Long QT Syndrome

Etiology

The causes of QT interval prolongation can be divided into congenital or acquired. Congenital causes are usually a result of mutations in ion channels (potassium, calcium, or sodium) with more than 15 identified mutations. In contrast, acquired QT interval prolongation may result from electrolyte abnormalities or drugs that affect those ion channels (see Image. Prolonged QT interval).[4][5][6]

Epidemiology

The prevalence of congenital causes, also known as Long QT syndrome (LQTS), is difficult to estimate but may be expected in 1 in 2,500 to 1 in 10,000 individuals. It is more common in females and usually presents with cardiac events in childhood, adolescence, or early adulthood. There are, however, case reports of it manifesting in the fifth decade of life. Family history is positive for Long QT syndrome in 40% and for sudden cardiac death in 30% of patients. Acquired causes are relatively more common than congenital causes. Some studies report the prevalence of QT prolongation in as many as 30% of patients in the intensive care unit.[7][8]

Pathophysiology

A QT interval duration largely depends on the duration of the ventricular action potential. This duration largely depends on the heart's closure or opening of ion channels, with the influx of positive ions (sodium, calcium) causing depolarization and the efflux of positive ions (potassium) causing repolarization. Any disturbance in these ion channels that leads to an excess of intracellular positive ions prolongs the action potential, leading to QT prolongation. The pathophysiology of congenital and acquired causes is explained below.

• Congenital: Mutation in genes coding for ion channel proteins results in their malfunction, leading to excess intracellular positivity. Though rare, this entity results in a high risk of sudden death. So far, mutations of any of 15 genes have been linked to Long QT syndrome, with KCNQ1 being the most common gene mutated and is the cause of Long QT syndrome type 1.
• Acquired: More commonly, prolongation of QT interval is acquired. As one can expect, disturbances of electrolytes (hypokalemia, hypocalcemia, hypomagnesemia) prolong QT. Also, certain medications affect those ion channels and lead to QT prolongation. Virtually all drugs that produce Long QT syndrome act by blocking the outward IKr current, which is mediated by the potassium channel encoded by the KCNH2 gene. Medications known to cause this include antiarrhythmic drugs such as sotalol and amiodarone, certain antibiotics such as macrolides and fluoroquinolones, antipsychotics such as haloperidol and olanzapine, and certain gastric motility agents (such as cisapride). A great resource for knowing which drugs prolong QT interval is www.crediblemeds.org.

History and Physical

Syncope is the most common symptom, usually experienced during exercise and high emotions (50% of the genetic variant). Syncope during swimming, including immediately after diving into the water, appears relatively specific for LQT1. Other presentations include near-syncope, cardiac arrest, or seizures. In 10% to 15% of individuals, death is the first sign. Also, certain types of Long QT syndrome have an additional non-cardiac phenotype. For example, hearing loss is present in Jervell and Lange-Nielsen syndrome. Skeletal abnormalities, such as short stature and scoliosis, are present in the LQT7 type (Andersen syndrome). Also, cognitive and behavioral problems and immune dysfunction may be seen in those with LQT8 type (Timothy syndrome).

Evaluation

Diagnosing prolonged QT starts by measuring the QT interval on ECG. This is often done on lead II or V5-6, whichever is longer. This should be done on several successive beats, of which the longest interval is chosen. If a U wave exists and is large (greater than 1 mm), and fused with T-wave, then this should be included in the QT measurement. On the contrary, if the U-wave is small or separate from the T-wave, then it should be excluded. The maximum slope-intercept method defines the end of the T wave. A helpful tip that helps identify prolonged QT intervals during the initial examination of the ECG is that a normal QT interval should be less than half the preceding RR interval.[9][4][10]

Due to the variation of QT interval with heart rate (higher heart rate has shorter QT interval, lower heart rate has longer QT interval), it is important to correct the QT interval for the heart rate. This is known as QTc. QTc is prolonged if it is greater than 440 ms in men or greater than 460 ms in women. A QTc greater than 500 is associated with an increased risk of torsade de pointes. While several equations exist to help correct heart rate variation, the Bazett formula (QTC = QT / √ RR) is the most commonly used. Though the Bazett formula seems relatively accurate in heart rates between 60 to 100 beats/min, it tends to overcorrect with higher heart rates and undercorrect with lower heart rates.

Once QTc is identified as prolonged, the next step in a workup is to look for acquired causes. The most common cause of QT prolongation in an ICU setting is usually drug-related. Serum potassium, calcium, and magnesium levels should be checked, as low serum of each can cause QT prolongation. Also, stimulating thyroid hormone (TSH) levels may be checked in patients with suspected hypothyroidism.

In the absence of reversible or acquired causes of QT prolongation, Long QT syndrome is diagnosed. In those patients, obtaining an electrocardiography of the patient and family members may be very helpful. Noncardiac phenotype (as discussed above) may aid in making the diagnosis. Genetic testing of the patient and family members is the gold standard; however, this testing is limited by cost. Pharmacologic provocation with epinephrine or isoproterenol is warranted in patients with a borderline presentation. The concept of this testing is that patients with Long QT syndrome have an abnormal response to sympathetic stimulation. Their ECG shows the failure of the QT interval to shorten with increased heart rates, or it may even show prolongation. In patients with LQT2, there is marked shortening with exercise, however, exaggerated lengthening of the QT interval as the heart rate declines during late recovery.

Treatment / Management

The goal of management is the prevention of lethal arrhythmias such as torsade de pointes (TdP). As described earlier, the longer the QT interval, the higher the risk is for torsade de pointes. A hemodynamically unstable patient should receive non-synchronized electrical defibrillation. Also, the first-line treatment is magnesium sulfate, and the benefit is independent of serum magnesium level. Temporary transvenous overdrive pacing should be considered for those who do not respond to magnesium sulfate. Isoproterenol and Class IB antiarrhythmic drugs, such as lidocaine and phenytoin, may also be used. [5][11][12][13]

For long-term management in congenital Long QT syndrome, beta-blockers are the first line choice, and they help prevent ventricular arrhythmias by stabilizing ventricular action potential and helping block sympathetic surges associated with arrhythmias. An implantable cardioverter defibrillator (ICD) is recommended in patients with Long QT syndrome who were resuscitated from a cardiac arrest. It is also indicated in those who have beta-blocker-resistant symptoms or have contraindications to beta-blockers. It also may be indicated in asymptomatic individuals who are suspected to be at high risk for ventricular arrhythmias.

Differential Diagnosis

The differential diagnoses for long QT syndrome include the following:

• Brugada syndrome
• Cardiac death
• Coronary artery anomalies
• Drug-induced QT prolongation
• Hypertrophic cardiomyopathy
• QT prolongation in the course of other diseases
• Seizure
• Short QT syndrome
• Sudden cardiac death
• Syncope