnerability to recurrence of AF is probably due to AF-induced changes in the electrophysiological properties of the atria. 6 Although the mechanisms that underlie AF-induced electrical

5 Atrial H5 Sinus rhythm (60/min) AF (600/min) + Number of AP s/unit time increased 10-fold Fig. 3 The way in which high atrial rate results in both rapid (within minutes) functional reductions in L-type calcium current (I CaL ) and slower (over days) genetically determined changes. Atrial tachycardia causes increased intracellular calcium loading, which is limited by the rapid and slower I CaL -reducing mechanisms, paying the price in reduction in action potential (AP) duration (APD) and in adaptation of ADP to rate. This in turn leads to a more stable arrhythmia, and the duration of atrial fibrillation (AF) increases. (Reproduced with permission from Nattel. 18 ) remain incompletely understood, there are indications that an increase in trans-sarcolemmal calcium influx may play an important role in the intracellular pathways that are involved in the process of tachycardia-induced electrophysiological. Animal experiments showed that infusion of verapamil during rapid atrial pacing 21 or short episodes of artificially induced AF 22 significantly reduced the time course of electrical. In contrast, digoxin (which promotes calcium overload) may aggravate this phenomenon. 23 It is important to note that these findings were obtained mainly in situations in which true electrical was probably not already present. Different results were obtained in experimental and in human studies when verapamil was given after the onset of persistent AF (which was mainly of longer duration) or before long-lasting (>24 h) atrial pacing. 15 Based on these findings, it is conceivable that verapamil could have different effects on high-rate activated cells in relation to the timing of administration, the duration of high atrial rate and the presence of other adjunctive factors (second factor). Despite the results from studies conducted in humans regarding the effects of treatment with verapamil on atrial refractoriness, there is growing clinical evidence that this drug could reduce the recurrence of AF after successful CV. In a retrospective study conducted in 61 patients cardioverted for chronic AF, Tieleman More depolarized time/cardiac cycle (minutes) Voltagedependent Greater Ca2+ load (minutes)?? ICaL inactivation [Ca 2+ ] i -dependent (days)? Decreased transcription of 1c -subunit I CaL I CaL mrna encoding 1c -subunit of L-type Ca 2+ channel APD, APD adaptation I CaL to rate Increased vulnerability to AF induction and maintenance et al. 5 reported that there was a peak incidence in relapse of AF during the first 5 days after CV, suggesting a temporary vulnerable electrophysiological state of the atria. Use of intracellular calcium lowering medication, including verapamil, diltiazem, dihydropyridines and betablockers, appeared to reduce the recurrence of the arrhythmia. De Simone et al. 24 first demonstrated, using a prospective randomized approach, the beneficial effect of oral pre-treatment with verapamil in combination with an antiarrhythmic drug in reducing the incidence of early recurrence of AF after external or internal electrical CV. Those investigators found a higher incidence of recurrence of AF in patients who received propafenone alone, before electrical CV, as compared with those who received propafenone in combination with verapamil. This suggests that intracellular calcium lowering drugs may reduce electrical, which consequently leads to a more rapid recovery after CV. The lack of benefit from long-term treatment with verapamil observed in that study strongly supports the hypothesis that recovery from electrical occurs in a few days and that, after this period, intracellular calcium lowering drugs may play only a marginal role in preventing the recurrence of arrhythmia. The preliminary results of the Verapamil and Early Recurrence of Atrial Fibrillation (VERAF) study clearly demonstrated how standalone

6 H6 Incidence (% of patients) P < P < Fig. 4 Data from the VERAF study 26 : the effect of administration of standalone verapamil (240 mg/day) 1 month before and 1 month after cardioversion (CV) of persistent atrial fibrillation (AF) as compared with standard therapy on early recurrence of AF (ERAF, within 7 days) or late recurrence of AF (LRAF, within 8 30 days), and consequent maintenance of sinus rhythm 1 month after CV. No additional antiarrhythmic drugs were given during the study. Verapamil is significantly more effective than standard therapy in preventing ERAF after successful electrical CV of persistent AF. verapamil given before electrical CV as compared with standard therapy (in which no adjunctive antiarrhythmic drugs were used) is highly effective in reducing the incidence of so-called early (within 1 week) recurrence of AF 25 in successfully cardioverted patients with persistent AF (Fig. 4) and, in particular, in reducing immediate (within 1 h) recurrence. 26 Furthermore, the mean shortest coupling interval of premature atrial beats recorded after CV was increased from 377 ± 147 ms to 507 ± 116 ms with verapamil, whereas no differences with respect to the density of atrial premature beats soon after CV were detected between patients who received verapamil and those who did not. 27 The clinical effect of the drug was not related to a reduction in the trigger, and thus it is possible that the mechanisms by which verapamil acts in this setting may involve the modification of remodelled electrophysiological parameters. In a very similar study, 28 verapamil was administered 4 weeks before electrical CV and subsequently continued for 1 month after restoration of sinus rhythm, and this was compared with digoxin treatment. In contrast to the results from the VERAF study, this study showed no beneficial effects of verapamil in preventing early recurrence of AF after CV. However, the study might have lacked statistical power (only 43 patients were included) to demonstrate differences regarding any favourable effect of the drug. The differences between the results of recent clinical trials and electrophysiological studies conducted in humans may also be explained, ERAF LRAF Sinus rhythm Verapamil Standard however, by the fact that verapamil could theoretically exert other favourable effects in patients with AF. Perhaps it acts to reduce the structural and ultrastructural cellular changes 9,21 related to the development of an atrial myopathy (structural ). Not only calcium lowering drugs but also other classes of drug may have therapeutic applications in modifying the process. A recent study conducted in animals 29 demonstrated for the first time that angiotensin II contributes to atrial electrical. In that study the shortening of the atrial refractory period during rapid pacing was prevented by treatment with candesartan or captopril, but it was increased by angiotensin II. Another study demonstrated the efficacy of losartan in regressing myocardial fibrosis in hypertensive cardiomyopathy. 30 The results of the first prospective and randomized study conducted in humans 31 showed that adding the angiotensin II receptor antagonist irbesartan to amiodarone is more effective than amiodarone alone in maintaining sinus rhythm after CV of persistent AF, suggesting that angiotensin II receptor antagonists could have a role to play in preventing atrial. Irbesartan reduced the immediate recurrence of AF (no patient had recurrence of AF over a period of 1 h after CV) and the subacute recurrence of AF during the first few weeks. This class of drug may prevent or moderate atrial not only by modifying electrical parameters but also by decreasing atrial stretch or preventing atrial fibrosis (a possible second factor). Conclusion G.L. Botto et al. Taken together, the results described above indicate that, to date, only limited and partially conflicting data are available on electrical, and the concept derived from the above studies that AF begets AF remains to be proven in humans. Moreover, the question of the extent to which the progressive nature of AF can be delayed or prevented by prompt CV of AF remains unanswered. The clinical information from these studies reveals that both calcium channel blockers and angiotensin II receptor antagonists may prevent or diminish the negative effects of prolonged AF on the success rate of conversion and maintenance of sinus rhythm. Further randomized prospective studies are needed to establish the actual role of verapamil and angiotensin II receptor antagonists in the prevention of recurrence of AF, mainly with

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