Atrial fibrillation (AF) is the most common arrhythmia in patients with hypertrophic cardiomyopathy (HCM), with a reported prevalence of AF in HCM of about 25 %.1 Patients with AF in HCM tend to be more symptomatic and have an increased stroke risk compared with patients without HCM.2 While the occurrence and treatment of (symptomatic) AF in HCM have been extensively studied, there is little data on the significance, prevalence, and management of subclinical AF in HCM. Detection of subclinical AF in this population may be important for the prevention and treatment of thromboembolic complications with anticoagulation, thus improving quality of life.3
Subclinical Atrial Fibrillation
The term subclinical or ’silent’ AF is defined as “the occurrence and detection of subclinical asymptomatic episodes of paroxysmal atrial fibrillation.”4 Greater than two million men and women have AF in the United States,5 albeit a recognized difficulty in assessment of true prevalence of subclinical AF. Symptomatic AF more often presents with hemodynamic compromise, while subclinical AF may manifest with more deleterious manifestations, i.e. acute ischemic stroke.
The Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) reported that 10 % of patients, out of 2,850 subjects who were older than 65 years of age with pacemakers, had subclinical AF.6 In addition, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study reported that 12 % of the study population was asymptomatic at baseline.7 It was also noted in the AFFIRM study that asymptomatic AF was found more commonly in men compared with women. Patients with asymptomatic AF had a lower incidence of congestive heart failure and coronary artery disease, albeit a higher incidence of cerebrovascular events. These patients also had a longer duration of AF, lower heart rate, and better left ventricular function.7 The ASSERT also showed that patients with asymptomatic AF had a 2.5-fold higher risk of developing ischemic stroke or systemic embolism.6 Clinical risk factors that were predictors of subclinical AF were age >75 years, cryptogenic stroke, diabetes mellitus, hypertensive heart disease, implantable cardiac defibrillator or pacemaker, ischemic stroke, mitral valve disease, neurological disease, obesity, obstructive sleep apnea, and prior radiofrequency catheter ablation of AF.4
Atrial Fibrillation in Hypertrophic Cardiomyopathy
In HCM patients, AF is four times more common than in the general population, and the age of onset is 10 years earlier.8 Factors predisposing to the development of AF in HCM include increase in age, decrease in left atrial function and increase in left atrial volume.9 Left atrial remodeling associated with HCM is a key pathophysiological mechanism for development of AF in this population. These patients also tend to be more symptomatic compared with patients without HCM. A plausible explanation may be the loss of the atrial kick, which plays an important role in patients with diastolic dysfunction.1,2,10,11However, left atrial size can be normal in HCM patients with AF, precluding evaluation for initiation of anticoagulation for prevention of thromboembolic complications based on left atrial size alone.10
In a cohort study by Kalra et al. that included 288 HCM patients with implantable cardiac defibrillators (ICDs), 27 patients (9 %) had subclinical AF. Of these, six patients went on to develop symptomatic AF over the course of 12 months, and two patients had embolic stroke.3 This study underscores the significance of early identification of subclinical AF in patients with HCM for prevention of thromboembolic complications by initiation of oral anticoagulation. Another retrospective study in HCM patients with cardiac rhythm management devices by Wilke et al. demonstrated that more than 50 % of patients developed de novo, predominantly subclinical, AF.12
Diagnosis of Subclinical Atrial Fibrillation
Twelve-lead Electrocardiogram
Diagnosis of subclinical AF is often challenging as patients are asymptomatic and do not seek medical attention. An electrocardiogram (ECG) may often fail to detect subclinical AF if it occurs outside the monitoring period. Prolonged cardiac monitoring detects more cases of subclinical AF in the cryptogenic stroke population compared with that of a 24-hour Holter monitor.13 Some of the other parameters that may be used in diagnosing subclinical AF in a resting ECG include ’P-maximum’, which represents prolonged atrial conduction time, and ’P-wave dispersion’, which represents non-uniform atrial conductivity, a surrogate for underlying remodeling occurring in the atria in patients with AF. A P-maximum of at least 110 ms has a sensitivity of 88 % and specificity of 75 %, and P-wave dispersion of at least 40 ms has a sensitivity of 83 % and specificity of 85 % for AF. 14A corrected QT interval (QTc) threshold ≥438 ms has a sensitivity of 59.4 % and specificity of 83.7 % as a predictor of AF in patients presenting with ischemic stroke.15 Presence of frequent atrial premature beats has also been suggested as a marker for predisposition to AF.16 None of these parameters, however, have been evaluated for predicting AF episodes in patients with HCM.
Biomarkers
Molecular biomarkers may be used in identifying the presence of subclinical AF. Occasionally, troponin is increased in patients with AF.17 Inflammatory markers such as serum interleukin-18 and C-reactive protein have been found to be high in patients with asymptomatic AF.18,19 In addition, plasma von Willebrand factor, fibrinogen, and D-dimer are also elevated in patients with AF compared with their matched controls.20,21 However, the clinical utility of these biomarkers in evaluating HCM patients for the presence of subclinical AF in outpatient clinics is not known.
Echocardiography
It is known that increase in left atrial size increases the risk of newonset AF.22Echocardiographic findings in the AFFIRM trial showed that asymptomatic patients had slightly larger left atrial dimension (4.4 cm versus 4.3 cm; p=0.01), while the left ventricular function was normal in this subgroup.7 Transesophageal echocardiography studies have also demonstrated a reduced left atrial appendage peak velocity, and the presence of left atrial spontaneous echocardiographic contrast in this patient subset, reflecting left atrial stasis.23 Concomitant mitral valve disease is also associated with an increase in the incidence of AF.24
Management of Subclinical Atrial Fibrillation in Hypertrophic Cardiomyopathy
Once a diagnosis of subclinical AF is made in patients with HCM, management options to prevent thromboembolic complications come into question. In patients with asymptomatic AF with rapid ventricular response, electrical or pharmacological cardioversion may be offered. Low-dose amiodarone (class IIa) is considered the most effective regimen, its use remaining limited in the young adult population due to the side effect profile. 25,26 Alternatively, disopyramide (class IIa), sotalol, dofetilide, and dronaderone (class IIb) can also be utilized.26 Due to the enlarged left atrium, the potential for clot formation is considerably increased in patients with HCM, thus leading to increased risk of thromboembolic stroke compared with the general population, about 0.8 % per year.2Prophylactic anticoagulation with warfarin or non-vitamin K oral anticoagulants (i.e. dabigatran, rivaroxaban, apixaban, or edoxaban) in HCM patients with clinical or overt AF is a class I recommendation (level of evidence: C).26 However, whether this recommendation can be extrapolated to HCM patients with subclinical AF is currently unknown, and merits further study with prospective, long-term follow-up data on clinical outcomes. Also, the threshold of subclinical AF burden that favors a risk:benefit ratio toward long-term anticoagulation, and warrants initiation of long-term anticoagulation, requires more investigation. The CHADS-VASc score has not been validated for predicting thromboembolic risk from AF in HCM, and should not be used for risk stratification and decision-making with regard to initiation of anticoagulation.26 If a decision is made to initiate anticoagulation, the choice of the anticoagulant can be decided as per individual needs considering other comorbidities, and the overall bleeding risk.
Outcomes of Subclinical Atrial Fibrillation in Hypertrophic Cardiomyopathy
Currently, only one study has measured the burden of subclinical AF in HCM patients.3 In this study, out of the 288 HCM patients implanted with ICDs, 27 patients (9 %) were diagnosed with subclinical AF and 51 patients (18 %) were known to have diagnosed AF. In the subclinical AF group, two patients (7.4 %) had embolic strokes who were not on any anticoagulation, and six patients (22.0 %) developed paroxysmal symptoms of AF over the course of 12.1 ± 5.9 months. In the diagnosed AF group, five patients (9.8 %) had an embolic stroke over the same time period. There was no statistical difference in the incidence of embolic stroke between the subclinical AF group and the diagnosed AF group (1.00).3
Conclusion
Subclinical AF in HCM is an underdiagnosed clinical entity with equal risk for thromboembolic complications compared with HCM patients with known AF.3 The true prevalence of subclinical AF in HCM is currently unknown, warranting further study. Patients with HCM should be screened or monitored for episodes of subclinical AF for early identification and appropriate treatment strategy. All patients with HCM diagnosed with AF should be initiated on anticoagulation, thus preventing thromboembolic events and improving quality of life in these patients.