Is there a link between cardiac dysfunction and SUDEP?
[Part 2: Questions; O'Brien TJ]
Sudden Unexpected Death in Epilepsy (SUDEP) is recognised as the most frequent cause of epilepsy-related death (Hesdorffer & Tomson, 2011). However, the reason these deaths occur is not understood. Seizures are known to affect cardiac rate, rhythm and electrophysiological function, and studies have noted changes the heart rate and electrophysiological function of epilepsy patients, both during and between seizures (Lamberts et al., 2014; Rugg-Gunn et al., 2004; Surges et al., 2010; Surges & Sander, 2012). One important line of research now emerging is the relationship between seizures and cardiac function, and any possible connection to SUDEP.
Little is known about how epilepsy might affect cardiac function at the molecular level. However, many of the ion channels associated with established epilepsy genes are connected with modulation of both brain and heart cellular excitability and cardiac pacemaker activity; for example, sodium channels (SCN1A, SCN5A), potassium channels (KCNQ1, KCNH2(HERG)), T-type calcium channels Cav3.2) and HCN channels (HCN2,4). Cardiac effects on patients might include Long QT syndrome and increased ventricular arrhythmias (Bardai et al., 2012). Recent Australian research found mutations in some of these genes for around 10% of the SUDEP cases studied (Tu et al 2011a; 2011b). A question arises from this information: could the existence of a dual phenotype, of both epilepsy and cardiac dysrhythmia, predispose people with epilepsy to SUDEP?
To further investigate the connection between epilepsy, cardiac function, and sudden death we have collaborated with the Cardiac Genetic Clinic at The Royal Melbourne Hospital to assess 74 families referred for investigation following a family member’s sudden, presumed cardiac death under the age of 45 years. Fifteen patients (20.3%) had a personal history of epilepsy (of whom 4 (26.7%) had an underlying electrophysiological disorder) and another 7 (9.5%) had a family history of epilepsy. This suggests that screening for cardiac pathology in patients with epilepsy may identify some at risk patients and allow intervention to potentially reduce the risk of SUDEP. Systematic referral to a cardiac genetics services for evaluation is also warranted for first degree relatives of a SUDEP victim (Eastaugh et al., submitted).
With a growing body of literature indicating that there is the potential for epilepsy and cardiac dysfunction to be emanating from common ion channel abnormalities that are being expressed in both the brain and the heart - a dual phenotype with a single genotype (Goldman et al., 2009; Hindocha et al., 2008) - our group asked the question; could epilepsy itself lead to the changes which are sometimes seen in the cardiac function and structure of a person with epilepsy?
One prime focus of research to unravel the heart/brain links is the function of HCN (hyperpolarization-activated cyclic nucleotide-gated) channels. Changes to these ion channels have been found in people with epilepsy (Bender et al., 2003), and also in animal models of both acquired and genetic epilepsies (Bender et al., 2003; Kuisle et al., 2006; Powell et al., 2008). Mutations and/or deletions in the HCN2 and HCN4 genes have been found in patients with cardiac dysfunction and an Australian study has identified specific mutations of these genes in three patients who died from SUDEP (Tu et al., 2011a; Stillitano et al., 2008; Wei-Qing et al., 2011).
We investigated cardiac function and HCN channel expression in two contrasting rat models; one with acquired and one with genetic epilepsy (Powell e al., 2014). We looked for changes in cardiac electrophysiology and for associated changes in HCN mRNA and protein expression in the heart chambers. The results were consistent across both rat models, despite the fact that the models differed in their type of epilepsy and also seizure type. Following a period of time with seizures, both models showed similar cardiac phenotypes consisting of prolonged QT intervals, and increased variability of heart rate. The molecular analysis demonstrated significant reduction in cardiac HCN2 mRNA and protein expression in both models thus providing a molecular correlate of the electro physiologic abnormalities.
These cardiac HCN channel expression changes, and electrophysiologic dysfunction, appear to be acquired consequences in both models studied. Furthermore, although one rat model was a genetic model of epilepsy, the HCN expression changes in the heart were not seen in young animals before seizure development. It is interesting to note that decreases in HCN expression have been reported in the brains of both animal models, but only after the development of the epilepsy (Kuisle et al., 2006), so the evidence supports the theory that the HCN changes in both the heart and the brain in these rat models are likely to be a secondary consequence of the recurrent epileptic seizures.
These findings give rise to another question; how is it that acquiring a neurologic disorder can influence cardiac ion channel expression and electrophysiologic function? During and following seizures there are profound changes in heart rate and QRS activity, driven by the major changes in autonomic nervous system. In patients with chronic epilepsy there are interictal autonomic changes that are more common than in those with recent-onset epilepsy (Sevcencu & Struijk, 2010).It is therefore possible that repeated exposure of the heart to severe autonomic stresses during seizures, and chronic autonomic dysfunction during seizures, result in secondary cardiac changes, (Dunser & Hasibeder, 2009) such as plastic changes in HCN expression in the heart, and then ultimately in electrophysiologic changes that predispose to cardiac arrhythmias.
What do these results mean to the management of patients? Cardiac electrophysiological changes – whether as a result of genetic mutation or acquired gene expression changes – resulting in electrophysiological changes such as long QT intervals could create a vulnerability to patients developing a fatal cardiac arrhythmia, particularly during the severe physiological stress of a seizure. This could therefore be a mechanism for SUDEP in humans. Furthermore, alterations in heart rate variability are suggestive of faulty regulation of autonomic function which could predispose to vulnerability to cardiac dysfunction. If indeed HCN2 repression changes are linked to detrimental cardiac function, then preventing or reversing this protein repression might prove beneficial for restoring normal cardiac function and therefore protecting against SUDEP in these patients. However, there is much that remains to be investigated and understood before we can confidently say that we understand the mechanisms underlying SUDEP, let alone offer realistic solutions. It is possible that SUDEP involves a combination of central, respiratory and cardiac mechanisms. Currently the biggest risk factor is lack of seizure control, especially nocturnal generalised tonic-clonic seizures. It is important to discuss epilepsy-related risks with our patients and work with them to achieve the best possible management of their condition.
Terence J O'Brien
James Stewart Professor of Medicine and Head of Department, Department of Medicine, RMH
The University of Melbourne
How to cite:
O'Brien TJ. Is there a link between cardiac dysfunction and SUDEP? In: Hanna J, Panelli R, Jeffs T, Chapman D, editors. Continuing the global conversation [online]. SUDEP Action, SUDEP Aware & Epilepsy Australia; 2014 [retrieved day/month/year]. Available from: www.sudepglobalconversation.com.