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Congenital Long QT syndrome
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Long QT syndrome (LQTS) is one of the commonest cardiac channelopathies with potentially lethal consequences. The hallmark characteristic of LQTS is the prolonged QT interval on an EKG. This syndrome can result in a range of clinical expressions from a lifelong asymptomatic state to symptomatic ventricular arrhythmias, including syncope and generalised seizures, as well as sudden cardiac death.[1] [2]
LQTS is classified as either congenital or acquired. As far as congenital LQTS is concerned, mutations in seventeen genes have been identified. Of these known mutations, there are three major ones, which are:
- KCNQ1 known as LQT1 (mutation on chromosome 11 resulting in an abnormal potassium channel protein).
- KCNH2 known as LQT2 (mutation on chromosome 7 resulting in an abnormal potassium channel protein).
- SCN5A known as LQT3 (mutation on chromosome 3 resulting in an abnormal cardiac sodium channel protein).
These three mutations account for approximately 80% to 90% of congenital LQTS cases. The remaining minor mutations account for 5% of cases and in approximately 10% of cases with clinically diagnosed LQTS, genetic testing is negative. [1][7]
In addition to the mutations described before, two distinct clinical phenotypes follow Mendelian inheritance patterns viz.
- Romano-Ward syndrome – an autosomal dominant inherited disorder.
- Jervell and Lange-Nielsen syndrome – an autosomal recessive inherited disorder which is also accompanied by congenital deafness. [1]
Epidemiological studies show that 1 in every 2,000 persons are genotype and phenotype positive, whereas the prevalence of those that are genotype positive but phenotype negative, is estimated to be 1 in 1,000. The penetrance of these mutations is therefore variable and by one estimate thought to be as low as between 10% to 25%. [1]
Acquired LQTS usually results from unwanted QT prolongation with potential QT-triggered arrhythmias from
- QT-prolonging disease states, or
- QT-prolonging medications, or
- QT-prolonging electrolyte disturbances. [3]
Diagnosis of LQTS
Evaluation of someone suspected with congenital LQTS requires obtaining a careful personal and family history as well as a physical examination and a 12 lead EKG. Essential to the diagnosis of LQTS is the finding of prolongation of the QT interval, which can be measured manually. The QT interval starts at the beginning of the QRS complex and ends at the point at which the T wave terminates. As the QT interval is affected by the heart rate (being shorter if the HR is elevated and longer if the heart rate is slow) it has to be corrected for the measured heart rate. Typically, Bazett’s formula is used to calculate the corrected interval (QTc) and is expressed as:
QTc = QT interval ÷ √RR interval (in sec)
In healthy adults, the normal QTc is 420±20 milliseconds. [4]
Genetic testing
Genetic testing is indicated for high or intermediate clinical suspicion of congenital LQTS according to personal and family history, QT prolongation on EKG and the so-called Schwartz score. [4]
A known mutation associated with congenital LQTS will be identified in at least 80% of cases that have a high clinical suspicion of LQTS.[1]
Schwartz Score
If congenital LQTS is suspected, the Schwartz score can be calculated, which provides a weighted, non-genetic scoring system for the diagnosis of congenital LQTS. It incorporates EKG findings such as measured QTc, and other clinical and historical factors, including a personal history of syncope, and a family history of LQTS and/or SCD. The Schwartz score is interpreted as follows:
- Low probability of LQTS: ≤ 1 point.
- Intermediate probability of LQTS: 1.5 to 3 points.
- High probability of LQTS: ≥ 3.5 points. [4]
Table 1: Mean QTc According to LQTS Mutation. [5]
In individuals with genetically confirmed LQTS the average QTc was 470 milliseconds. [4]
According to each of the major LQTS mutations the average QTc durations are shown in Table 1.
Studies have shown that QTc is important in risk stratification of individuals with congenital LQTS. The longer the QTc the more likely it is that a cardiac event will occur. With reference to the three major LQTS mutations, the percentage of individuals with a normal QTc was the highest in those with LQT1 and lowest in those with LQT3 – see Table 2. [5]
Table 2: Silent Mutation Carriers with a Normal QTc. [5]
The risk of a first cardiac event is higher among those who had a longer QTc with LTQ1 and LTQ2. First cardiac events in LTQ3 were shown, however, not to be affected by longer QTc intervals. Overall, the cumulative event-free survival progressively decreases at longer QTc values. [5]
Prior et al, devised a risk stratification scheme according to the age of onset of first cardiac symptoms, to guide therapeutic decisions for patients with known LQTS genotypes. They determined the age cut-off of 40 years allowed for risk stratification to identify the higher risk group (those with cardiac symptom onset before age 40) versus the lower risk group (those with cardiac symptom onset after age 40). [5]
There is data to show that compared to LQT2 and LQT3, patients with LQT1 become symptomatic later in life:
- LQT1 - 45% symptomatic by 10 years of age vs. 54% later in life.
- LQT2 became symptomatic earlier - 57% symptomatic by 16 years of age vs. <50% later in life.
- LQT3 became symptomatic markedly earlier - 75% symptomatic by 16 years of age vs. <50% later in life. [2]
Treatment
Beta blocker therapy
The 2017 American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend that, unless contraindicated, universal beta-blocker therapy should be initiated for all patients with congenital LQTS, whether asymptomatic or symptomatic. The rationale for this is the risk of torsades de pointes in congenital LQTS is related to catecholamine surges. Beta blocker therapy is effective in reducing mortality in all 3 major LQTS genotypes but most effective in LQT1 which is most likely due to the sympathetic sensitivity found with this particular mutation. [6]
Untreated asymptomatic genotyped LQTS patients over long-term follow up have been shown to have a high risk for cardiac events (36%) including SCD (13%). Beta blocker therapy for LQTS has been shown to significantly reduce mortality from cardiac event rates ranging from 71% in previously untreated symptomatic individuals to 6% in those on beta blocker therapy. [2]
Other treatment modalities
If breakthrough cardiac events occur on beta-blocker therapy or if beta-blocker therapy is contraindicated other treatment modalities for consideration are:
- Mexiletine, which is a class Ib antiarrhythmic agent which reduces the QT interval.
- Left cardiac sympathetic denervation (LCSD). This intervention reduces the norepinephrine release to the heart. It reduces the risk of cardiac events but is not curative.
- Implantable cardioverter-defibrillator (ICD). Most individuals with major LQTS genotypes will not require ICD implantation. This intervention is generally reserved for LQTS patients with resuscitated cardiac arrest and those with recurrent major cardiac events.
- Cardiac pacing. This is infrequently indicated for patients with LQTS. [6]
Long-Term Outcomes
The data on long-term outcomes in the medical literature is sparse largely due to the low prevalence of the disorder. Risk stratification for LQTS patients is complicated by:
- Marked variance in the expressivity of genetic mutations.
- Multitude of treatment options available
- Marked differences in treatment approaches between healthcare institutions.[2]
Studies have reported that mortality associated with cardiac events in untreated symptomatic LQTS is extremely high at ~70%.[2][8] For untreated asymptomatic patients the mortality risk has been shown to be 13%. LQTS mortality has decreased significantly over the last 30 years due to available treatment options, although a recent 2017 study still showed a sizable proportion of LQTS patients continue to have breakthrough cardiac events syncope, seizures, and ICD shocks, despite maximal therapy. [2]
Table 3: Trends in Breakthrough Cardiac Events (BCE) and Sudden Cardiac Death (SCD) for LQTS (% of patients/year) [2]
Conclusion
The annual mortality rate associated with LQTS has significantly improved with effective treatment options, tailored to the individual’s risk profile. Congenital LQTS, a condition that until recently was widely regarded by the life industry as uninsurable, may now be considered for life cover by careful consideration of the applicant’s age, their LQTS genotype, as well as their symptoms status and current treatment.
Author
Nico van Zyl MBBCh MSc
VP & Chief Medical Director
Hannover Life Reassurance Company of America
June 2024
References
- Schwartz PJ et al. Congenital long QT syndrome: Epidemiology and clinical manifestations. Available from https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/. Viewed on 14 May 2024.
- Rohatgi RK et al. Contemporary Outcomes in Patients with Long QT Syndrome. Journal of the American College of Cardiology. 7/25/2017 Vol 70 (4) pp 453-462.
- Berul CI. Acquired long QT syndrome: Definitions, pathophysiology, and causes. Available from: https://www.uptodate.com/contents/acquired-long-qt-syndrome-definitions-pathophysiology-and-causes/. Viewed on 14 May 2024.
- Schwartz PJ et al. Congenital long QT syndrome: Diagnosis. Available from https://www.uptodate.com/contents/congenital-long-qt-syndrome-diagnosis/. Viewed on 14 May 2024.
- Prior SG et al. Risk Stratification in the Long-QT Syndrome. New England Journal of Medicine. 5/8/2003 Vol 348 (19) pp 866-1874.
- Schwartz PJ et al. Congenital long QT syndrome: Treatment. Available from: https://www.uptodate.com/contents/congenital-long-qt-syndrome-treatment/. Viewed on 14 May 2024.
- Ackerman MJ et al. Gene test interpretation: Congenital long QT syndrome genes (KCNQ1, KCNH2, SCN5A). Available from: https://www.uptodate.com/contents/gene-test-interpretation-congenital-long-qt-syndrome-genes-kcnq1-kcnh2-scn5a/. Viewed on 14 May 2024..
- Schwartz PJ. Idiopathic long QT-syndrome: Progress and questions. The American Heart Journal. 2/1985 Vol 109 (2) pp 399-411.
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