Clinical Significance of Atrial Fibrillation in

Clinical Significance of Atrial Fibrillation in Hypertrophic Cardiomyopathy Iacopo Olivotto, MD*, Barry J. Maron, MD†, and Franco Cecchi, MD

Address * Cardiologia S. Luca, Azienda Ospedaliera Careggi, Via Jacopo Nardi 30, Florence, 50132, Italy. E-mail: [email protected] †

Minneapolis Heart Institute Foundation, 920 East 28th Street, Suite 40, Minneapolis, MN, 55407, USA. E-mail: [email protected]

Current Cardiology Reports 2001, 3:141–146 Current Science Inc. ISSN 1523–3782 Copyright © 2001 by Current Science Inc.

Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with hypertrophic cardiomyopathy (HCM), and it bears numerous pathophysiologic consequences that potentially affect patient outcome and symptoms. However, studies regarding the impact of AF on the long-term prognosis of HCM patients have been limited in number, with sometimes conflicting results. Recently, studies on community-based patient populations showed that AF is associated with long-term clinical deterioration, embolic complications, and increased cardiovascular mortality due to heart failure and stroke. The consequences of AF on the long-term prognosis of HCM patients are not uniformly unfavorable, however, and in about one third of patients the arrhythmia is compatible with an uneventful course.

Introduction Hypertrophic cardiomyopathy (HCM) was originally regarded as a rare disease characterized by a high risk of sudden death due to sustained ventricular arrhythmias occurring selectively in young patients [1–5]. More recently, however, studies on relatively unselected regional HCM populations have shown sudden death to be a less frequent occurrence, and HCM to be compatible with normal life expectancy [6,7••,8–10]. Nevertheless, during their lives, a substantial proportion of patients with HCM experience progressive clinical deterioration and heart failure, associated with increased morbidity and mortality [2,3,10,11•]. In this respect, clinical aspects of the disease previously underappreciated in the literature, including atrial fibrillation (AF), have recently been identified as important predictors of long-term outcome and deserve careful scrutiny [10,11•,12–23]. To date, published studies that specifically address the prognosis of HCM patients with AF and treatment strategies are limited and have reported conflicting results [10,11•,12–15].

Prevalence of Atrial Fibrillation in Hypertrophic Cardiomyopathy Populations Atrial fibrillation is relatively common in patients with HCM (Table 1; Fig. 1) [2,3,10,11•,12,13]. In two studies including almost 500 patients with HCM followed at our institutions for more than 9 years, AF was the most common major complication [10,11•]. When the two populations were analyzed together, AF was documented in 22% of patients, with an incidence of 2% new cases per year [24]. AF presented as paroxysmal in more than two thirds of patients (often leading to chronic AF), and as chronic in the remaining one third. Although prevalence increased markedly with age, AF was present in a substantial proportion of younger patients; mean age at onset of the arrhythmia was 54 years for paroxysmal and 57 years for chronic AF [24]. Thus, in the face of potentially normal life expectancy for HCM patients, the management of AF and its complications represents a major challenge in younger patients with this disease.

Predisposing Factors and Potential Arrhythmogenic Triggers The chain of pathophysiologic events leading from a genetic mutation to the phenotypic expression of HCM, including ventricular and supraventricular arrhythmias, is incompletely resolved. However, different mechanisms can be postulated that potentially predispose to (or trigger) AF, each probably contributing to variable degrees in the single patient (Fig. 2). 1. Progressive left atrial dilatation associated with diastolic dysfunction [25–28], which in its most dramatic expression evolves toward a pathophysiologic pattern similar to that observed in restrictive cardiomyopathies, or with progressive left ventricular systolic dysfunction, dilation, and wall thinning in patients evolving toward the end-stage phase [29]. 2. Left atrial stretch and dilatation associated with moderate-to-severe mitral regurgitation, usually in the context of outflow obstruction and systolic anterior movement of the mitral valve, but occasionally due to primary structural mitral valve abnormalities [30–32]. In our experience, however, severe mitral regurgitation is present only in about 15% of patients with AF. 3. Hemodynamic alterations related to specific genetic defects, as have been proposed to explain the increased occurrence of AF in a form of familial HCM due to a particular b-myosin heavy chain mutation [33•].

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Table 1. Prevalence of atrial fibrillation in hypertrophic cardiomyopathy populations Study Glancy et al. [13] Savage et al. [49] McKenna et al. [50] Cecchi et al. [10] Maron et al. [11•] Olivotto et al. [24]

Patients, n 167 100 86 202 277 480

Prevalence of atrial fibrillation, %

Follow-up, y

10 12 14 28 18 22

3 — 2.6 10.1 8.1 9.1 Figure 1. Prevalence of arrhythmias documented by 12-lead echocardiography (ECG) or ambulatory (Holter) ECG in 202 consecutive patients with hypertrophic cardiomyopathy followed at a communitybased institution in Florence, Italy for an average of over 10 years. A-V—atrioventricular; S-A—sino-atrial; VF—ventricular fibrillation; VT—ventricular tachycardia. (Adapted from Cecchi et al. [10].)

4. Prolongation and nonuniformity of left atrial potential propagation, presumably reflecting an atrial myopathy. Such electric instability is relatively independent of atrial dimensions and may lead to an intrinsic propensity of the atria to fibrillate even in the absence of dilatation, as has been suggested by a study employing high-definition signal-averaged electrocardiography (ECG) [34]. It is possible to speculate that the degree of atrial myopathy and atrial potential dispersion may vary based on the underlying genetic substrate, with certain mutations proving significantly more profibrillatory than others [33•]. 5. Myocardial ischemia and autonomic dysfunction, both of which have been documented in HCM patients [35–38], may represent important factors triggering AF in predisposed patients [39•]. In clinical practice, several predictors of AF have been identified, such as increased age and left atrial dimension, and functional limitation due to congestive symptoms. Among these, left atrial dilatation has a particularly strong

independent predictive value for AF [24,28]. Conversely, other features such as the degree of left ventricular thickness and the presence of basal outflow obstruction do not appear to be associated with increased risk of AF [24,28]. In the routine outpatient assessment of HCM patients, serial left atrial dimension evaluations can be useful in association with P-wave duration on the signal-averaged ECG and presence and frequency of nonsustained supraventricular tachycardia on the 24-hour ambulatory ECG. The combination of these three noninvasive parameters (left atrial dimension, P-wave duration, and supraventricular arrhythmias on Holter ECG) may allow the identification of patients at higher risk of developing AF with sufficient accuracy [34].

Pathophysiologic Consequences The onset of AF brings about two important consequences, such as the loss of atrial systole and a rapid increase in the mean ventricular rate; both these effects interact synergisti-

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Figure 2. Arrhythmogenic substrates and potential triggers for atrial fibrillation in hypertrophic cardiomyopathy (HCM). Hypothetical sequence of events leading from a primary genetic mutation to the development of atrial fibrillation via multiple pathophysiologic processes and abnormalities known to occur in HCM. LV—left ventricular; LVOT—left ventricular outflow tract.

cally to further impair an already abnormal left ventricular filling pattern (Fig. 3). Consequently, in the acute phase immediately following acute onset, AF can cause a sudden fall in cardiac output and subsequent dramatic hemodynamic and clinical deterioration in HCM patients [13], leading to pulmonary edema, myocardial ischemia, or syncope [13,16,23]. In predisposed patients, this chain of events has been shown to elicit malignant arrhythmias and occasionally even lead to sudden death [16,19,40]. In 1986, Stafford et al. [16] described the case of an adolescent boy who survived cardiac arrest with documented ventricular fibrillation. During a subsequent electrophysiologic study, AF with rapid ventricular response was induced, which elicited signs of myocardial ischemia on the ECG and rapidly degenerated into ventricular fibrillation [16]. A potential association between AF and sudden death is also suggested by the observation, in one study, that about 20% of those HCM patients who survived a documented cardiac arrest showed supraventricular arrhythmias, including AF, at the onset of symptoms preceding the collapse [40]. Nevertheless, in the majority of patients with HCM, AF is not associated with dramatic clinical events during the acute phase. However, in the long term, the arrhythmia has a marked tendency to recur and eventually become chronic. The Framingham Study has recently demonstrated that, in the general population, AF is associated with a 1.5 to 1.9 relative risk for all-cause mortality after correcting for variables such as age, hypertension, diabetes, and concomitant cardiovascular diseases [41••]. Multivariate analysis suggested that excess mortality was directly attributable to the arrhythmia [39•,41••], and that AF was not an innocent marker of associated cardiac events. The pathophysiologic mechanisms by which recurrent and chronic AF may affect long-term clinical outcome of HCM

patients are unresolved and require further investigation. However, a disproportionate increase in mean ventricular rate and reduced cardiac output on effort, recurrent myocardial ischemia, and the well-documented risk of thromboembolic complications associated with AF are likely to play an important role (Fig. 3) [16–24].

Effects on Cardiovascular Mortality Based on early clinical studies, AF has been generally reported as a particularly adverse occurrence in HCM, with respect to increased risk for both cardiovascular mortality and disease-related complications [10–13,16–24]. However, much of the interest in HCM has focused on left ventricular outflow obstruction and sudden death risk factors in young patients [1–3]. Therefore, studies that have specifically addressed the prognosis of patients with HCM and AF are limited in number and have produced conflicting results [10,11•,13–15]. The initial report in this regard found no difference in survival between patients with and without AF, although this arrhythmia was associated with clinical impairment and thromboembolic complications [14]. This study, however, was based on selected patients followed at a tertiary referral center [42]; thus, owing to referral and patient selection bias, it is possible that other risk factors may have played a more prominent role than AF in determining clinical outcome. Of note, the group of HCM patients in sinus rhythm used as controls in this study showed a much low survival rate (82% and 41% at 10 and 20 years, respectively) than, for example, patients in sinus rhythm from community-based hospital populations [10,11•]. This fact may well have concealed an adverse effect of AF on long-term outcome when the two groups with and without AF were compared [14].

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Hypertrophic Cardiomyopathy Figure 3. Acute and chronic pathophysiologic consequences of atrial fibrillation in hypertrophic cardiomyopathy patients. LV—left ventricular.

Preliminary data addressing the impact of AF on the outcome of an unselected HCM cohort identify AF as an important predictor of adverse outcome for HCM patients [24]. Among 480 patients with HCM followed for an average of 9 years, AF was associated with an almost fourfold increase in cardiovascular mortality, which was due to a significant increase in heart failure- and stroke-related death. Conversely, AF did not seem to increase the risk of sudden and unexpected death in HCM patients [7••,24]. The impact of AF on cardiovascular mortality was independent of other important clinical variables such as age and New York Heart Association (NYHA) class, and increased progressively during follow-up [24]. Of note, however, the impact of AF was very heterogeneous in individual patients, and more than one third of the patients with the arrhythmia were free from major cardiovascular events and limiting symptoms at the end of the follow-up period [24].

Cardioembolic Complications Cardioembolic stroke and other embolic events are a known complication in HCM patients [14,18,20–22] and have been shown to cause substantial disability and death in these patients [7••]. The association of embolic complications with AF is strong. Among 900 patients assembled from four regional cohorts, 51 (6%) experienced cerebral stroke or other systemic thromboemboli over an average follow-up period of 7 ± 7 years (annual incidence 0.8%). About 90% of the patients with thromboembolism had a history of paroxysmal or chronic atrial fibrillation [43]. In another study, HCM patients with documented AF had an eightfold increase in embolic complications as compared with those in sinus rhythm [24]. Similar to the case in patients with heart failure or coronary artery disease [44,45], there was no significant difference in the occurrence of embolic events between the paroxysmal and the chronic forms of the arrhythmia [24].

Effects on Clinical Status and Functional Limitation Acute There is great individual variability with regard to clinical consequences associated with acute onset of AF in HCM, ranging from a total lack of symptoms to syncope or pulmonary edema [14]. On average, however, patients with AF show marked functional impairment as compared with those in sinus rhythm during the acute phase of the arrhythmia [13,14,24]. Such clinical deterioration is well accounted for by the pathophysiologic consequences of AF, including loss of atrial systole, increased ventricular rate, and reduced cardiac output, as previously described (Fig. 3). Thus, it is possible that the pre-existing degree of left ventricular diastolic impairment may be the most critical determinant of the acute individual patient response to onset of AF [25–27]. Of note, a pre-existing impairment in ejection fraction and peak ejection rate as assessed by radionuclide scan may also be predictive of acute clinical deterioration during AF [14]; thus, baseline left ventricular systolic function may also influence the individual acute response to AF. Chronic The deleterious effects of AF on the clinical status of HCM patients, however, are not confined to the acute phase at the onset of the arrhythmia. Over the long term, patients with AF experience significant symptomatic impairment and functional limitation as compared with patients remaining in sinus rhythm, even with optimal management of rhythm and control of ventricular rate [14,24]. Indeed, during a 9-year follow-up period, patients with AF had an almost threefold increase in the likelihood of being in NYHA class III-IV at the end of the follow-up period, as compared with those who remained in sinus rhythm [24].

Clinical Significance of Atrial Fibrillation in Hypertrophic Cardiomyopathy • Olivotto et al.

Clinical Heterogeneity of Atrial Fibrillation in Hypertrophic Cardiomyopathy Patients It is important to underline that the unfavorable consequences of AF on the long-term prognosis of HCM patients as shown in group patient analyses are not invariable, but rather show great heterogeneity among individual patients. Indeed, although in most HCM patients AF is associated with adverse outcome in terms of increased HCM-related mortality, symptoms, and acute cardiovascular events, there is a sizeable subgroup in whom the clinical course seems largely unaffected by AF. In our experience, 35% of patients with AF were alive, free of thromboembolic complications, and with no or only mild symptoms (NYHA class I-II) at the end of follow-up [24]. Of note, AF patients with benign outcome had a similar age and follow-up duration compared with those with adverse prognosis, but included a much lower proportion of patients with chronic AF at the end of followup (38% vs 60%, P < 0.05) [24]. These preliminary observations suggest that preventing or delaying the development of chronic AF may be important in improving the outcome of HCM patients.

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Finally, both paroxysmal and chronic AF represent clear indications for oral anticoagulation in HCM patients, as a preventive measure for thromboembolic complications [2,7,10,18,20–22,39•]. Among 190 patients with a history of chro ni c or parox ysmal AF foll owed at four institutions in Italy and the United States [43], the cumulative incidence of systemic thromboembolism among nonanticoagulated AF patients was twice that of those AF patients receiving warfarin (31% vs 15%; P = 0.01).

Conclusions Atrial fibrillation is the most common sustained arrhythmia observed in the clinical course of HCM patients and represents a key element associated with disease progression and adverse outcome in these patients, by virtue of its hemodynamic consequences and the strong association with embolic complications including stroke. However, the acute and long-term effects of AF in the individual HCM patient are variable and not uniformly unfavorable. Thus, further dedicated studies are required to identify patients at risk of developing AF and its complications, and to develop precise preventive and therapeutic antiarrhythmic strategies.

Treatment Options At present, current treatment strategies are based on the experience with AF in HCM but are also often inferred from patients with other cardiac conditions or in individuals with AF unassociated with structural heart disease [39]. It is reasonable to suggest that an aggressive approach to recent-onset AF with cardioversion in conjunction with prophylactic antiarrhythmic treatment may be beneficial in terms of disease progression and complications, over conservative strategies based on ventricular rate control. In one retrospective study, HCM patients with paroxysmal AF and chronic administration of low-dose amiodarone (usually 200 mg/d) required fewer cardioversion attempts, less often experienced thromboembolic events, and remained in sinus rhythm longer than those who received conventional therapy (including digoxin, verapamil, badrenergic blocking agents, and class I antiarrhythmic drugs) [14]. Other studies have reported the safety of lowdose amiodarone treatment and its potential protective effect in HCM patients with ventricular arrhythmias [46,47]. Sotalol is possibly a promising alternative option to amiodarone and has often been employed empirically, although further evidence is required regarding its longterm efficacy in HCM patients [48]. New treatment modalities based on devices such as the implantable atrial defibrillator are untested in HCM [39•]. In patients with chronic AF, rate control may be achieved by the use of calcium-channel blockers, b-blockers, or digitalis, either alone or in combination [10,14]. When persistently elevated ventricular rates are associated with functional limitation, consideration should be given to atrioventricular node ablation with rate-responsive pacemaker implantation [39•].

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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