Readers, in this new monthly section, “Sudden Death: Update,” Section Editor Dr. Kathryn Glatter will include information on the Brugada Syndrome, hypertrophic cardiomyopathy, ICDs, and much more.

Long QT syndromes
Long QT syndrome (LQTS) is one of the more common and well-known of the ion channelopathies.^1–8 It can be inherited as a dominant gene or be seen in cases of acquired LQTS after taking drugs including antipsychotic or anti-arrhythmic drugs, or allergy medications.

Epidemiology
Currently, it is estimated that 1 in 5,000 people carry a long QT syndrome genetic mutation. With the inclusion of drug-induced or acquired LQTS cases, many of whom have the same genetic ion channel defects as seen with congenital LQTS, some experts believe that the true incidence of LQTS is actually 1 in 1,000. Certainly it is one of the more common genetic causes of sudden death; it has been diagnosed with increasing frequency, as more physicians are educated regarding LQTS.

Our institution, the University of California, Davis, located in northern California, has become a major referral center for the study and diagnosis of LQTS. We have been referred an increasing number of LQTS patients with no family history of sudden death whose ECG incidentally shows a prolonged QT interval (Figure 1).

It is very important for the clinician to realize that LQTS is an autosomal dominant mutation with incomplete penetrance. Often patients think the mutant gene somehow “skipped” their generation; obviously, the gene can never skip, but incomplete penetrance could render it undiagnosable in the patient.

Clinical Features
The majority of patients who harbor an LQTS mutation will never experience any symptoms. Most LQTS families are discovered when a young person dies suddenly but has a normal autopsy — other family members are found to have a prolonged QT interval on ECG. At least 10% of affected patients may present with sudden death as their first (and last) symptom.

Each genetic subtype (described below) has its own trigger for events.^10–14 LQT1 patients (55% of the total) usually experience symptoms (syncope, cardiac arrest, or sudden death) during adrenaline-driven type of activities such as running, exercise, or with strong emotion (e.g., during an argument). An unexplained drowning in a person able to swim could be due to an LQT1 mutation.^3–8 LQT2 (HERG; 40% of the total) mutations may cause sudden death due to auditory triggers, as with an alarm clock or the telephone ringing.^3–8 The rare LQT3 (sodium channel; < 5%) subtype may occur during sleep or during periods of slow heart rates.

Although LQTS is an autosomal disease, females are far more likely to experience symptoms than males. LQTS can be diagnosed in some cases by noting a prolonged QT interval (> 450 ms) on the electrocardiogram. However, up to 30% of gene-positive patients may have a normal or only borderline prolonged QT interval, making diagnosis impossible in some cases.⁹ Exercise testing may reveal an otherwise concealed form of LQTS.

There is a small association in the literature between Sudden Infant Death Syndrome (SIDS) and LQTS, although probably fewer than 5% of all SIDS cases are due to ion channel mutations.¹⁰ Other, more common causes of SIDS include placing the infant prone, co-sleeping with adults, and inborn errors of metabolism.

As with many ion channelopathies, which cause unexplained sudden death, autopsy findings are unremarkable. Venous blood saved in an EDTA-tube (or perhaps snap-frozen myocardial tissue) can be tested at a research laboratory for the presence of LQTS ion channel mutations. It usually takes a year (or more) to laboriously search for all known LQTS genes to see if the patient’s gene is there. Roughly 50% of the patients will ultimately have their gene identified, while the remaining 50% have genes, traffic proteins, etc. that remain unknown.

Figure 1

ECG taken from an 8-year-old girl, whose long QT syndrome was incidentally discovered on a routine ECG. There is no family history of sudden death or cardiac arrest. Leads II (top) and V3 (bottom) are shown at paper speed 10 mm/sec. QTC = 530 ms. She was genotyped as LQT3, the sodium channel subtype.

Pathophysiology
The fundamental defect in LQTS is prolonged ventricular repolarization. This prolongation occurs intermittently, depending on if the defective ion channel is being used at that particular point in time. The QT interval can be normal or only mildly prolonged, yet prolong abruptly in the wrong circumstance.

In the wrong setting, as the QT interval increases, early after-depolarizations (EADs) occur and initiate torsades de pointes, or polymorphic ventricular tachycardia (“twisting of the points”). If the arrhythmia self-terminates (or if the patient is shocked out of the arrhythmia by an ICD), syncope will occur. If the arrhythmia persists, it can degenerate quickly into ventricular fibrillation, cardiac arrest, and even sudden death.

Genetics
To date, a total of six genes have been identified as causing long QT syndrome.^11–13 The mutant ion channel which causes clinical LQTS is inherited in an autosomal dominant fashion with incomplete penetrance and was originally known as the “Romano-Ward Syndrome.” With the advent of genetic testing, it has become clear that each LQTS genetic subtype represents a unique disease with different triggers to arrhythmias.

The genes which encode the potassium channels KVLQT1 (on chromosome 11) and minK (on chromosome 21) interact to form the cardiac IKs (inward slow potassium) current; mutations in each cause LQT1 and LQT5, respectively. The potassium channels HERG (on chromosome 7) and MiRP1 (on chromosome 21) interact to form the IKr (inward rapid potassium) current, and defects in each cause LQT2 and LQT6, respectively. Mutations in the sodium cardiac channel SCN5A cause LQT3 (on chromosome 3). The gene responsible for LQT4 was recently identified as a mutation in the ankyrin-B protein. The potassium channel mutations cause a “loss of function” in the channel (or a “dominant-negative effect” in the case of the HERG mutation), whereas defects in the sodium channel cause a “gain of function.”

In the unlikely event that a mutant copy of the IKs channel is inherited from each parent (mutations in the KVLQT1 and minK genes), the child will suffer from a clinically severe form of autosomal dominant LQTS and also from autosomal recessive congenital deafness. This condition is known as the “Jervell and Lange-Nielsen Syndrome” (JLNS).¹² JLNS was first described in 1957, in a Norwegian family, in which three congenitally deaf children died suddenly before the age of 10. It is actually quite rare, with an estimated incidence of 1.6–6.0 cases per million.

Such families with JLNS usually present with a SIDS-type of death and the presence of congenital, severe deafness. Obviously, both parents have LQTS in such cases and should be counseled regarding their risk of sudden death, offered therapy, etc. Denial often plays a major role in such families. Other, normally hearing siblings of the JLNS proband may carry the mutant gene and should be identified and offered therapy.

Treatment
There is no consensus on how to treat patients with LQTS.^1,3–5 Most physicians would advocate an implantable defibrillator (ICD) for those patients who have survived a cardiac arrest, or possibly even in those with syncopal events.¹⁴ Because the difference between syncope and sudden death in these patients is likely luck (e.g., the arrhythmia terminated), some physicians view syncope in LQTS patients with the same ominous outcome as an aborted cardiac arrest.

Dual chamber pacemakers, even with beta-blocker therapy, have been shown to be ineffective in symptomatic patients.¹⁵ With the ease of placing ICDs, most physicians would simply place an ICD (single chamber for most cases; dual chamber if the patient needs pacing functions, including with the LQT3 subtype) rather than a pacemaker. Sympathectomy to modify the effect of adrenaline upon the heart has been shown to be ineffective at preventing events.¹

Most physicians would advocate beta-blocker therapy in asymptomatic LQTS patients.^3–5 The exact dose or type of beta-blocker medication to be used is unclear. In patients unable (or unwilling) to take medications, an ICD may then be recommended. Restriction from heavy physical activity is also suggested in affected patients. Data from the International LQTS Registry have shown that symptomatic LQT1 patients have a low recurrence rate after starting beta-blocker medication (19% recurrence), LQT2 patients have an intermediate rate (41% recurrence), and LQT3 patients a higher rate (50%).3 If the physician knows the general genetic subtype based on the patient’s personal or family history, one could tailor therapy based on that information. In other words, the LQT1 subtype responds very well to beta-blocker therapy alone plus restriction from physical activity, whereas the LQT3 subtype does not and possibly could require a prophylactic ICD.