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Are patients with epilepsy more susceptible to heart disease than the general population? There is growing evidence to indicate that cardiovascular disease may be a major contributing factor to the increased rate of premature mortality in patients with epilepsy compared to the general population. Epidemiologic studies indicate that the risk may be as high as 3-fold compared to the general population. What’s more shocking is that this elevated risk likely plays a bigger role than the well-known entity sudden unexpected death in epilepsy (SUDEP). The mechanisms for these findings are manifold and in general can be attributed to the concept of the “Epileptic Heart,” which can be defined as “a heart and coronary vasculature damaged by chronic epilepsy as a result of repeated surges in catecholamines and hypoxemia leading to electrical and mechanical dysfunction.”

Accelerated Atherosclerosis

A large US national health survey by Zack and Luncheon suggests that when compared to the general population, patients with epilepsy have a higher incidence of heart disease, including coronary artery disease, angina pectoris, and myocardial infarction. The greatest difference was seen in the 45-64 year age group, which is slightly younger than for the typical population. An Austrian study reported ischemic heart disease to be 1.9-fold more common in patients with epilepsy and sudden cardiac death than in the general population. The most convincing evidence comes from the Stockholm Heart Epidemiology Program, where a 4.83-fold increased incidence of myocardial infarction is found in patients with chronic epilepsy compared to the general population, after controlling for multiple variables. Pathologic cardiac findings provide further evidence of accelerated heart disease with obstructive coronary artery disease seen in 36% of cases of epilepsy patients with sudden cardiac death, along with other structural changes including myocardial fibrosis, left ventricular hypertrophy, and cardiomegaly. The physiologic basis for these changes relates to repeated seizure-induced hypoxemia, myocardial ischemia, and the cardiotoxic effects of sudden catecholamine surges.

Cardiac Arrhythmias

Patients with epilepsy had a 2.8-fold greater risk of cardiac arrest and ventricular fibrillation than the general population in the Amsterdam Resuscitation Studies. In the Oregon Sudden Unexpected Death study, patients with epilepsy were slightly younger than those without epilepsy and in two-thirds of patients, there was no observed antecedent seizure activity, as confirmed by witnesses of the cardiac arrest. In patients with implantable cardioverter defibrillators, a history of epilepsy was associated with a 3.53-fold risk of life-threatening ventricular tachyarrhythmias and 4.14-fold increased incidence of cardiac death. Atrial fibrillation, a known risk factor for stroke, was also found to be present in 9.7% of patients with epilepsy in a large U.S. nationwide analysis of 1.4 million hospitalizations.

EKG Evidence of Cardiac Pathology

Seizure-induced catecholamine surges can provoke a wide variety of acute EKG changes that signify severe rhythm, conduction, and repolarization abnormalities, including bundle-branch block, ST-segment changes, and T-wave inversions. Tachycardia, and more rarely ictal bradycardia and asystole, have all been reported in the acute ictal and post-ictal phases. Repolarization abnormalities as measured by T-wave alternans (TWA), a well-established marker of risk for lethal arrhythmias leading to sudden cardiac death in the cardiac population, offers a window onto arrhythmogenic risk in patients with epilepsy. In patients with chronic epilepsy, TWA can be elevated to highly abnormal levels interictally and correlate with epilepsy disease duration, refractory status, and greater seizure frequency. There is also recent evidence of acute elevations of TWA during active seizures, with the highest levels observed during generalized tonic–clonic seizures, which are strongly correlated with elevated risk for SUDEP.

Effects of Antiseizure Medications

Although sodium channel blocking antiseizure medications (ASM) constitute some of the most common medications used to reduce seizure recurrence, they have also been implicated in cardiac arrhythmogenesis. Agents such as carbamazepine and lamotrigine have been implicated in increasing the risk for sudden cardiac death by as much as 3-fold. Moreover, Mintzer and colleagues found that enzyme-inducing medications can have deleterious effects on the lipid profile, even in younger patients without clear cardiovascular risk factors. In patients taking lipid-lowering therapy, enzyme-inducing ASM may reduce the effectiveness of their lipid-lowering drugs and contribute to accelerated atherosclerosis.

Autonomic Dysfunction in Chronic Epilepsy and Vagus Nerve Stimulation

Autonomic dysfunction is a well-recognized phenomenon in patients with chronic epilepsy and has been found to be associated with elevated SUDEP risk. Heart rate variability (HRV) reflects the balance between sympathetic and parasympathetic inputs to the heart, whereby lower HRV is associated with higher sympathetic tone or decreased vagal input. Both TWA and HRV are reliable predictors of increased cardiac mortality and malignant arrhythmias in cardiac and general populations. Vagus nerve stimulation (VNS) therapy, in addition to reducing seizure frequency, has been shown to reduce sympathetic activity and TWA in patients with refractory epilepsy. In studies involving large cohorts of cardiac failure patients, VNS has the capacity to reduce TWA, a marker of increased risk for lethal ventricular fibrillation, and the protective effect lasts for least 3 years. The question of the potential for dual protective effect of VNS in seizure reduction and cardioprotection represents a major area of clinical investigation.

Conceptual Change in Understanding Premature Death in Epilepsy

Close examination of the results by Stecker and colleagues indicated that the patients with epilepsy constituted 4.4% of all cases with sudden cardiac death in the Portland, Oregon, area, where the study was carried out. These data translate to approximately 16,100/year or 44 cases/day of sudden cardiac death nationwide, which is 4.5-fold that of the rate of SUDEP cases annually. The epidemiologic data changes the framework we use to estimate the burden of disease and overall mortality in chronic epilepsy.

Cardiac Mortality in Epilepsy

Cardiac Assessment and Dynamic Monitoring in Patients with Epilepsy

Routine cardiac evaluation in epilepsy patients is not currently standard of care. In light of the mounting evidence of cardiac damage with chronic epilepsy and the potential effects of antiseizure medications, we propose that patients with refractory seizures, particularly those with generalized tonic-clonic seizures, and those with additional cardiovascular risk factors, be considered for further cardiac evaluation.  We recommend a determination of risk for sudden cardiac death with routine 12-lead EKG recordings, and in select cases, multi-day ambulatory EKG monitoring using cardiac patches, as well as full cardiologic evaluation for patients in the highest category of cardiac risk for sudden cardiac death. Cardiac risk determination will not only play an important role in the epilepsy monitoring unit to improve patient safety, but will also guide the long-term comprehensive management of patients with refractory epilepsy.

Conclusion

Patients with chronic epilepsy are a vulnerable population in whom a higher incidence of cardiac disease and sudden cardiac death is seen. Future interventions to modify these cardiac markers and to confer cardiac protection to reduce the risk of sudden cardiac death in patients with epilepsy are an important area of study in the future.

 

Suggested Readings

Bardai A, Lamberts RJ, Blom MT, Spanjaart AM, Berdowski J, et al. Epilepsy Is a risk factor for sudden cardiac arrest in the general population. PLoS ONE 2012;7(8): e42749. https://doi.org/10.1371/journal.pone.0042749.

Mintzer S. Plumbing and wiring: atherosclerosis in epilepsy [editorial]. Epilepsy & Behavior 2014;41:274–5.

Verrier RL, Pang TD, Nearing BD, Schachter SC. The Epileptic Heart: Concept and clinical evidence. Epilepsy & Behav 2020 Feb 25;105:106946. doi: 10.1016/j.yebeh.2020.106946

Zack M, Luncheon C. Adults with an epilepsy history, notably those 45–64 years old or at the lowest income levels, more often report heart disease than adults without an epilepsy history. Epilepsy Behav 2018;86:208–10.

 

Dr. Trudy Pang is an Assistant Professor of Neurology at Harvard Medical School and Director of Clinical Neurophysiology and Adult Epilepsy Fellowship at Beth Israel Deaconess Medical Center. She is also the Director of the comprehensive Women’s Health in Epilepsy Program, a collaborative effort across Boston medical institutions to address the special needs of women with epilepsy.
Dr. Richard Verrier is an Associate Professor of Medicine, Division of Cardiovascular Medicine, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center. He has investigated sudden cardiac death for more than three decades, having published more than 300 original articles. He is the inventor of 12 licensed patents for diagnosis and treatment of heart rhythm abnormalities and prediction of sudden cardiac death.