SCN5A—A Mechanistic Link Between Inherited Cardiomyopathies and a Predisposition to Arrhythmias?

The supreme goal of all theory is to make the irreducible basic elements as simple and as few as possible without having to surrender the adequate representation of a single datum of experience.—Albert Einstein, 1933¹

A wide variety of genetic disorders have been recognized in patients with idiopathic dilated cardiomyopathy (IDC). Mutations in contractile proteins, such as troponin and titin, have been demonstrated.^{2 - 3} Mitochondrial transfer RNA (tRNA) abnormalities have been found in patients with hearing disorders and maternally inherited cardiomyopathy.⁴ Furthermore, specific abnormalities in immune function may result in IDC. Cohorts of patients with IDC have been noted to have anticardiac antibodies, altered immunoglobulin absorption, and abnormal cytokine profiles.^{5 - 7}

Recent work has identified a group of inheritable cardiomyopathies characterized by disorders of contraction and electrical conduction. Dysfunction in the ryanodine receptor has been implicated in arrhythmogenic right ventricular cardiomyopathy type 2, an inherited disorder characterized by right ventricular fatty infiltration and dysfunction as well as a predisposition to ventricular arrhythmias.⁸ Lamin A/C mutations result in a spectrum of clinical disorders including cardiomyopathy and increased rates of sudden death and atrioventricular block.^{9 - 10}

In this issue of JAMA, the study by Olson and colleagues¹¹ suggests that defects in the SCN5A sodium channel gene may result in IDC. The concept is intriguing because channel dysfunction (channelopathy) has generally been thought to result in disorders of cardiac rhythm, but not of contraction. Nevertheless, given that electrical signals trigger calcium release and subsequent contraction (ie, excitation-contraction coupling), it is logical that ion channel abnormalities could well result in decreased contractile function. This hypothesis is further supported by the evidence that various other ion channelopathies result in skeletal myopathies, such as periodic paralysis.¹²

Mutations in SCN5A have long been known to result in a variety of cardiac rhythm disorders, including long-QT syndrome, Brugada syndrome (an autosomal dominant inherited disorder characterized by abnormalities in the ST segments of the right precordial leads on electrocardiogram and an increased risk of sudden cardiac death), and an inherited form of sick sinus syndrome.^{13 - 15} The report by Olson et al identifies for the first time an association between SCN5A and contractile function, an important finding for several reasons. First, the identification of another genetic mutation responsible for IDC will increase the ability of clinicians and clinical researchers to better understand the mechanisms of this disease. Second, although this finding may not directly alter treatment at this time, it will allow for more effective screening of family members of affected patients. And third, as more and more culprit genetic disorders are identified in patients with cardiomyopathy, a smaller number of truly idiopathic cases will remain.

The study by Olson et al¹¹ may contribute to the understanding of patients with atrial fibrillation; 44% of patients with SCN5A mutations had atrial fibrillation. Thus far, only a handful of known genes have been identified that predispose individuals to atrial fibrillation.^{15 - 17} In evaluating patients with atrial fibrillation, such genetic defects may allow clinicians and investigators to diagnose patients previously believed to have idiopathic or “lone” atrial fibrillation.

Most interestingly, patients with SCN5A defects often had disorders of both rhythm and contraction. This is contrary to the traditional paradigm in cardiovascular disease, in which patients are known to have a primary disorder of either rhythm or contraction. Cardiologists often undertake exhaustive searches to identify the primary disorder and then devise treatment strategies around such findings. Olson et al present an elegant, unified pathophysiological explanation for how a single error in the myocyte gene program can result in a spectrum of clinical syndromes. Such genetic defects in one type of ion channel and resulting in myriad signs and symptoms may be a somewhat new finding for some cardiovascular disorders, but it is not an entirely new concept. For instance, abnormalities in chloride ion channels result in myriad clinical findings in patients with cystic fibrosis.¹⁸ Furthermore, recent basic science research suggests that a unified theory may explain some acquired disorders of cardiac function. Catecholamine-induced ryanodine receptor dysfunction can lead to alterations in calcium handling and subsequent arrhythmic and myopathic abnormalities.¹⁹

Several points mentioned by Olson et al¹¹ raise questions and are worth further discussion. Mutations in SCN5A have been found in a variety of clinical syndromes, with distinct clinical presentations and electrocardiographic findings. However, it is unclear how mutations in the same channel could result in such very different disorders. The answer may lie in a closer examination into sodium channel physiology. Initial work in the 1950s by Hodgkin and Huxley suggested that sodium channels have 2 gates, the M gate, which is responsible for activating the channel, and the H gate, which is responsible for closing the channel.²⁰ M-gate function is critical for initiation of the action potential while H-gate function is essential for repolarization of the action potential. In reality, the channel is likely to exist in several substrates, adding an additional level of complexity to sodium channel physiology.²¹ Given this level of intricacy, it is feasible that various mutations in SCN5A could result in specific, different structural changes. Loss of function mutations could result in failure of opening of the channel, which could interfere with depolarization and result in bradycardic disorders. Change in function mutations could keep the channel open too long, resulting in prolonged depolarization and a subsequent increased risk of tachyarrhythmias. How sodium channel defects result in sinus node dysfunction (such as sick sinus syndrome) is less clear, given that sinus node pacemaker cells rely principally on calcium and not sodium for depolarization.²²

Olson et al also note that clinical sequelae of these disorders are considerably more common in men than in women with the same mutation. This is consistent with other forms of cardiomyopathies, yet the reasons are not clear. It is possible that men are more likely to have coronary artery disease at a younger age than women and that symptoms in men are secondary to their coronary disease, and not from the particular genetic defect. It is also possible that clinically significant disease only becomes apparent after multiple injuries to the myocyte occur.

There are also several possible inconsistencies in the investigation by Olson et al. First, given the prevalence of SCN5A mutations in multiple known disease states that predispose to arrhythmias, it is possible that these patients are having undiagnosed tachycardia-induced cardiomyopathies. The authors state that their patients with atrial fibrillation did not have rapid ventricular responses and that patients with ventricular tachyarrhythmias only had nonsustained ventricular tachycardia. They suggest that this excludes tachycardia-induced cardiomyopathies. It could be argued that their methods of detection (serial electrocardiograms and 24-hour Holter monitoring) are not sensitive enough to make such a conclusion. Given that ruling out tachycardia-induced cardiomyopathy is central to the authors’ hypothesis, further testing may be warranted.

Furthermore, it is unclear why patients with other SCN5A mutations, such as those with Brugada syndrome, do not have cardiomyopathies. The authors state that these patients are generally not screened for left ventricular dysfunction, die early, and are excluded from IDC epidemiologic studies. Therefore, patients with Brugada syndrome may in fact have unappreciated cardiomyopathies that are not diagnosed. It is difficult to estimate the true prevalence of Brugada disease. Nonetheless, because of increased recognition of the syndrome, as well as better treatment modalities (such as prophylactic defibrillators), it can be assumed that the number of patients with a diagnosis of Brugada syndrome has increased significantly during the last several years. Yet, little published data suggest that these patients have symptomatic or asymptomatic ventricular dysfunction.^{23 - 24}

The impact of the report by Olson et al¹¹ is unclear. Despite the wide variety of genetic defects now identified in patients with dilated cardiomyopathy, the approach to and treatment of the disease remain similar. Further insight into the pathophysiology of inherited channelopathies may be difficult to achieve using traditional techniques. Human embryonic stem cells have been found to recapitulate cardiac ontogeny in vitro.^{25 - 26} Future work may be performed best by creating a model for specific defects using genetically manipulated embryonic stem cells. These cells could be kept in vitro allowing for molecular and functional analysis of the cells over time.

Given the low overall prevalence of the mutation, screening the general population for SCN5A mutations is not warranted at this time. On the other hand, it may be wise to screen patients with IDC or conduction disease for SCN5A mutations. In the past, this approach may not have changed treatment strategies, but it may be warranted now in such patients to perform further diagnostic testing and even consider prophylactic therapies. Clearly, further investigation is required to evaluate the efficacy of such an approach.

A unified pathophysiologic explanation for cardiomyopathy may not directly change how patients are treated but does provide further support for some current therapeutic approaches. It supports use of β-blockers because these agents may improve contractile function and prevent arrhythmias. The findings also support using primarily markers of contractile function, such as ejection fraction, to identify patients who might benefit from implantable cardiac defibrillators.

Insight into the genetic alterations responsible for cancer has led to the development of specific targeted therapies, maximizing the efficacy and minimizing the adverse effects of therapeutic interventions.^{27 - 28} Currently, most cardiomyopathies are generally treated the same way, regardless of the genetic alterations responsible. As a result of studies, such as that reported by Olson et al, genetically tailored therapy for cardiovascular disease may one day become reality.