Arrhythmias in Fabry Cardiomyopathy

Abstract

Background:

Prior studies suggest that the incidence of ventricular arrhythmias is high in patients with Fabry cardiomyopathy. This study evaluated the incidence of significant arrhythmias in a series of patients with Fabry cardiomyopathy.

Hypothesis:

Arrhythmias are important causes of morbidity and mortality in Fabry Cardiomyopathy.

Methods:

This study was a retrospective chart review of 19 patients with known Fabry cardiomyopathy. Device interrogation reports were reviewed for those who had implantable devices. Electrocardiogram, Holter monitor, and event monitors were reviewed in those who did not have implantable devices.

Results:

Eighteen of nineteen patients were on enzyme replacement therapy (ERT). Nine (47%) out of 19 patients had implantable devices. Implant indications included symptomatic bradycardia, nonsustained ventricular tachycardia, conduction abnormalities, palpitations, and syncope. Mean follow‐up in the patients with devices was 50 ± 23 months. Two patients received implantable cardioverter‐defibrillator (ICD) shocks, 1 of which was inappropriate for atrial fibrillation. Patients were paced in the atrium 71% ± 37% of the time and paced in the ventricle 49% ± 52% of the time. Four patients with devices were paced more than 95% of the time. Patients with an ICD had lower heart rates prior to ICD implant than the group that did not have devices (60 ± 10 vs 78 ± 16, P = 0.03). Of the patients without devices, only 1 had sudden cardiac death. Patients with implanted devices had higher left ventricular (LV) mass indices compared to patients without implanted devices (136 ± 40 g/m2 vs 93 ± 19 g/m2, P = 0.008).

Conclusions:

Significant ventricular arrhythmias are uncommon in patients with Fabry cardiomyopathy on ERT, but utilization of pacing is high. Sudden cardiac death in Fabry cardiomyopathy may be related to bradycardia.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

Fabry disease is an X‐linked disorder caused by a deficiency in the lysosomal enzyme alpha‐galactosidase A (alpha‐Gal A).1 The enzyme deficiency leads to deposition of glycosphingolipids in a variety of tissues, which ultimately causes symptoms and/or dysfunction in multiple organ systems including the heart.2 Fabry disease is rare, with an estimated prevalence of 1 in 17,000 to 1 in 117,000 individuals.3, 4 Males with mutations generally develop clinical manifestations, whereas females may develop a variable degree of symptoms due to random X‐chromosome inactivation. The disease progresses slowly, with children and adolescents having neuropathic pain, angiokeratomas, dyshydrosis, and gastrointestinal symptoms. Young adults may have progression of previous symptoms, and may start developing proteinuria and edema. Adults develop renal failure, heart disease, and cerebrovascular accidents, which are important causes of premature death.5 Cardiac involvement is common and generally presents by the fourth decade of life.

Storage of globotriaosylceramide can occur in cardiomyocytes, conduction system cells, valvular fibroblasts, vascular smooth muscle, and endothelial cells.6 Abnormal storage can lead to energy starvation, as well as common cell signaling pathways that lead to fibrosis and myocyte hypertrophy. Clinical manifestations include chest pain, shortness of breath, palpitations, heart failure, syncope, and sudden cardiac death. Left ventricular hypertrophy is a prominent finding. Hypertrophy is typically symmetric, but asymmetric hypertrophy simulating hypertrophy accompanied by outflow tract obstruction can be seen in up to 5% of cases.7, 8 A registry of 2869 patients with Fabry disease showed a 5% incidence of major cardiovascular events during the natural history period, mainly heart failure and myocardial infarction.9 The pathophysiology of Fabry cardiomyopathy may differ in women vs men. Men generally have hypertrophy before they have scarring and loss of contractile function. In women, loss of myocardial function and development of fibrosis as measured by late gadolinium enhancement on magnetic resonance imaging do not necessarily require myocardial hypertrophy.10

Rhythm and conduction abnormalities are common in Fabry disease. Significant ventricular arrhythmias and sudden cardiac death have been reported.11, 12 A study of 1448 untreated patients from the International Fabry Registry reported ventricular arrhythmias in 14% of affected men and 20% of women.13 In another series of 78 patients, atrial fibrillation was seen in 17% of patients and nonsustained ventricular tachycardia (NSVT) in 8%.14 The high incidence of ventricular arrhythmias seen in these patients has led to implantation of implantable cardioverter‐defibrillators (ICDs) for sudden death prevention. Sinus node dysfunction, atrioventricular block, and bundle branch block have also been observed.15 Symptomatic bradycardia leading to pacemaker implantation may be required in 5% to 10% of patients in long‐term follow‐up.16 Autopsy studies of patients with Fabry disease who died of primary cardiac events show a much higher rate of bradycardia and pacemaker use, up to 40%.17 This study sought to examine the incidence of clinically significant arrhythmias in a series of patients with Fabry cardiomyopathy.

Methods

Retrospective chart review was conducted of patients who were followed in the cardiology clinic at the University of Alabama at Birmingham. Data collected included cardiac comorbidities, echocardiographic parameters, symptomatic arrhythmias, reason for device implantation, and interrogation data. Left ventricular (LV) mass was calculated using the American Society of Echocardiography recommended formula: LV mass = 0.80 (ASE‐cube LV mass) + 0.6 g,18 and the mass was indexed to height as well as body surface area.

Statistical comparisons of continuous variables were made using unpaired Student t test. Statistical comparisons of binary variables were made using χ 2 analysis. Results were considered significant for a P value <0.05. The protocol was approved by the institutional review board at the University of Alabama at Birmingham.

Results

Nineteen patients (11 males, 8 females) ages 18 to 72 years were studied. Comorbidities included coronary artery disease in 3 patients (16%), valvular regurgitation of at least moderate severity in 9 patients (47%), chronic renal insufficiency in 11 patients (53%), and the hypertrophic variant of Fabry cardiomyopathy in 4 patients (21%). All patients had normal ejection fraction. Eighteen of the nineteen patients were on enzyme replacement therapy (ERT). Antiarrhythmic drug use was infrequent, with 1 patient on amiodarone and 1 on sotalol. The mean follow‐up for the entire cohort was 53 months.

Nine patients (47%) had implantable devices, of which 7 were ICDs and 2 were pacemakers. Implant indications included symptomatic bradycardia, NSVT, conduction abnormalities, palpitations, and syncope. Device interrogation data were available for 8 of the 9 patients.

The mean follow‐up for patients with devices was 50 ± 23 months. Two patients received ICD shocks. One shock was inappropriate for noise in the device header, which was treated with generator exchange. Another patient, who had previously been shocked inappropriately for atrial fibrillation, had shocks for ventricular fibrillation 63 months after implantation in the setting of multisystem organ failure, as a terminal event.

Patients were paced in the atrium 71% ± 37% of the time and paced in the ventricle 49% ± 52% of the time. Four of the 8 patients with devices were paced more than 95% of the time. Patients with devices had lower heart rates prior to implant (60 ± 10 vs 78 ± 16, P = 0.03) than the group that did not have devices implanted.

Of the patients without devices, mean follow‐up was 56 ± 27 months. One patient had sudden cardiac death. One patient had atrial fibrillation. Five patients had Holter or event monitors placed. Sinus bradycardia with heart rates as low as 41 bpm were documented in these patients, all asymptomatic without evidence of chronotropic incompetence.

Patients with implantable devices had higher LV mass (237 ± 72 g vs 176 ± 36 g, P = 0.03), LV mass indexed to body surface area (136 ± 40 g/m2 vs 93 ± 19 g/m2, P = 0.008) as well as higher LV mass indexed to height (144 ± 37 g/m vs 103 ± 19 g/m, P = 0.006) compared to patients without devices.

Discussion

Cardiac manifestations are a common cause of morbidity and mortality in Fabry disease. Cardiomyopathy, myocardial infarction, hypertension, and rhythm abnormalities are observed. Patients are treated with standard therapy for hypertension and heart failure. In addition, pacing is used for symptomatic bradycardia or significant conduction abnormalities, and ICDs are used for malignant tachycardias. There are no standard guidelines for ICD use given the small number of patients, variable phenotypic expression of disease, and scant data on ventricular arrhythmia incidence and sudden cardiac death. In this situation, clinicians may use prognostic features known to be important in other cardiomyopathies, such as NSVT on monitoring, unexplained syncope, aborted sudden cardiac death, and family history of malignant arrhythmias and sudden cardiac death, in making decisions about ICD therapy.

Early trials of ERT with agalsidase alpha and agalsidase beta demonstrated benefit in renal and neurologic disease, decreased microvascular endothelial deposits of globotriaosylceramide in the heart, and decreased QRS duration with therapy.19, 20 Galactose infusion therapy in a patient considered for cardiac transplantation improved the ejection fraction from 31% to 55% after 2 years of therapy.21 There is also evidence that ERT improves systolic and diastolic function,22 decreases LV mass and wall thickness,23, 24 and can lower the incidence of arrhythmias.25

In our series, the incidence of clinically significant ventricular arrhythmias, with a mean follow‐up of 53 months, was low. Only 1 patient had ventricular fibrillation in the setting of multiorgan failure as a terminal event. Left ventricular hypertrophy correlates with arrhythmias, and ERT has been shown to improve LV mass. It is thus possible that ERT can decrease the burden of ventricular arrhythmias, but given the limited number of patients and short follow‐up periods in clinical trials, this has not yet been demonstrated. Another patient without the device had sudden cardiac death, but antecedent events and rhythm disturbances leading to this event are unknown. Interestingly, there is a high incidence of bradycardia and frequent need for pacing. Significant bradycardia may be a sign of worsening disease, and it is possible some of the sudden deaths reported in prior case series may have been bradycardic arrests, not tachyarrhythmic arrests.

We also observed that patients who required implantable devices had higher LV mass than patients without devices. Analysis of the Fabry registry has shown that left ventricular hypertrophy is a strong predictor of cardiovascular events, with an odds ratio of 4.77 for cardiovascular events.9 Infiltration of the conduction system leading to bradycardia and atrioventricular block15 as well as tachycardia11 has been described. Therefore, the degree of hypertrophy may be a predictor for arrhythmic events as well as overall cardiovascular events in Fabry cardiomyopathy.26

A limitation of our study was that there was a shortage of agalsidase‐beta (Fabrazyme; Genzyme Corp., Cambridge, MA) starting June 2009. The recommended dose in the United States was decreased from 1 mg/kg biweekly to 0.3 mg/kg biweekly.27 This dose is different from the Fabrazyme dose approved in some other countries, and different from the 0.2 mg/kg biweekly agalsidase‐alfa (Replagal; Shire Plc., Dublin, Ireland) that is used outside of the United States. Although we do not have enough data to make conclusions about the efficacy of various doses, we recognize that the incidence of and changes in hypertrophy and rhythm abnormalities may be related to the availability and doses of therapy.

Conclusion

Although use of an ICD for secondary prevention of sudden death in Fabry cardiomyopathy is warranted, it is not yet clear what criteria should be used when determining when to implant an ICD or pacemaker for primary prevention of sudden death in Fabry patients. Larger clinical trials designed specifically to study cardiovascular outcomes, as well as longer follow‐up periods in registries, will clarify the role of ERT and device‐based therapy in Fabry cardiomyopathy.