Genetics of sudden cardiac death Bezzina, Connie R; Lahrouchi, Najim; Priori, Silvia G
Circulation research,
2015-Jun-05, Letnik:
116, Številka:
12
Journal Article
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Sudden cardiac death occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Genetic studies conducted during the past 20 years have ...markedly illuminated the genetic basis of the inherited cardiac disorders associated with sudden cardiac death. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels, and the cardiomyopathies, which have been attributed to mutations in genes encoding a broader category of proteins, including those of the sarcomere, the cytoskeleton, and desmosomes. We discuss the challenges currently faced in unraveling genetic factors that predispose to sudden cardiac death in the setting of sequela of coronary artery disease and present the genome-wide association studies conducted in recent years on electrocardiographic parameters, highlighting their potential in uncovering new biological insights into cardiac electric function.
Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, ...systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.
Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal ...mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy.
We searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end.
This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.
The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain.
We performed a systematic review and pooled analysis of ...prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval CI, 1.44-4.92, P<0.001), with the greatest risk observed among those induced with single or double extrastimuli. Annual event rates varied substantially by syncope history, presence of spontaneous type 1 ECG pattern, and arrhythmia induction. The lowest risk occurred in individuals without syncope and with drug-induced type 1 patterns (0.23%, 95% CI, 0.05-0.68 for no induced arrhythmia with up to double extrastimuli; 0.45%, 95% CI, 0.01-2.49 for induced arrhythmia), and the highest risk occurred in individuals with syncope and spontaneous type 1 patterns (2.55%, 95% CI, 1.58-3.89 for no induced arrhythmia; 5.60%, 95% CI, 2.98-9.58 for induced arrhythmia).
In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features.
Since the identification of the first SCN5A mutation associated with long QT syndrome in 1995, several mutations in this gene for the alpha subunit of the cardiac sodium channel have been identified ...in a heterogeneous subset of cardiac rhythm syndromes, including Brugada syndrome, progressive cardiac conduction defect, sick sinus node syndrome, atrial fibrillation and dilated cardiomyopathy. Robust clinical evidence has been accompanied by bench studies performed in different models spanning from in vitro expression systems to transgenic mice. Together, these studies have helped establish genotype-phenotype correlations and have shaped our understanding of the role of the cardiac sodium channel in health and in disease. Remarkably, these advances in understanding have impacted on clinical management by allowing us to start developing gene-specific risk stratification schemes and mutation-specific management strategies. In this Review, we summarize the current understanding of the molecular mechanism of SCN5A-associated inherited arrhythmias, focusing on the most recent development of mutation-specific management in SCN5A-associated long QT syndrome type 3. We also briefly discuss arrhythmia-causing mutations in the genes encoding the beta subunit of the cardiac sodium channel and in those encoding proteins in the associated macromolecular complex.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease occurring in patients with a structurally normal heart: the disease is characterized by ...life-threatening arrhythmias elicited by stress and emotion. In 2001, the ryanodine receptor was identified as the gene that is linked to CPVT; shortly thereafter, cardiac calsequestrin was implicated in the recessive form of the same disease. It became clear that abnormalities in intracellular Ca(2+) regulation could profoundly disrupt the electrophysiological properties of the heart. In this article, we discuss the molecular basis of the disease and the pathophysiological mechanisms that are impacting clinical diagnosis and management of affected individuals. As of today, the interaction between basic scientists and clinicians to understand CPVT and identify new therapeutic strategies is one of the most compelling examples of the importance of translational research in cardiology.
Abstract Background Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine ...is used to block late sodium current and to shorten QT interval in LQT3 patients. Objectives The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients. Methods The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine. Results The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 ± 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 ± 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 ± 0.17 to 0.03 ± 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097). Conclusions Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy.
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