Mayo 2009 | Vol 6 | N.º 5 | CNIC-7 [PDF (264K)]

Sudden cardiac death: translating basic science into clinical care

Abstract | Clinical, epidemiological and laboratory data suggest that genetics plays an important role in the risk of sudden cardiac death (SCD). We have witnessed considerable strides in our understanding of SCD disorders with advances in genetics and the discovery of several mutations linked to lethal familial diseases. These diseases are responsible for a considerable percentage of deaths in young, previously healthy individuals. Unfortunately, conventional clinical tests are often insufficient for recognizing individuals at risk.  To compensate for clinical limitations, cardiology has fully embraced genetic technology, which can provide irrefutable evidence of the risk of suffering or being spared from an inherited disease. However, despite unquestionable advances, researchers have not yet been able to achieve a minimal understanding of genetic and environmental modulation of the phenotype or to provide an objective analysis of the benefits of genetic technology in overall patient care. The GenCardio consortium, a multidisciplinary team of investigators, clinicians and institutions, was created to address some of the scientific, medical, social and economic challenges that we face in the field of cardiovascular genetics and to assist with policymaking in the field.

BACKGROUND
Cardiac electrical activity is a complex process, strongly dependent on genetic, structural and environmental factors. Several elements are needed to achieve coordinated cardiac activity, including ion channels, structural proteins and gap junctions. These elements are responsible for the generation and transmission of electrical and mechanical impulses across myocytes and must remain in complete balance to prevent arrhythmogenesis. Disruption of any of these mechanisms may tilt the balance towards a devastating outcome of erratic electrical activity or fibrillation, which is responsible for sudden cardiac death (SCD). SCD refers to natural death from cardiac causes and occurs within one hour of the onset of acute symptoms.¹ Ventricular fibrillation (VF) is the most common cause of SCD, which affects ~800,000 individuals annually in the Western world, causing more deaths than AIDS, lung and breast cancer and stroke combined ², ³. Consequently, cardiac arrhythmias and SCD continue to be major contributors to morbidity and mortality in our society⁴, ⁵.

Risk factors in sudden cardiac death
Epidemiological studies have shown that demographics and socioeconomic status play important roles in the risk of SCD. The incidence of SCD increases with increasing age in both men and women, among both Caucasians and African Americans.⁶ The incidence of SCD is three to four times higher in men than in women.⁶ Rates of SCD are higher in African-Americans than in whites.², ⁷ Lower socioeconomic status has also been associated with an increased risk of SCD.  The incidence of post-MI SCD, for instance, is threefold higher in men with lower levels of education as compared to those with higher education.⁸

Lifestyle factors are major determinants of SCD. Smoking is a particularly important risk factor.⁹  Individuals who smoke more than 20 cigarettes per day have an annual incidence of SCD that is about 2.5 times higher than that among non-smokers.¹⁰   Individuals who consume more than five drinks per day have increased risks of ventricular arrhythmia and SCD.¹¹   Emotional stress is also known to exacerbate the risk of SCD, both transiently and over a longer period of follow-up.¹²  Moderate levels of physical activity are associated with a lower risk of SCD;  however, the risk is elevated during periods of rigorous activity.¹³  Obesity is also directly associated with an increased risk of SCD, including those weight-stable obese subjects without cardiac dysfunction.¹⁴  The Framingham study has demonstrated a threefold greater incidence of SCD among hypertensive individuals as compared to non-hypertensive patients.¹⁵  In addition, large-scale clinical trials have demonstrated that the manipulation of lipid profiles with statins and fish-oil supplements has a beneficial effect in reducing overall mortality and SCD.¹⁶ 

The most common underlying cause of SCD is coronary heart disease, which accounts for as much as 60-80% of all cases in adult series ¹⁷ . The risk of SCD is also increased in a variety of cardiomyopathies, many of which have an important genetic component. Finally, heart failure is emerging as an important risk factor for SCD, and a low ejection fraction is recognized as an indication for the implantation of a defibrillator to prevent SCD.

A role of inheritance has been suggested by several observational epidemiological studies¹⁸, ²⁰ that showed that SCD is more frequent in families with a previous history of the disease. A variety of heritable monogenic disorders are responsible for a notable proportion of cases; in the young, these monogenic disorders may be responsible for up to 40% of SCD²¹. In fact, SCD is often the first clinical manifestation of an inherited cardiac disease in young people.

Role of Genetics in Sudden Cardiac Death
There has been considerable progress in understanding the genetic components of SCD, thanks to research on mendelian forms of the disease. SCD can be caused by mutations in genes mainly encoding four families of proteins: sarcomeric, which cause hypertrophic cardiomyopathy (HCM); cytoskeletal, which cause dilated cardiomyopathy (DCM); desmosomal, which cause arrhythmogenic right ventricular cardiomyopathy (ARVC); and ion channels, which cause electrical diseases or channelopathies, such as long QT syndrome (LQTS), short QT syndrome (STQS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) ²², ²⁴. As research continues to advance, mixed categories that overlap between proteins and diseases may also be observed. For example, while familial arrhythmias in the structurally normal heart were previously thought to be caused exclusively by mutations in ion channels, the recent identification of long QT mutations in ankyrin B²⁵ and caveolin 3²⁶—proteins responsible for the location of ion channels—suggests that abnormalities in cardiac rhythm and conduction may also be caused by channel-associated proteins.

The prevalence of arrhythmogenic diseases with monogenic inheritance is probably underestimated, because they go often unrecognized. The estimated prevalences range from 1/5000 for BrS²⁷ to 1/4000 for arrhythmogenic right ventricular cardiomyopathy²⁸, 1/3000 for LQTS²⁹, and 1/500 for hypertrophic cardiomyopathy³⁰. Several of these diseases are highly lethal in the teenage years, and some of them, like HCM, are the most common cause of SCD in athletes³⁰,  taking a severe psychological toll on families and communities in addition to the obvious loss of a young productive life.  

CLINICAL APPROACH TO SUDDEN CARDIAC DEATH.
In the event of a SCD, the autopsy becomes the key diagnostic tool when macro- and microscopic analyses provide a conclusive diagnosis in cardiomyopathies. In these cases, clinicians have several non-invasive and invasive diagnostic tools available to identify family members at risk for the disease. However, on average, one-third of autopsies do not identify a pathologically defined cause of death. These deaths are classified as “natural” or arrhythmogenic and are usually caused by primary electrical diseases. The presence of an unclear diagnosis carries important implications for family members who may remain undiagnosed and therefore be potentially at risk of SCD. 

Likewise, patients who recover from an unexplained cardiac arrest or who experience syncope of arrhythmogenic origin carry a significant risk of SCD recurrence. A thorough clinical evaluation is indicated in these cases. However their investigation remain one of the most challenging problems in clinical cardiology. It is well known that as although clinical tests, including magnetic resonance imaging and electrophysiological studies, are useful for assessing risk in these individuals, they have significant limitations and may leave some susceptible carriers at risk. For asymptomatic family members, clinical techniques face three main limitations: the low penetrance of arrhythmogenic diseases, the limited sensitivity and specificity of clinical techniques as a means of identifying precisely which members are affected, and the lack of a standard clinical approach, with high practice variability across centres. Clinical practice variability has made it difficult to achieve a sufficiently large and homogeneous cohort of patients that can be used to obtain clear risk stratification and therapeutic algorithms, and we believe that the lack of standardized protocols has slowed the advancement of a mechanistic understanding of the disease and, most importantly, has hindered the management of family members of SCD patients.

An illustrative example can be found in a recent publication by referral centres of LQTS in which less than half of affected patients were protected with β-blockers despite the fact that this medication is recommended in prevention guidelines for genetic carriers³¹. Similarly, provocative testing such as the use of epinephrine (for LQTS or CPVT), flecainide (for BrS) and electrophysiological studies are performed inconsistently and with protocols that are physician-dependent.

USE OF GENETIC TESTING IN THE DIAGNOSIS OF SCD.
Our understanding of the molecular basis of cardiac ion channel abnormalities has increased exponentially, and a growing list of primary electrical causes has reduced the number of unexplained SCD cases ³². In fact, recent studies suggest that more than one-third of unexplained SCD cases harbour a putative cardiac channel mutation³³.
Genetic testing is emerging as a complementary diagnostic tool for patients with unexplained cardiac arrest, for those with syncope of arrhythmogenic origin, and especially for their asymptomatic relatives³⁴. Genetic tests not only can confirm the disease in SCD or syncope patients but can also define which family members may be at risk for the disease. The discovery of the causative genetic defect in the family enables the distinction of those members at risk, who will need close clinical follow-up (genetic carriers), from those who are spared from the disease (non-genetic carriers). In addition, in some diseases like LQTS, genetic testing is important for guiding specific therapy³⁴. In borderline cases such as those with an unclear diagnosis, genetic testing may also be of value35 although it has not yet been widely advocated because of the limited cost-effectiveness of current molecular methods for single gene screening.

Owing to the added value of genetic tools and the limitations of clinical cardiac technology, genetic testing is rapidly becoming part of the standard of clinical care and medical decision-making under the emerging theme of personalized and preventive medicine. Notwithstanding its potential, genetic testing carries a number of limitations.  First, it still fails to uncover the causative defect in a great proportion of patients (25% of LQTS, 75% of BrS, 40% of CPVT and 60% of ARVC)³⁵. Three plausible explanations for this are the presence of mutations in unknown genes; the presence of mutations in noncoding sequences, such as promoters or introns³⁵; and the presence of mutations in genes that are not currently thought to be associated with the disease.

As our understanding of the genetic mutations that result in life-threatening arrhythmias has advanced, the search for candidate genes has expanded from genes encoding direct sarcolemal proteins or transmembrane channels to genes implicated in trafficking mechanisms and regulatory pathways³⁵. For example, recent publications have demonstrated that mutations in caveolin-3 or in the glycerol-3 phosphate dehydrogenase-1-like (GPD1L) genes can cause modification of the sodium current and thus cause type-3 LQTS (associated with a gain of function of the sodium current) and BrS (associated with a loss of function)²⁶, ³⁶. Similarly, the multiprotein complex composed of dystrophin and syntrophins, which plays a major role in preserving the integrity of the myocellular membrane, has been implicated in sodium channel function³⁷. Interactions between ion channels and structural proteins may explain how structural defects may translate into arrhythmic mechanisms, as in DCM or in ARVC³⁵.

Second, even if genetic tests identify the causative mutation, this is usually not sufficient to explain the clinical phenotype. For example, combinations of type-3 LQTS, BrS and congenital heart block have been described as a result of the same mutation in SCN5A³⁸, and all three phenotypes have been documented even within the same family³⁹. In addition, the severity of the disease may be very different in patients carrying the same mutation40. The reasons for such interfamily and intrafamily variability are not fully understood, but environmental factors and genetic modifiers are thought to play a key role35.

The concept of genetic modifiers has been raised as a result of very recent evidence that has shown that additional mutations or even common polymorphisms can modulate the effect of a particular mutation and thus determine the phenotype⁴¹, ⁴³.. These additional mutations or polymorphisms can occur at the same gene as the primary mutation or in other genes encoding proteins interacting with the target channel. For example, the common polymorphism H558R in SCN5A mitigates the in vitro effects of a nearby mutation on the sodium channel ⁴², ⁴³.

A rescue effect has also been observed in the case of a Cx40 promoter polymorphism in patients with SCN5A mutations44.

Third, genetic testing, although effective in patients with a clear diagnosis, is not effective in patients without a clear phenotype, such as individuals with syncope of unknown origin.  The use of genetic technology in these unclear cases is complicated by the inability to direct the analysis towards a known gene; consequently, the screening of all genes associated with SCD at present becomes exceedingly cost- and time-consuming. While the advances in the field have been significant, these limitations continue to be an important hurdle as we seek to further improve our understanding of inherited diseases.

GENCARDIO PROJECT
Because there is a low prevalence of inherited cardiac diseases, the approach to their diagnosis and treatment is often based on small studies. In order to address the current limitations of the knowledge base, we believe that the role of additional genetic and environmental modifiers and the clinical, social and economic impact of using genetic technology to characterize inherited arrhythmic diseases should be addressed using a multidisciplinary, multicentre and homogeneous clinical approach. We have therefore created the GenCardio consortium (National Research Group on Inherited Cardiac Diseases and Sudden Cardiac Death), a collaborative research network of cardiologists, geneticists, biophysicists, epidemiologists and ethicists funded through Spain’s National Center for Cardiovascular Research (CNIC) of the Instituto de Salud Carlos III, in order to address several of the challenges in the field of cardiovascular genetics.

The GenCardio consortium has three main objectives. The first objective is to further refine and standardize the clinical approach to SCD. The second is to advance our understanding of the role of genetics and genetic modifiers in SCD, as well as the economic implications of genetic testing in clinical care.  Our final objective is to investigate how the environment influences predisposition to SCD.

The GenCardio consortium will organize a multicentre collection of three  populations: patients and family members with inherited cardiac arrhythmias (Registry of Inherited Arrhythmias, REGINA), including BrS, LQTS, SQTS, CPVT and early stages of ARVC; patients with idiopathic ventricular fibrillation (IVF); and patients with syncope of unknown origin. For these populations, we will develop a standardized clinical protocol, including genetic analyses, to guarantee homogeneity across centres. This clinical protocol will allow us to evaluate the role of clinical procedures, including non-invasive and invasive testing, and to detect the causes of primary electrical disease in patients with inherited cardiac arrest and their families and in patients with syncope or cardiac arrest of unknown origin.

In addition to a thorough clinical assessment, we will characterize the basic mechanisms of disease in these patients using genetic, molecular and biophysical technology, with the intent of providing a better understanding of the pathophysiologic mechanisms involved in arrhythmogenesis. Finally, our study will also allow for a thorough epidemiologic assessment of the genetic, environmental and clinical modulators of the arrhythmic phenotypes, as well as an economic analysis of the incorporation of genetic technology in the clinical care of patients with known inherited diseases and in patients with IVF or syncope of unknown origin.

The long-term objective of our consortium is to develop clinical, genetic, and epidemiological tools to improve diagnosis and risk stratification of patients with suspected inherited arrhythmogenic diseases and families with the diseases and to evaluate the cost-effectiveness of the genetic approach. Finally, the data generated will enable us to better diagnose and treat patients with unclear phenotypes and prevent cardiac events in family members.