Long QT syndromes

Long QT syndromes

Long QT syndromes are a group of inherited disorders of heart rhythm characterised by prolonged QT interval in the ECG and life-threatening ventricular arrhythmias. Prevalence of long QT syndrome varies from one in 5,000 – 10,000 in various regions.

The initially described syndromes were an autosomal dominant Romano Ward syndrome and the autosomal recessive Jervell Lange-Nielsen syndrome. Now it is known that both are two ends of a spectrum with homozygous individuals having deafness due to defective endolymph secretion in the middle ear which is mediated by potassium channels.

Most common varieties of LQTS are LQT1, LQT2 and LQT3. LQTI contributes about 50%, LQT2 about 35-40% and LQT3 about 10-15%. The other varieties are quite rare, with only few families being described.

LQT1 is due to defect in the gene encoding for the alpha subunit of the potassium channel conducting the slow component of the delayed rectifier current. Delayed rectifier current is the major repolarizing current during phase 3 of the cardiac action potential.

Defect in the beta subunit leads to LQT5. The gene for LQT1 is KCNQ1 and in those who are homozygous for it, JLN1 is manifested. The gene for LQT5 is KCNE1 and JLN2 manifests when it is homozygous. JLN stands for Jervell and Lange-Nielsen syndrome.

Just as LQT1 and LQT5 are related to the same channel, LQT2 and LQT6 are related to the rapid component of the delayed rectifier current. KCNH2 encodes for the alpha subunit and KCNE2 encodes for the beta subunit.

LQT2 is more severe and has a higher penetrance than LQT1 and females are more affected than males, while it is the other way round in LQT1. While LQT2 events are precipitated by sudden arousal, LQT1 events are related to exercise.

LQT3 is different from the other varieties as it is mediated by the sodium channel. While the previously discussed varieties are due to loss of function of the channel, LQT3 is due to gain of function of the sodium channel.

The allelic disorder in which there is a loss of function of sodium channels is Brugada syndrome, another important arrhythmogenic disorder prone for life threatening ventricular arrhythmias.

While LQT1 and LQT2 are related to sympathetic states, the arrhythmias in LQT3 occur during rest or sleep. Hence beta blockers, the sheet anchor of therapy in other varieties, is less effective.

LQT4 is unique in that it is not due to a defect in a cardiac ion channel, but due a defect in the anchoring proteins which anchor the ion channels to the plasma membrane or the sarcoplasmic reticulum.

It is due to mutation in ankyrin-B gene ANK2 and LQT4 is characterised by severe sinus bradycardia and paroxysmal atrial fibrillation, in addition to a long QT interval.

LQT7 or Andersen syndrome is also due to a defect in the potassium channel but has additional features of hypokalemic periodic paralysis and dysmorphic features. KCNJ2 encoding for the inwardly rectifier potassium channel conducting IK1 current is the culprit in Andersen syndrome.

LQT8 is also called Timothy syndrome and is due to a defect in the calcium channel CACNA1c. Timothy syndrome is also associated with other features like congenital heart disease patent ductus arteriosus, ventricular septal defect, tetralogy of Fallot and dysmorphic facial features like flat nasal bridge, low set ears and deformed teeth. There are several other genotypes of LQTS which are rarer than these eight and more are being added.

Long QT syndromes have common phenotype of delayed depolarization, caused by ion channel mutations, which in turn causes QT prolongation and a propensity for ventricular tachyarrhythmias. These arrhythmias can cause, hypotension and syncope and sometimes sudden cardiac death.

Clinical features, age at onset, family history, ECG and finally genetic testing are the important steps in the evaluation of a suspected long QT syndrome. Over the years, increased awareness and improved genetic testing has caused an increase in the number of diagnosed cases of long QT syndrome, though the true prevalence may not have increased.

But the variability in the ECG is striking, with about one third of the mutation positive LQTS carriers having a QT interval which overlaps with that of healthy normal individuals. Moreover, various factors like age, gender, central nervous system disorders, changes in electrolytes and several medications can affect the QT interval.

There is a lot of variation in the symptoms as well, with even one third of the LQTS mutations in certain families never having any symptom. Different subtypes have different risks for cardiac events and clinical signs and symptoms do not adequately differentiate the LQTS subtype, though the symptom triggers may give an indication.

Similarly, the response to beta blockers may also vary depending on the sub type. For example, LQT3 does not respond well to beta blockers. But it responds to sodium channel blockers.

The term concealed long QT syndrome, is used to indicate individuals with genotype of long QT syndrome and a phenotype with normal QT interval. They are usually detected on family screening of those with manifest long QT syndrome.

Implantable defibrillators are often needed in LQTS symptomatic on maximally tolerated doses of beta blockers for prevention of sudden cardiac death. Certain varieties associated with bradycardia in childhood may benefit from pacemaker implantation.