The Inherited Arrhythmia Syndromes

The Inherited Arrhythmia Syndromes

Danna Spears


The Inherited arrhythmia syndromes are relatively uncommon, but their true prevalence is difficult to accurately quantify, as gene carriers may not manifest disease. Reported prevalence ranges from 1/2000 in long QT syndrome (LQTS)1 and Brugada syndrome2 to 1/10,000 for catecholaminergic polymorphic ventricular tachycardia (CPVT).3 This chapter will summarize the experience of pregnant women with the above disorders, as well as mothers with inheritable cardiomyopathies who are also at risk of ventricular arrhythmias. There are no formal guidelines for management of these pregnancies, rather suggestions to consider based on limited data. The general approach to management of these disorders during pregnancy includes identification of high-risk features, avoidance of arrhythmia provocation, arrhythmia prophylaxis when possible, and appropriate neonatal screening.


Creating an individualized labor and delivery plan with multidisciplinary input from electrophysiology, genetics, maternal fetal medicine, and anesthesiology should improve outcome for the pregnant woman and her baby. Maternal risk factors and history of cardiac “events” (cardiac arrest, ventricular arrhythmia, or syncope) should be taken into consideration when determining intrapartum monitoring and the method of delivery. For example, maternal cardiac telemetry should be considered when the mother has a history of cardiac dysfunction or cardiac events. Ideally, genetic testing of the affected mother should be completed prior to delivery to allow for the option of cord blood testing for the family variant in the offspring at the time of delivery. The mother should avoid all medications with the potential to provoke arrhythmia-related events and continue the most protective antiarrhythmic treatment such as beta-adrenergic blocking agent4 (discussed below). Anesthetic planning should include review of all maternal medications to avoid inadvertently putting the mother at greater than a priori risk.5,6

In general, for a woman with a primary arrhythmia disorder and normal cardiac function, unassisted vaginal delivery is not contraindicated.7 However, in some arrhythmia disorders, adverse outcomes are more likely during exertion or emotional
stress, that is, when the heart rate is elevated.8 Because the mother’s heart rate increases significantly in the active pushing phase of labor, and ˜20% of women achieve 100% of their maximum age-predicted heart rate at this time,9 higher-risk women may benefit from epidural anesthesia, and assisted or operative delivery. However, the impact of mode of delivery and anesthesia on sympathetic activation and circulating maternal and fetal catecholamine levels is not well studied. In fact, there is little agreement between small published studies.9,10,11,12 TABLE 5.1.1 summarizes the suggestions for management of the pregnant woman with an inherited arrhythmia.

After delivery, the mother’s prophylactic antiarrhythmic medications should be continued as the postpartum time is especially high risk for certain inherited arrhythmias. The infant should have a 12-lead ECG and consultation with a pediatric cardiologist and geneticist prior to hospital discharge. Experienced clinicians and genetic counselors can provide subsequent recommendations for family screening13,14 (see Part 1, Chapter 3) and ongoing cardiology care if the infant carries the family variant.


Inherited Arrhythmia

Increased Risk during Pregnancy

Arrhythmia Triggers

Peripartum Monitoring?

Indications for Cesarean Delivery

Fetal Phenotype?


Yes, postpartum esp. LQT2

QT prolonging medications

With oxytocin







Hx of cardiac arrest or unstable rhythm


Brugada (AD SCN5A and others)


Fever, bupivacaine, lidocaine, propofol







Heart failure or unstable arrhythmias




Vasodilation, hypotension




AD, autosomal dominant; AR, autosomal recessive; ARVC, arrhythmogenic right ventricular cardiomyopathy; CPVT, catecholaminergic polymorphic ventricular tachycardia; esp, especially; HOCM, hypertrophic obstructive cardiomyopathy; Hx, history; LQTS, long QT syndrome; VP, variable penetrance.


LQTS is a disorder of myocardial repolarization associated with a prolonged QT interval on the surface ECG and usually inherited in an autosomal dominant fashion.15 Torsades de pointes (TdP) is the form of polymorphic ventricular tachycardia (VT) classically described in LQTS and is the triggered arrhythmia that leads to syncope and sudden death.16 There are at least 15 genetically distinct subtypes of LQTS, but the three most commonly encountered forms are due to mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQTS3).17 The diagnosis of LQTS and its association with some fetal and neonatal losses are discussed in Part 3, Chapter 7.

Pregnancy is a significant modulator of outcome in LQTS.18,19,20 There is some heterogeneity in the literature regarding risk of arrhythmia during pregnancy, but the bulk of data suggests that there is likely no significant increase in risk until after delivery.21,22,23 Prior to commercial genetic testing, the incidence of syncope and sudden death in mothers with LQTS was 3.8% prior to pregnancy and 9.0% during pregnancy. The event rate increased substantially to 23.4% in the first 9 months postpartum.18 Even in a low-risk cohort, that is, mothers with no events prior to pregnancy, the risk of postpartum events remained significantly elevated (9%).18 In these early studies, only a minority of women were using a beta-blocker at the time of their event; since then beta-blocking agents have been found to protect against cardiac events.24,25

In the genomic era, it has become evident that the genetic LQT subtype is also an important modulator of pregnancy-related arrhythmia risk.21,26 For example, postpartum cardiac event rates are <1% in LQT1, 16% in LQT2, and have not been reported in LQT3.20,21

The factors responsible for the increase in cardiac events during the postpartum period are not well understood. After birth, estrogen levels fall, and oxytocin and prolactin levels increase. Falling levels of estrogen may increase the expression of myocardial adrenergic receptors27 and may also influence mechanisms regulating intracellular calcium balance, predisposing to afterdepolarizations and arrhythmogenesis.28,29,30 In female transgenic rabbits with a KCNH2 G628S pathogenic variant, prolactin and oxytocin were found to increase QT interval and action potential duration and predispose to ventricular arrhythmia.31 Environmental factors that abruptly increase maternal heart rate such as sudden acoustic stimuli or sudden intense emotion may also be important arrhythmia triggers, especially for LQT2 mothers because of the pronounced failure of repolarization to accommodate to rapid increases in heart rate.

Beta-Adrenergic Blocking Agents in LQTS

Beta-adrenergic blocking agents are highly effective in the prevention of maternal arrhythmia events in LQTS and are the first-line therapy for arrhythmia prophylaxis in this condition.4 Beta-blockade is most effective in patients with LQT1 and LQT2 and advocated by most in LQT3.9,32 There is strong evidence to support the efficacy of beta-blockade in preventing pregnancy-related arrhythmia events: beta-blocker use significantly reduces postpartum major cardiac event rates from 3.7% to 0.8%.19,20 There are abundant data supporting the safety of commonly used beta-blockers in
pregnancy.1,33 The beta-blockers with proven efficacy in LQTS include nadolol, propranolol, metoprolol, and atenolol; however, atenolol should not be used in pregnancy, as it is associated with significant intrauterine growth restriction (pregnancy class D).34,35,36,37,38 Of the beta-blockers with demonstrated efficacy in LQTS, nadolol, propranolol, and metoprolol are pregnancy risk Category C. There is some evidence that metoprolol, particularly the shorter acting formulation with twice-a-day dosing, is inferior to nadolol or propranolol, particularly in individuals with a prior history of arrhythmia events.39 Overall, nadolol was found to be most effective and is considered the beta-blocker of choice overall, but especially in higher risk patients, including LQT2 mothers, women with QTc >500 ms, and individuals with a prior history of syncope or cardiac arrest.32,35,36,37,39 Nadolol dosing up to 1 to 1.5 mg/kg/d is the typical dose used in LQTS. If nadolol is poorly tolerated or not available, propranolol, another noncardioselective beta-blocker, can be considered.

Data on the use of nadolol in pregnancy are limited. However, nadolol has a long half-life and is excreted in the breast milk to a greater degree than propranolol or metoprolol40,41; thus it is likely to accumulate to some degree in the nursing infant. Although the American Academy of Pediatrics classified nadolol as compatible with breast-feeding,42 nursing infants of mothers consuming nadolol should be closely observed for symptoms of beta-blockade including bradycardia and hypotension. It is estimated that the neonate would receive about 5.1% of the maternal weight-adjusted dose. Propranolol, on the other hand, shows a low risk for accumulation in a breast-feeding infant.42 There is increasing experience with the use of bisoprolol, particularly in LQT1; however, small sample size and lack of data supporting its safe use in pregnancy preclude its routine use in this population.43

Gestational Surveillance of LQTS

There are no clear guidelines for surveillance of LQTS over the course of pregnancy, but important principles include confirmation of the diagnosis, treatment with beta-blocker for arrhythmia prophylaxis, and realization that the fetus has a 50% chance of carrying the family variant. Beta-blockers should blunt the maximum maternal heart rate, with the dose adjusted to ensure resting heart rate <100 bpm during pregnancy. Periodic Holter monitoring may be useful as a guide to heart rate trends over the course of 24 to 48 hours. Although maximal, symptom-limited treadmill testing is not routinely performed in pregnancy, a modified treadmill test may be useful to ensure adequate beta-blockade in high-risk LQTS mothers.

Labor and Delivery Plan for LQTS

The plan for labor and delivery should be individualized. Low-risk women (no history of arrhythmia events) who are adequately treated with beta-blocker can safely proceed with spontaneous vaginal delivery unless maternal or fetal indications for assisted or cesarean delivery are present. Although active pushing is expected to increase the maximal heart rate, it is expected that the heart rate response would be blunted in a woman with adequate beta-blockade.8 Maternal intrapartum rhythm monitoring is not necessary, as event rates are extremely low.

Any pharmacologic therapy in an individual with LQTS should be reviewed for potential QT prolongation.6 Oxytocin, commonly used during labor and delivery, has some potential for QT prolongation, but this should not preclude its use when indicated.44,45,46 A reasonable approach to oxytocin use is to optimize serum potassium and magnesium levels and to obtain an ECG at baseline, and then 1 to 2 hours after oxytocin is initiated. The drug should be discontinued if the QTc exceeds 500 ms or increases by 60 ms from baseline.45,46 Theoretically oxytocin may also predispose the LQT-positive fetus to QT prolongation and ventricular arrhythmias, but this has not been reported. Decisions regarding analgesia, including neuronal axial blockade, should be made according to maternal preference and estimated obstetric risk.

Maternal TdP requires immediate recognition and treatment, including defibrillation for sustained arrhythmia.47 Pharmacotherapy should be reviewed for potentially QT-prolonging drugs, and they should be immediately discontinued. Electrolyte imbalance, particularly hypokalemia or hypomagnesemia, should be corrected. Treatment of bradycardia or frequent pauses with temporary pacing followed by beta-blockade, and addition of lidocaine if needed, may be required for management of ongoing ventricular arrhythmias.

There is evidence that fetal loss, both miscarriage and stillbirth, is increased with familial LQTS compared to the general population.48 These findings are irrespective of fetus genotype and occur to a greater extent when the mother, not the father, has LQTS.48 Any fetal loss should be tested for the family variant.

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Dec 30, 2020 | Posted by in CARDIOLOGY | Comments Off on The Inherited Arrhythmia Syndromes
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