The Risk of Cardiac Events and Genotype‐Based Management of LQTS Patients

Abstract

This review discusses the risk of cardiac events and genotype‐based management of LQTS. We describe here the genetic background of long QT syndrome and the eleven different genes for ion‐channels and a structural anchoring protein associated with that disorder. Clinical Background section discusses the risk of cardiac events associated with different LQTS types. Management and Prevention section describes in turn gene‐specific therapy, which was based on the identification of the gene defect and the dysfunction of the associated transmembrane ion channel. In patients affected by LQTS, genetic analysis is useful for risk stratification and for making therapeutic decisions. A recent study reported a quite novel pathogenic mechanism for LQTS and suggested that treatments aimed at scaffolding proteins rather than specific ion channels may be an alternative to antiarrhythmic strategy in the future.

GENETIC BACKGROUND

Congenital long QT syndrome (LQTS) is a familial disorder with an autosomal dominant (Romano‐Ward syndrome and Timothy syndrome) or recessive trait of inheritance (Jervell and Lange‐Nielsen syndrome). LQTS is associated with prolonged QT interval in the electrocardiogram, abnormal T‐wave morphology, and a propensity to recurrent syncope, which are caused by polymorphic ventricular tachyarrhythmia known as torsade de pointes (TdP). ¹ , ²

LQTS is a primary electrical disease caused by mutations in eleven different genes for ion channels and a structural anchoring protein, located on chromosomes 3, 4, 6, 7, 11, 17, and 21 (Table 1). ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ Mutations in KCNQ1 (LQTS1) and KCNE1 (LQTS5) are responsible for defects in the slowly activating component of the delayed rectifier potassium current (I_Ks). The mutations in HERG (LQTS2) and KCNE2 (LQTS6) are, in turn, responsible for defects in the rapidly activating component of the delayed rectifier potassium current (I_Kr). Mutations in SCN5A alter the function of the sodium channel (I_Na) and are responsible for LQTS3. ³

Table 1.

LQTS Subtypes

Phenotype	Subtype	Locus	Gene	Ion Channel
Romano‐Ward syndrome; Jervell and Lange‐Nielsen syndrome	LQTS1	11p15.5	KCNQ1 (KvLQT1)	↓IKs alpha subunit
	LQTS2	7q35‐36	KCNH2 (HERG)	↓IKr alpha subunit
	LQTS3	3p21‐24	SCN5A (Nav1.5)	↑INa alpha subunit
	LQTS4	4q25‐27	ANK2 (ANKB)	Targeting protein
	LQTS5	21p22.1‐22.2	KCNE1 (minK)	↓IKs beta subunit
	LQTS6	21p22.1‐22.2	KCNE2 (MiRP1)	↓IKr beta subunit
Andersen–Tawil syndrome	LQTS7	17q23	KCNJ2 (Kir2.1)	↓IK1 (IKir2.1)
Timothy syndrome	LQTS8	6q8A	CACNA1C (Ca v 1.2)	Ica‐L alpha subunit
	LQTS9	3p25	CAV3	Caveolin 3
	LQTS10	11q23	SCN4B	Nav beta‐4 subunit
	LQTS11	7q21‐q22	AKAP9	A‐kinase anchoring protein 9

Five out of eleven genes encode for cardiac potassium channels; one codes for cardiac sodium channels (SCN5A) and one for the Ankyrin B (ANKB) protein, which is involved in anchoring of ion channels to the cellular membrane (LQTS4). ⁵ Abnormalities of T‐wave morphology and QT interval prolongation have also been reported in patients with Andersen's syndrome (LQTS7), an hereditary periodic paralysis disorder caused by reduction in the inwardly rectifying potassium current (I_Kir2.1). ⁶

Perturbed inactivation of Ca²⁺ channel activity known as Timothy syndrome (LQTS8) has been caused by mutations in Ca_v1.2 gene, which encodes for an alpha subunit of the calcium channel I_ca‐L. ⁷ , ⁸ , ⁹ Timothy syndrome is characterized by lethal ventricular arrhythmias with prolonged QT interval in the electrocardiogram, autism, hypoglycemia, immune deficiency, and multiorgan dysfunction (congenital heart disease, webbing of the fingers and toes). ⁷

Recent studies reported the mutations in caveolin‐3 (LQTS9) as well as a mutation in A‐kinase anchoring protein (LQTS11), which may underlie novel pathogenetic mechanisms of LQTS. ¹⁰ , ¹¹ Mutations in SCN4B is also a novel LQTS‐susceptibility gene (LQTS10), which encodes for beta‐4 subunit of the cardiac sodium channel. ¹²

Approximately 500 different mutations have already been associated with LQTS, but most identified mutations occur in LQTS1, LQTS2, and LQTS3 genes. It is anticipated that many more mutations in these genes and in new LQTS candidate genes will be identified in the future. ⁴ , ¹³

CLINICAL BACKGROUND

Sympathetic stimulation, such as exercise, strong emotion, and loud noise, has been associated with playing a role in the genesis of QT prolongation and TdP in some forms of LQTS. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ These adrenergic conditions give rise to early after depolarizations and triggered activity, and produce a marked dispersion of ventricular repolarization, particularly in LQTS1 and LQTS2 genotypes. ¹⁸ , ¹⁹

The highest rate of cardiac events such as syncopal episodes, aborted cardiac arrest, or sudden cardiac death (SCD) was shown to occur during adolescence in the LQTS subjects. ²⁰ , ²¹ , ²² , ²³

The recent data suggest that female gender, corrected QT interval (QTc ≥ 500 ms), LQT2 genotype, and frequency of cardiac events before age 18 years were associated with increased risk of having any cardiac events between the ages of 18 and 40 years. ²⁴ The LQTS3 genotype and the recent syncope (<2 years in the past) were shown to be significant risk factors after age 40 years. ²⁵

LQT1 syndrome has been reported both experimentally and clinically as well as to be more sensitive to sympathetic stimulation (physical or emotional stress) and more responsive to beta‐blockers than either LQT2 or LQT3 of syndrome. ^{14 , 26} , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³²

Exercise‐related events, especially swimming, dominate the clinical picture in patients with LQTS1. ¹⁵ , ¹⁶ , ³³ A sudden startle in the form of an auditory stimulus (alarm clock) is the predominant trigger of cardiac events in LQT2 syndrome, whereas cardiac events also occur during rest or emotion. ¹⁵ LQTS3 patients are susceptible to cardiac events occurring at rest and during sleep. ¹⁹ , ³⁴

Sixty‐five percent of the patients with a given genotype are more likely to experience cardiac events under conditions similar to their first classified event. But the greater probability of becoming symptomatic under one condition does not exclude the possibility of a cardiac events occurring under different circumstances. ¹⁴ Use of clinical information in determining genetic screening for LQTS was reported. ³⁵

The cumulative survival curves demonstrate that the age at which LQTS becomes clinically manifest is also gene specific. LQTS1 patients are the youngest to experience cardiac events; 86% of them have their first episode by age 20. In contrast, symptomatic LQTS2 and LQTS3 patients are also at risk of the onset of cardiac events later in life. ¹⁴ However, 48% cumulative probability of cardiac events concerns LQTS2 females between ages 16 and 40; only LQTS1 and LQTS3 males show a higher risk of cardiac events. This observation emphasizes the need to carefully follow and treat LQTS patients (particularly females) who remain at high risk of cardiac events despite asymptomatic course in childhood and adolescence. ³⁶ , ³⁷

The lethality of cardiac events (the risk of death during a cardiac event), which is significantly higher in the LQTS3 patients than in the LQTS1 and or LQTS2 patients, may also suggest the need for more aggressive treatment of LQTS3 patients. ³⁴ QT interval duration was identified as the strongest predictor of risk for cardiac events in LQTS1 and LQTS2 patients. QTc exceeding 500 ms identifies patients with the highest risk of becoming symptomatic by the age of 40. ¹⁵ , ³⁸ , ³⁹ Males with LQTS3 may represent a group at higher risk, irrespective of QT interval duration. ³⁴ , ³⁹ A normal QT interval in family member without identifying mutations portends a good prognosis. ⁴⁰ , ⁴¹

Patients with the LQTS associated with syndactyly (Timothy syndrome) and with congenital deafness (Jervell and Lange‐Nielsen syndrome) are at higher risk of cardiac events. ⁷ , ⁴² Patients with Andersen's syndrome seem to have bidirectional ventricular arrhythmias but not a high incidence of cardiac arrest. ⁶

The recent data indicate that the type of biophysical ion channel dysfunction and location of LQTS1 and LQTS2 mutations may have important influence on the phenotypic manifestations and clinical course of patients with these disorders. ⁴³ , ⁴⁴

Patients with mutations in the pore region of the HERG gene had more severe clinical manifestations of the genetic disorder and experienced a higher frequency of arrhythmia‐related cardiac events occurring at earlier age compared with patients with nonpore mutation. ⁴³

Another genotype–phenotype study indicates that in type 1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder. ⁴⁴

MANAGEMENT AND PREVENTION

There were three classical modalities of treating LQTS: beta‐adrenergic blocking agents (beta‐blockers), ² , ^{14 , 45} , ⁴⁶ , ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ elective pacing (pacemakers), ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² and left cervicothoracic sympathetic ganglionectomy. ⁵³ , ⁵⁴ , ⁵⁵

Beta‐blockers have been used as standard therapeutic and preventive measures in patients with clinical diagnosis of LQTS. ² , ¹⁴ , ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸ The mechanism of beta‐blocker action is to prevent the increase in repolarization dispersion induced by sympathetic stimulation. ²⁶ , ²⁷

Beta‐blocker treatment is effective in about 60–70% of LQTS patients in all age groups. ²³ , ²⁴ , ²⁵ , ⁴⁷ Beta‐blockers effectively reduce but do not completely eliminate the risk of fatal or near‐fatal cardiac events in high‐risk patients with LQTS. ²³ , ²⁴ , ²⁵

Beta‐blocker therapy does not improve magnesium (Mg) deficiency; the latter may become a triggering mechanism of life‐threatening arrhythmias. Management with intravenous magnesium sulfate may be a possible therapeutic option for an acute episode of TdP, but not for chronic treatment. ⁵⁶

The evidence of pause or bradycardia‐dependent arrhythmias and symptomatic bradycardia induced by beta‐blocker therapy should be considered an indication for use of cardiac pacing as an adjunct to beta‐blockers. ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² The cardiac pacing prevents pauses and shortens the QTc interval by enhancing the repolarizing potassium currents as the result of increased heart rates. Beta‐blocker therapy with pacemakers does not prevent sudden death in LQTS patients. ⁵⁰ , ⁵¹

Left cardiac sympathetic neural denervation is considered for LQTS patients, with syncope, TdP, or cardiac arrest, who do not respond to beta‐blockers. ⁵³ , ⁵⁴ , ⁵⁵ It is an effective method of surgical antiadrenergic therapy, especially during early childhood, in which cardioverter‐defibrillator implantation may be technically more difficult. ⁵⁴ , ⁵⁵

The implantable cardioverter‐defibrillators (ICDs) have been used successfully in cases TdP persist despite therapy with the classical modalities. ⁵⁷ , ⁵⁸ The ICDs will not prevent the precipitation of torsades but will prevent sudden cardiac death when torsades are prolonged or generate to ventricular fibrillation. The use of beta‐adrenergic blocking agent should be continued because emotional distress associated with the unnecessary shocks from the cardioverter‐defibrillator may cause adrenergic stimulation and torsades. Implantation of an ICD with continued use of beta‐blockers can be effective in reducing SCD in LQTS patients with previous cardiac arrest and in patients with experiencing syncope and/or VT. ⁵⁷ , ⁵⁸

The identification of specific ion current abnormalities in genetically diagnosed LQTS patients has provided understanding of electrophysiologic mechanisms underlying LQTS, but more importantly it opened new therapeutic options. ⁵⁹

The role of I_Ks impairment in facilitating adrenergic‐dependent arrhythmias has been documented to have implications for beta‐blocker therapy in LQTS1 patients. ¹⁴ , ²⁷ , ²⁹ , ³¹ , ⁴⁷ Eighty percent of them remained free from recurrences with a total mortality rate of 4%. Only a few LQT1 patients required therapy other than antiadrenergic intervention. ¹⁴

The use of potassium channel openers is another attractive therapeutic option in LQTS1 patients with potassium channel abnormalities. ⁶⁰ , ⁶¹ , ⁶² Experimental administration of nicorandil, the ATP‐sensitive potassium channel opener, contributed to a decrease in QT interval duration, monophasic action potential duration and dispersion, as well as eliminated early afterdepolarizations in LQT1 patients. ⁶¹ Currently, these agents may be considered only as adjuncts to the standard therapy.

Gene‐specific management for LQT2 is more problematic. The efficacy of beta‐blockers in LQT2 patients was already demonstrated. ¹ , ²⁶ The experimental prevention with beta‐blocker therapy for life‐threatening arrhythmias triggered by a loud noise suggests their effectiveness also for LQT2 patients at risk under this specific condition. ¹⁵ But Priori et al. have found a high rate of cardiac events in patients with LQTS2 and LQTS3 genotypes treated with beta‐blockers. These observations suggest that cardioverter‐defibrillator may be a reasonable alternative in high‐risk LQTS2 and LQTS3 patients. ⁶³

It is known that elevated levels of serum potassium increase outward potassium currents in patients with potassium current abnormalities. ¹⁴ In LQTS2 patients with mutation in HERG gene and with defects in the rapidly activating component of the delayed rectifier potassium current (I_Kr), extracellular potassium levels are increased following intravenous potassium chloride injection and oral spironolactone administration (I_Kr), which results in raised channel activity and improved repolarization. ⁶⁴ Preliminary clinical observations indicate that long‐term oral potassium supplementation and/or administration of spironolactones in LQT2 patients decrease QT interval duration and QT dispersion. ⁶⁵ , ⁶⁶ However, renal potassium homeostasis causes difficulties in achieving high potassium with chronic oral therapy. ⁶⁵

LQT3 patients are at higher risk of longer cycle lengths and they did not tolerate very well with use of beta‐blocker therapy, which can reduce heart rate. LQT3 patients may benefit from pacemakers, which would also allow safe use of beta‐blockers, because their QT interval tends to shorten significantly at faster heart rates. ¹⁴ Since this mutation causes the inward flow of sodium ions during repolarization, administration of sodium channel blockers, especially class Ib drugs, is the right choice for potential genetically driven therapy. ²⁸

Schwartz et al. were the first to use mexiletine in patients with mutations in the sodium channel SCN5A gene. ⁶⁷ Mexiletine, lidocaine, and tocainide in low doses were found to block abnormal inward current, normalizing sodium channel inactivation. ²⁸ , ⁶⁷ , ⁶⁸ Under clinical conditions, intravenous lidocaine or oral mexiletine may be considered in patients who present LQTS3 and TdP. These agents yielded in few LQT3 patients a very significant QT interval shortening. ⁶⁷ , ⁶⁸ This spectacular electrocardiographic effect does not mean that class Ib antiarrhythmic drugs will prove effective in preventing cardiac events in LQT3 patients. Effective chronic therapy results with class Ic antiarrhythmic drug flecainide, a late sodium current blocker, were reported for LQTS3 deltaKPQ mutant. ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³

Even though the data regarding therapy for LQT3 patients remain numerically limited, their high mortality rate despite therapy and particularly at the first episode suggests considering internal cardioverter‐defibrillator implantation with use of beta‐blockers for prophylaxis of SCD.

Little is known about risk stratification and management of patients with Andersen's syndrome. The benefit of prophylactic treatment with beta‐blockers has not been defined in these patients. The beneficial role of calcium channel blockers and flecainide has also been proposed on the basis of bidirectional ventricular arrhythmias suppression observed in a few patients. ⁷⁴ , ⁷⁵ , ⁷⁶

Lifestyle modification is recommended for patients with clinical and/or molecular LQTS diagnosis (see Table 2). ¹⁴ , ⁷⁷ , ⁷⁸

Table 2.

Lifestyle Modifications Recommendations for LQTS Patients on the Basis of Genotype

Recommendations	LQTS1	LQTS2	LQTS3
Avoid competitive sport activity	+++	++	+
Avoid swimming without supervision	+++	+
Avoid emotional stress	+++	+++	+
Avoid exposure to acoustic stimuli mostly during sleep	+	+++	++
Avoid drugs that may prolong QT interval	++	+++	++
Avoid drugs that may deplete potassium/magnesium	++	+++	++

Genetic analyses are very important for identifying all mutation carries within an LQTS family. Although genetic analysis is not yet widely available, it is advisable to try to make it accessible to LQTS patients. In patients affected by LQTS, genetic analysis is useful for risk stratification and for making therapeutic decisions. ⁷⁹ Asymptomatic gene carriers could be advised to avoid stressful conditions and competitive sport as well as drugs knows to prolong the QT interval. Depending on the malignancy of the disease in the family, beta‐blockers can be started for prophylaxis of life‐threatening arrhythmias. ¹⁴ , ⁷⁷ , ⁷⁸

Conversely, family members identified as “non‐gene carriers” can be assured that they can conduct a completely normal life. ⁸⁰ Furthermore, silent mutation carriers should receive genetic counseling to learn about the risk of transmitting LQTS to offspring. With rare exceptions, LQTS is an autosomal dominant disease, and these silent gene carriers should be informed that 50% of their offspring may be expected to carry the same mutations. ⁸¹ Molecular diagnosis, therefore, has to be scheduled for their newborn infants unless they have obvious QT prolongations. ⁸² , ⁸³ , ⁸⁴

The discovery in 1995 of cardiac channel mutations causing “cardiac channelopathy” opened new therapeutic options for LQTS patients. However, a recent study reported a quite novel pathogenic mechanism for LQTS. ¹⁰ , ¹¹ The LQTS‐associated mutations in the scaffolding protein caveolin‐3 alter the properties of the caveolar‐localized cardiac sodium channel and confer a gain‐of‐function phenotype to the structurally intact sodium channel. ¹⁰ The latter study suggests that treatments aimed at scaffolding proteins rather than specific ion channels may be an alternative to antiarrhythmic strategy in the future.