MOLECULAR ASPECTS OF CARDIAC CHANNELOPATHIES

Authors: Mukund Joshi1, Rajesh Pandey2, Kuldip Singh Sodhi2, Jasbir Singh2

1(MSc Medical Biochemistry), Department of Biochemistry, MMIMSR, Mullana, Ambala, Haryana, India.

2Professor. Department of Biochemistry, MMIMSR, Mullana, Ambala, Haryana, India.

Cardiac Channelopathies•Cardiac channelopathies are a group of clinical syndromes that affect the cardiovascular electrical system, specifically the myocardial ion channels [including Na+, K+, & Ca2+].

•Channelopathies occur when one of the proteins forming the channels does not function properly, either due to genetic mutation or acquired malfunction.

•As a result, the electrical properties of the patient’s heart are altered, changing the surface ECG and/or predisposing them to life-threatening, pro-arrhythmic events. These syndromes include:

INTRODUCTION

•Long QT Syndrome (LQTS)

•Short QT Syndrome (SQTS)

•Brugada Syndrome (BrS)

•Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

•Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

•This group of emerging entities has been recently brought to light as some of the underlying causes of sudden infant death syndrome [SIDS].

•There are a large number of distinct dysfunctions known to be caused by ion channel mutations. The genes for the construction of ion channels are highly conserved amongst mammals and one condition, hyperkalemic periodic paralysis.

Simplified classification of human channelopathies .

PREVALENCETen years ago a prevalence of 1:10,000 would have been judged to be an overestimation; whereas the current world wide prevalence of all cardiac channelopathies is thought to be at least 1:2000–1:3000 per individual in the general population.

Channelopathies are likely responsible for about half of sudden arrhythmic cardiac death cases. The most prevalent and well-known disorder in this group is congenital LQTS.

The average prevalence of LQTS has been reported to be 1:2500– 1:5000 per individual. Much higher LQTS prevalence numbers, 0.8–1.5% of the population, have been found in some ethnic groups with founder effects.

Kv7 channels structure, tissue distribution, human channelopathies, and disease target

CARDIAC NA+ CHANNELOPATHIES

Mutations in SCN5A, the gene encoding the Na+ channel-subunit expressed in the human heart, cause inherited susceptibility to ventricular arrhythmias (congenital long-QT syndrome [LQTS] including prolongation of ventricular action potentials, dispersion of repolarization, QT-interval and T-wave abnormalities in surface ECG recordings [LQTS3]; idiopathic ventricular fibrillation [VF]), cardiac conduction disease (CoD), and dilated cardiomyopathy (DCM) with atrial arrhythmia Mutations in SCN5A may also present with more complex phenotypes representing combinations of LQTS, CoD, and Brugada syndrome (BrS1).

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Examples of LQTS3 combined with either BrS19 or congenital heart block, cases of BrS1 with impaired conduction, or combinations of all 3 phenotypes have been documented. Moreover, certain mutations may manifest different phenotypes in different individuals and families

SCN4B Mutations Cause LQTS10

Akin to the K channel subunits responsible for LQTS5 and LQTS6, the Na channel 4 subunit encoded by SCN4B has been established as a novel, albeit rare, LQTS susceptibility gene (LQTS10), identified in a multigenerational Mexican-mestizo family, the missense mutation conferred a secondary gain of function on the Na+ channel such that the accentuated late Na current mimicked that of classic LQTS3-associated mutations in SCN5A.

TISSUES AFFECTED BY CHANNELOPATHIES

Affected Tissue

Skeletal Muscle Cardiac Muscle

CNS PNS

Inherited myotonia and periodic paralysisSCN4A (Nav 1.4)

Paramyotonia congenetia

Myotenia fluctuans

Cardiac arrhythmiaSCN5A (Na v 1.5)

Long QT Syndrome 3

epilepsy syndromes SCN1A,(Nay 1.1), SCN2A (Na„1.2)

generalized epilepsy with febrile seizures plus (GEFS+) severe myoclonic epilepsy in infancy (SMEI) benign familial neonatal infantile seizures (BNIFS)

Pain syndromes SNC9A(Nav1.7) erythermalgia(= erythromelagia)

familial rectal pain

Skeletal Muscle Cardiac Muscle

CNS PNS

Myotonia permanens

Acetazolamide responsive myotonia

Hyperkalemic periodic paralysis

Normokalemic paralysis

Movement.disorders: SCN8A (Nay 1.6) paroxysmal dystonia Morvan syndrome Isaak syndrome

intractable childhood epilepsy generalized tonic-clonic seizures (ICEGTC) infantile spasms (West syndrome)

skeletal muscle cardiac muscle CNS Others Ataxias

Episodic ataxia 2 (CACNA1A) spinocerebellar ataxia 6 (CACNAIA) KCNA1 (potassium channel) episodic ataxia Myotonias CLCN1 (chloride channel) e.g. Thomsen myotonia, Becker myotonia, myotonia congenital, Generalized myotonia, myotonialevior MyastheniasKCNQ2 (potassium channel) myokymia Hypokalemic periodic paralysis 1 (CACNA1S

Long QT syndrome 5 (KCNE1), Jervell-and Lange-Nielsen Syndrome (KCNE1, KCNQ1), inducible long QT syndrome(KCNE2) long QT syndrome 1 (KCNQ1) long QT syndrome 2 (hERG

Cortical hyperexcitability epilepsy syndromes Generalized epilepsy (CACNB4) Benign familial neonatal convulsions 1 (KCNQ2) Benign familial neonatal convulsions 2 (KCNQ3) nocturnal frontal lobe epilepsy (CHRNA4)

Dominant disordl inant deafne: (KCNQ4) Hyperthermia: Malignant hyperthermia 5 (CACNA1 S), malignant hyperthermia 1 (RYR1) Central core dise (RYR1) Renal disorders Polycystic kidney disease (PKD1), Dent's disease (CLCN5), Bartter syndrome (CLCNKB),

CNS PNS

Post traumatic stress disorder

Alzheimer's disease

Parkinson's disease

Bipolar disorder and Schizophrenia

Peripheral nerve hyperexcitability syndromes

Cartoon illustrating the genes associated with inherited arrhythmogenic diseases grouped by ion channel/function.

Napolitano C et al. Circulation. 2012;125:2027-2034

INTERPRETATION OF THE GENETIC TESTING RESULTS OF CHANNELOPATHY

•For asymptomatic long QT syndrome, Brugada syndrome and short QT syndrome patient family members, silent mutant gene carriers, positive drug challenge test patients and asymptomatic individuals with spontaneous ECG abnormality, accurate diagnosis is of critical importance.

•Theoretically, genetic testing is the “gold standard” to determine the preventive and follow-up plan, therapeutic strategy and prognostic estimation for these patients.

However, for example Brugada syndrome, restricted by limited clinical and genetic data, cardiologists are usually confronted with the following challenges:

(1) For 70%-80% of Brugada syndrome patients, the genetic test results are negative

(2) Even if the genetic test results are positive, the mutations may be harmless nonsense mutations

(3) Mutations may be harbored in all of us. For example, the SCN5A mutant gene is mutated in 2-5% of “normal” individuals although the associated mutations of Brugada syndrome are usually found in the seven transmembrane domains and pore-forming segments while the mutations of “normal” individuals are often located in linking areas; .

(4) For most Brugada syndrome patients with identified mutations, the mutations are usually “private”, so it’s impossible to use mutant function studies for every patient;

(5) The invitro mutant function study results may be different from the pathophysiological condition in vivo.

Practically, these are the toughest conundrums to cardiologists. Once the channelopathy diagnoses are established, patients and their families would endure tremendous psychological and social suffering; conversely, if diagnoses are overlooked, each arrhythmic event could be deadly.

Faced with relatively young individuals who could be at risk, which course of action is appropriate for the cardiologist? This is a deep dilemma indeed

GENE THERAPY FOR THE TREATMENT OF BRADYARRHYTHMIAS

Schematic representation of possible gene and cell therapy strategies for the treatment of bradyarrhythmias. ES, embryonic stem cell.

GENE THERAPY FOR THE TREATMENT OF TACHYARRHYTHMIAS

Schematic representation of possible utilization of gene and cell therapy strategies for the treatment of tachyarrhthmias.

CONCLUSIONS AND FUTURE PERSPECTIVES

•The description of new phenotypes is progressing rapidly. The genetic structure of cardiac channelopathies is complex.

•There are still many unanswered questions that are currently being addressed by hundreds of research groups all over the world. The penetrance and expressivity of the cardiac channelopathy phenotypes are particularly fascinating topics.

•Insight into new methods of diagnostic and treatment strategies, such as gene-specific therapy, will hopefully be forthcoming.