Genetics and Arrhythmias

Linda Moulton, RN, MS, Owner, Critical Care ED and C.C.E. Consulting Faculty, Order and Disorder Electrophysiology Training Program, C.C.E. Consulting, New Berlin, Illinois
Linda Moulton, RN, MS, Owner, Critical Care ED and C.C.E. Consulting Faculty, Order and Disorder Electrophysiology Training Program, C.C.E. Consulting, New Berlin, Illinois
The role of genetics as the etiology for arrhythmias is slowly inching its way toward center stage. We see this with many unexplained episodes of sudden cardiac death (SCD) and in the descriptor ‘idiopathic’ attached to many diagnoses. This article touches on the most common of arrhythmia diagnoses which have been linked to genetics thus far.

Congenital Long QT Syndrome (LQTS)

This is an inherited condition, the classic form of which is characterized by prolongation of the QT on the ECG. Symptoms associated with LQTS include syncope, seizures, and sudden cardiac death from ventricular arrhythmias, mainly torsades de pointes. LQTS is caused by mutations of genes that encode for proteins that modulate ion channel structure, function, signaling, or trafficking, and thus alter repolarization, increasing the risk for ventricular arrhythmias. LQTS is a common cause of unexplained syncope and sudden death in healthy young people and carries a high mortality rate when not diagnosed and treated. The incidence of LQTS is 1:2,000 live births, and about 51% of family members are mutation carriers.1 Four percent of gene carriers experience SCD, although 30–50% of carriers never have symptoms. Thus far, 12 different genetic variants of LQTS have been identified.2-4 The presentation of LQTS varies depending on the genetic type. The most common types and the ones about which most are known are LQT.1-3 For LQT1 and LQT2, precipitators are exercise (running, swimming, sports) or emotion (fright, fear, anger, loud noises). On the other hand, events for LQT3 and some LQT2 patients occur primarily at sleep or rest. It is quite uncommon for palpitations, tachycardia or premonitory presyncope to occur prior to an arrhythmic event. This is because torsades is usually too fast to support any circulation or perceptible cardiac contractions. Patients who should be evaluated for LQTS include those experiencing syncope during or after exercise; those with syncope during physical or emotional stress; those with atypical, sudden, unexpected, or frequent syncope; patients with ventricular tachycardia (VT); and those who survive cardiac arrests. Initial findings may include a prolonged corrected QT on the ECG. However, there is a high incidence of positive genetic testing for LQTS occurring in those with normal QTs. Families of patients who test positive for LQTS should be evaluated. Treatment includes beta-blocker therapy; 75% of LQT1 and LQT5, and 50% of LQT2 and LQT6, have events which are adrenergically precipitated. However, beta blockers are not completely effective due to non-compliance and lack of dosing guidelines. If a cardiac arrest or syncope occurs while the patient is on beta blockers, ICD implantation is indicated.5

Brugada Syndrome

Brugada syndrome was first described as a new clinical entity in 1992. Brugada patients have no structural heart disease and a history of syncopal episodes or SCD from ventricular fibrillation (VF). The average age at diagnosis is 40; the youngest diagnosed was 2 days and the oldest 84 years. Brugada syndrome accounts for 4–12% of all SCDs and 20% of deaths in which the heart is structurally normal. The incidence is 5 in every 10,000 people.6–8 Brugada syndrome is a genetically determined, autosomal dominant pattern; it involves mutations of the gene SCN5A (60 mutations are known), which is also responsible for the LQT3 syndrome. These two abnormalities have actually been seen occurring together. The arrhythmic effect occurs through alterations in the sodium channel. There are 4 possible sodium channel mechanisms: 1) the sodium channels fail to express; 2) an alteration of voltage dependence and time dependence of the sodium channel current activation, inactivation, or reactivation occurs; 3) the sodium channel is partially inactivated and recovers slowly; and 4) the sodium channel inactivates in an accelerated manner. Brugada syndrome has been reported in various parts of the world for almost 100 years, though with a variety of names. The syndrome known as SUNDS or SUDS (sudden unexplained nocturnal death syndrome), found in Southeast Asia, is actually the syndrome identified as Brugada. In the Phillipines, Brugada was first reported in the medical literature in 1917, and was called ‘bangungut’, meaning ‘to rise and moan in sleep’. The Japanese reported it in 1959, and called it ‘pokkuri’, or ‘sudden and unexplained ceased phenomenon’. In 1997, the Thai literature called it ‘Lai Tai’, or ‘death during sleep’. An acquired Brugada-like syndrome has been reported, precipitated by drugs. These drugs are the sodium, calcium and beta blockers, antianginals, psychotropic drugs, antihistamines, cocaine, and alcohol. Brugada patients present with a history of syncopal episodes or SCD from VF. Bradycardia has often been related to arrhythmia initiation. Not all deaths occur at night. In addition, the tachycardia often terminates spontaneously as the patient seems to wake up after agonal respirations. Patients who present with a history of SCD are at the highest risk for a recurrence (69%). Those who present with syncope and spontaneously appearing Brugada ECG signs have a recurrence rate of 19%. Those who are at highest risk are males with inducible VT/VF and spontaneously elevated ST segments. During sinus rhythm, the ECG signs of overt Brugada syndrome are found in the right precordial leads: V1, V2, V3. There may be RBBB and abnormal ST elevation in the right precordial leads. These findings may be overt, concealed, or intermittent. The ECG findings are of three types. Type 1 has a coved ST segment elevation ≥ 2 mm (0.2 mV) followed by a negative T wave. Type 2 has a saddleback appearance and a high take-off ST segment elevation of ≥ 2 mm; this is followed by a trough with a ≥ 1mm ST elevation and either a positive or biphasic T wave. Type 3 has a saddleback or coved appearance and an ST elevation 9–10 The ECG in sinus rhythm shows Epsilon waves in V1–V3 (a notch seen in the terminal portion of the QRS) plus anterior precordial T wave abnormalities and a delayed upstroke of S waves. In addition, the signal-averaged ECG is very abnormal. There are multiple LBBB VT morphologies, most coming from perivalvular regions. Since the VT usually originates from the right ventricular free wall, the VT will usually demonstrate poor R wave progression from V1–V4. Some cases of ARVD are thought to be acquired; some, a congenital abnormality of development. Two are inheritance patterns: autosomal dominant with 30% to 50% of family members showing ARVD1–ARVD9, and Naxos disease, a typical ARVD plus nonepidermolytic palmoplantar keratosis (a disorder of the epidermis causing hyperkeratosis of the palms and soles and woolly hair). Cases that are categorized as major will present with severe RV dilation, RV aneurysm/severe segmented RV dilatation, widened QRS of > 110ms in V1–V3, presence of Epsilon waves, and fibrofatty replacement in the right ventricular wall. Milder cases will present with mild RV dilatation, regional hypokinesis, inverted T waves, late potentials, LBBB ventricular premature beats, and a family history. Medical therapy for the VT may include sotalol, beta blockers, and amiodarone. Ablation of stable VTs may be performed, but it must be kept in mind that this is a progressive disease. ICD therapy is used in cases where multiple risk factors are present.

Catecholaminergic Polymorphic VT (CPVT)

This is an inherited condition that is adrenergically mediated. CPVT is caused by a mutation of the genes which encode for proteins responsible for control of intracellular calcium. In CPVT there is an alteration in the calcium release from the sarcoplasmic reticulum. There are two types of CPVT: the autosomal dominant type, which is associated with mutation in the gene encoding the cardiac ryanodine receptor (RyR2), and the recessive form, which is associated with homozygous mutation in the gene encoding the cardiac isoform of calsequestrin (CASQ2).11–12 The clinical presentation of CPVT is very similar to that seen in LQTS. There is usually a history of syncopal episodes, which are triggered by physical exercise or psychological stress. However, these symptoms manifest in LQTS at puberty, while with CPVT they usually manifest in childhood, with a mean age of eight. The presenting VT for the two syndromes is also different, with torsades being the arrhythmia associated with LQTS and a bidirectional VT with beat-to-beat 180° rotation of the QRS being associated with CPVT. (The exception is LQTS Type 7, Anderson Syndrome, which may have bidirectional VT.) The diagnosis of CPVT is made through the ECG and during exercise testing. Eighty percent of patients will have PVCs during exercise testing. As the level of exercise increases, ventricular arrhythmias become more frequent, until polymorphic or bilateral VT is recorded. At the completion of testing, rate and rhythm frequency decrease until the ventricular activity disappears. There may be occasional runs of SVT and VT. If CPVT is left untreated, 80% of patients will develop symptoms by 40 (syncope, VT, VF). The overall mortality is 30–50%. CPVT is a frequent cause of unexplained arrest in patients with no known structural heart disease. The first-line therapy for CPVT is beta blockers. The efficacy is less than in LQT1 and about equivalent to that for LQT2. After beta-blocker therapy is established, the patient should be re-stressed. If VT still recurs, an ICD should be implanted. Beta-blocker therapy must be continued with the ICD in order to prevent VT storm or possible SCD, which may occur even with the ICD.

Screening of Family Members

Hofman et al13 conducted screening of families with LQTS, Brugada syndrome, and CPVT, and initiated prophylactic treatment on a large number. Sixty-five percent of positive LQTS relatives were treated and 71% of CPVT relatives were treated, mostly with beta-blocker therapy. For Brugada syndrome, the symptomatic 6% were treated, 4 with an ICD and one with a pacemaker. Of particular note is the fact that 108 LQTS patients with positive genetic findings and post-cardiology workup that were treated had QTc Genetic Testing As a result of the recognition of the volume of possible family members who may inherit these diseases and the potentially lethal outcome, companies are springing up which offer a wide panel of genetic tests and have geneticists and genetic counselors on call. One such company offers tests for hypertrophic cardiomyopathy (17 genes), dilated cardiomyopathy (23 genes), LQTS (12 genes), short QT syndrome (3 genes), Brugada syndrome (5 genes), ARVD (7 genes), and CPVD (2 genes). Therefore, a physician may have a family tested and receive expert guidance on how to proceed with treatment and prophylaxis. The body of knowledge related to genetics and arrhythmias will continue to grow. Genetic links have been identified for atrial fibrillation, WPW, short QT syndrome, and sudden infant death. Implications for treatment in addition to legal and ethical issues abound.


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