Cardiac Channelopathies
Cardiac channelopathies are a group of heterogeneous disorders that affect the ion channels of the heart. These disorders cause cardiac arrhythmias in otherwise healthy and typically young individuals and can lead to syncope, cardiac arrest and sudden death. The ion channels mediate the flow of potassium, sodium and calcium across the myocytes. Inherited channelopathies can be due to mutations in  sodium, potassium, or calcium ion channel genes and are characterized by prolonged ventricular repolarization and risk for polymorphic ventricular tachycardia-and/or ventricular fibrillation.

Inherited Long QT Syndrome
Inherited Long QT Syndrome (LQTS) is the most common of these disorders and occurs with a frequency of approximately 1 in 3,000. Symptoms of LQTS include syncope and seizures due to a characteristic dysrhythmia called torsades de pointes (TdP). Failure of the heart to revert to its normal rhythm leads to ventricular fibrillation. Various triggers such as exercise, emotion, auditory stimulus, sleep/rest and QT-prolonging drugs are known to cause these cardiac events in affected individuals.
LQTS can be diagnosed by a prolonged QT interval on a resting electrocardiogram (ECG). A corrected QT interval (QTc) of 470 msec in males and 480 msec in females is usually diagnostic of the disorder, although the ECG is not always sufficiently sensitive or specific to diagnose LQTS. Diagnostic testing can be extensive and, in addition to an ECG, may include an echocardiogram, provocative testing and similar evaluation of key family members. LQTS is inherited in an autosomal dominant pattern and shows incomplete penetrance. At least 1/3 of mutation carriers are asymptomatic. Identifying affected family members can be difficult, but is imperative.

Mutations in five cardiac ion channel genes are responsible for up to 75% of the cases of familial LQTS. KCNQ1, KCNH2 and SCN5A encode large transmembrane proteins that comprise the core alpha subunit for the respective ion channels IKS, IKR and INa. KCNE1 and KCNE2 are small, single exon genes that form auxiliary subunits of the mature IKS and IKR potassium channels respectively.

Several studies have examined  genotype-phenotype correlations for LQTS. Schwartz et al. in 2001 analyzed relationships between genotypes and triggers for life-threatening arrhythmias. Among LQT1 patients, 62% had events triggered by exercise and only 3% had events during sleep/rest. Among LQT2 and LQT3 patients, the rate of events during exercise was much lower and during emotion and sleep/rest much higher. The percentage of lethal events was highest in LQT3 and lowest in LQT1.

Frequency of Cardiac Events¹⁰

Subjects from the International LQTS Registry & BIOMED LQTS Research Group

Moss et al. in 2000 examined cardiac event rates by genotype before and after treatment with β-blockers. They followed a total of 869 patients for 5 years. Their findings showed that treatment significantly reduced cardiac events in LQT1 and LQT2 patients. No protective benefit was demonstrated among patients with the LQT3 genotype.

Effectiveness of β-Blocker Treatment⁷

Rate of cardiac events over five years for subjects from the International LQTS Registry

Some evidence suggests that the diagnosis, course of disease and selection of appropriate treatment depend on the genetic mutation(s) that a particular patient carries.

Acquired LQTS
Multiple external factors such as abnormal electrolyte balance, heart failure and various other medical conditions can lead to a prolonged QT interval. A common cause of acquired LQTS, however, is exposure to certain medications. Over 50 FDA approved medications have been implicated in acquired LQTS. There have been reports of both mutations and polymorphisms that are associated with an increased risk of acquired LQTS.

Approximately 50-55% of individuals affected with CPVT harbor a mutation in the RYR2 gene which encodes the pore-forming subunit of the cardiac calcium release channel. RYR2 is the basis of the FAMILION CPVT Test.  Mutations in the RYR2 channel are annotated as Type 1 CPVT (CPVT1)

The majority of cardiac events in CPVT occur during childhood, adolescence and young adulthood.  CPVT should be regarded as highly lethal.  If left untreated, 30% of CPVT patients will develop symptoms by age 10, 80% by age 40 with an overall mortality rate of 30 – 50%.

Adapted from: Napolitano C, et al. Diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia. Heart Rhythm. 2007;4:675-678.

The efficacy of β-blockers in CPVT is lower than that of LQT1.  Nearly 50% of patients taking a β-blocker will continue to experience cardiac arrhythmias and may require an implantable cardioverter defibrillator (ICD).  A two year study by Priori et al. indicated that among CPVT patients with an ICD, 50% of them received an appropriate shock.

Brugada Syndrome (BrS)
Loss of function variants in the sodium channel gene SCN5A account for 15-20% of the cases of BrS. BrS also causes ventricular arrhythmias, but the ECG is characterized by right precordial ST segment elevation and incomplete right bundle branch block rather than a prolonged QT interval. BrS is usually diagnosed at a later age than LQTS, often not until age 40. Implantation of an ICD is the only established effective treatment.

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