(USMLE topics, cardiology) Long QT syndrome: causes, pathophysiology, how LQTS causes TdP, diagnosis and treatment.

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Long QT syndrome, LQTS, is a condition that affects the heart’s electrical activities. LQTS is largely a genetic disorder: children inherit mutations from their parents that either cause the disease since birth, or make them more susceptible to develop it later in life when triggered by certain medications or metabolic imbalances.
LQTS itself is not the problem, many people with the syndrome don't have any symptoms and may not even be aware of it. However, it predisposes the patient to a life-threatening type of abnormal heart rhythm, known as torsades de pointes, which may lead to fainting, seizures, or sudden cardiac arrest. This complication is usually triggered when heart rate accelerates by adrenergic stimulation, such as during exercise, stress or strong emotions. LQTS can cause sudden death in seemingly healthy young people.
On an electrocardiogram that records electrical activities of the heart, P wave represents atrial depolarization, QRS complex is produced by ventricular depolarization, and T wave corresponds to ventricular repolarization. The QT interval, measured from the start of Q wave to the end of T wave, reflects the time taken for ventricular depolarization and repolarization, which is basically the duration of action potentials in the cells of the ventricles.
An action potential is essentially a brief reversal of electric polarity of the cell membrane. It is made possible by the flow of ions in and out of the cell, through specific ion channels. Basically, the depolarizing phase is caused by sodium influx; early re-polarization is due to initial outflow of potassium; plateau phase occurs when potassium efflux is balanced by calcium influx, and repolarization is when potassium efflux dominates calcium influx. The duration of repolarization is determined by the balance of current flow through these ion channels.
The rate of repolarization is slightly different for the 3 layers of the heart wall: the epicardium, mid-myocardium or M-cells, and endocardium. Because M-cells have less potassium channels and more sodium channels, they repolarize more slowly. On an ECG, the peak of T wave reflects repolarization of epicardial cells, while the end of T wave corresponds with repolarization of M-cells.
Long QT syndrome is due to prolongation of underlying action potential durations, and is most commonly caused by mutations in various ion channels that affect the balance of ion flow. Specifically, a reduced outward current caused by loss of function of potassium channels, or an increased inward current caused by gain of function of sodium or calcium channels, would increase the duration of repolarization. If inward currents exceed outward currents during the plateau phase, early after-de-polarizations and consequently extra heartbeats can be triggered. Mutations in ion channels also disproportionately lengthen action potentials in M-cells, increasing the difference in refractoriness of the different layers. This can cause electrical impulses to travel around in loops, known as re-entrant pathways, producing the characteristic wave pattern of torsades de pointes.
For diagnosis, patient’s QT interval is measured. But because QT interval varies with heart rate, a corrected QT interval, QTc, is calculated after measurement. Diagnosis, however, cannot rely on QTc values alone. Asymptomatic patients can have longer than normal QTc and develop no arrhythmias, while patients with established long QT syndrome may have normal QT intervals at rest. Diagnosis must therefore also include genetic testing, personal history of fainting, and family history of sudden death.
Treatment aims to prevent a long QT heart from developing dangerous arrhythmias. Most patients are treated with beta-blockers. Medications that shorten QT interval may also be prescribed. On the other hand, medications that prolong QT interval or precipitate development of torsades de pointes must be avoided. Patients are also advised to seek immediate treatments for conditions that may result in low potassium in the blood.

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