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Introduction:

Congenital LQTS is a genetic disorder that can lead to abnormal electrical activity in the heart muscle known as an arrhythmia.  The many different mutations that lead to congenital LQTS are commonly called channelopathies.  Channelopathies are disorders caused by mutations in genes that encode for protein channels.  These mutations lead to disrupted flow of sodium, potassium, and calcium ions in and out of the cardiac muscle cell.  This abnormality can result in loss of consciousness, arrhythmias requiring cardiopulmonary resuscitation (CPR), and death.  An abnormal electrocardiogram (EKG) can identify patients with this disease.  On the EKG, patients often have a prolonged QT interval and/or abnormal T wave morphology.

            When measuring the degree of QT interval prolongation, it is necessary to correct for the patient’s heart rate, termed QTc.   This is done with Bazett’s Formula:

 

Epidemiology:

            In the United States, the incidence of congenital LQTS is estimated to be one in 7,000-10,000.  There is a female preponderance, ranging from 1.6-2.0:1. Patients often first present with a temporary loss of consciousness in their late teens to early twenties. 

Currently, there are ten types of identified ion channel mutations that lead to LQTS, and they are classified as LQTS1-10.

Of the ten types of channelopathies, the first three, LQTS 1-3, are the most prevalent and most studied. LQTS1 occurs in 30-35%, LQTS2 in 25-30%, LQTS3 in 5-10%, LQTS4 in 1-2%, and LQTS5 in 1% of cases.  LQTS6-10 are all rare.

Subtypes:

For the three most prevalent subtypes, there are triggers that can lead to abnormal cardiac events.  For LQTS1, these triggers include stress and exercise, especially swimming.  LQTS2 can be triggered by loud noises and stress.  For LQTS3, something as benign as rest and sleep can trigger an abnormal cardiac event.  Patients with LQTS1 and 2 are urged to avoid triggers to decrease their risk of cardiac events.  There is limited information for the seven other types of LQTS.  Of the three predominant subtypes, LQTS3 has the greatest risk of cardiac events at 0.60%/year, followed by LQTS2 at 0.56%/year, and LQTS1 at 0.30%/year.

            The table below further describes the 10 subtypes of LQTS.

  

Sub-type

Frequency

Gene

Mutation Effect

ECG finding

LQTS 1

30-35%

KVLQT1

K+  Efflux

Broad, late-inset, T wave

LQTS 2

25-30%

HERG

K+  Efflux

Widely-split, low-amplitude, T wave

LQTS 3

5-10%

SCN5A

Prolonged Na+ influx

Biphasic or peaked, late-onset, T wave

LQTS 4

1-2%

ANKB

Build-up of Na+ within cell and Ca2+ outside of cell

Variable Qt interval prolongation

LQTS 5

1%

Mink

K+  Efflux

Not defined

LQTS 6

rare

MiRP1

K+  Efflux

Not defined

LQTS 7

rare

KCNJ2

K+  Efflux

Modest prolongation of Qt interval

LQTS 8

rare

CACNA1C

Prolonged Ca2+  influx

Exaggerated Qt interval prolongation

LQTS 9

rare

CAV3

Prolonged Na+ influx

Not defined

LQTS 10

Extremely rare, found in 1 family

SCN4 β

Prolonged Na+ influx

Not defined

Diagnosis:

            Diagnosis of LQTS is challenging.  Patients can be referred for evaluation for many reasons.  The symptomatic patients are those who have had unexplained syncope or have been successfully resuscitated from an abnormal cardiac event. The asymptomatic patients are those found to have a prolonged QTc interval on routine electrocardiogram or with a first-degree relative diagnosed with the disease.  In both the asymptomatic and symptomatic groups, the QTc interval can be normal on initial presentation.  However, symptomatic patients are more likely to have an abnormal QTc interval than asymptomatic patients.

A scoring system has been developed to aid in diagnosis.  It uses EKG findings, a patient’s history of syncope, and his or her family history to determine risk of LQTS.  A high score is diagnostic. However, patients with an intermediate score usually need to undergo further work-up.   This work-up can include an exercise stress test or an epinephrine stress test.  Epinephrine is a medication used that increases the heart rate and can simulate exercise.  

            Recently, genetic testing has become commercially available for the diagnosis and sub-typing of LQTS.  The genetic test is able to identify patients with the most frequent mutations.  It is possible, however, for a patient to have LTQS and have a non-diagnostic test if the patient’s mutation is infrequent or the mutation has not yet been identified.  Currently, it is recommended to perform genetic testing on those with the clinical diagnosis of LQTS and on all first-degree relatives of patients with known LQTS. 

Treatment:

            Treatment of LQTS is guided by the individual’s risk of sudden cardiac death.  Patients who have survived sudden cardiac arrest are considered to have the highest risk of a recurrent event. In these patients, medical treatment with beta-blockers and placement of an implantable cardioverter-defibrillator is strongly recommended. 

For patients without prior cardiac events, therapy is initiated with a beta-blocker medication and lifestyle modifications. This treatment is especially important for those patients with prolonged QTc intervals, as increasing QTc interval is directly related to increased risk of sudden cardiac death. 

After lifestyle modification and beta-blocker therapy, patients who continue to suffer from syncope and/or ventricular arrhythmias are recommended to have an ICD placed. 

With the advent of reliable genetic testing and a better understanding of the pathophysiology of the various mutations, “personalized” pharmacotherapy is currently being developed.  Possible therapies may include potassium supplementation for LQTS 2 and mexiletine, an anti-arrhythmic medication, for LQTS 3.  Finally, knowing the patient’s genotype assists the decision for early ICD implantation.  Current guidelines allow for consideration of early ICD placement in patients with LQTS 2 and LQTS 3.