Friday, September 29, 2023
In the 1960s, cardiologists observed that loss of consciousness would occasionally develop in patients treated with quinidine for control of arrhythmias, such as atrial fibrillation. This was due to a cardiac arrhythmia named "torsades de pointes" (TdP) by the French cardiologist Dessertenne.[1] Dessertenne noticed that the arrhythmia had a characteristic appearance on the electrocardiogram (ECG), which he termed "twisting of the points (torsades de pointes)." TdP was soon recognized as a "proarrhythmic" complication that can also occur with other antiarrhythmic drugs that prolonged the QT interval on the ECG. In the 1990s, nonsedating antihistamines[2] were found to prolong the QT interval and, subsequently, many drugs in other classes have been identified. Since 1997, 6 drugs in 5 different clinical categories have been removed from the market due to their association with QT prolongation and TdP. Thirty drugs remain on the market in the United States that have this potential (www.QTdrugs.org).
The sequential waves of a cardiac cycle on the normal ECG are designated P, Q, R, S, and T. The QT interval is measured from the beginning of the QRS complex to the end of the T wave and is approximately 0.4 seconds in most healthy individuals (Figure 1). It represents the time of contraction and relaxation of the cells of the heart muscle.
Population studies have defined the upper limit for the normal QT interval and identified factors that lead to prolongation. Because the QT interval decreases when the heart rate increases, it is conventional to apply a correction factor for the measured QT interval to correct for differences in QT caused by making measurements at different heart rates. The most commonly used correction is the Bazett equation.[3] However, it is known to be inaccurate at very slow or high heart rates, and many experts now recommend using either the Fridericia, Framingham, or Hodges formula.[4-7] Some modern ECG recorders allow the operator to select the rate correction formula to be used in reports.
The corrected QT interval, or QTc, is usually less than 0.42 seconds in men and less than 0.45 seconds in women. This difference in QTc between the sexes has been studied in recent years and has relevance to drug safety; this issue will be addressed below.[8]
There are many commonly used medicines that have the negative side effect of increasing the QT interval. It is standard clinical practice to measure the QT interval to monitor the beneficial or harmful effects of multiple drugs. For some, such as sotalol or dofetilide, a small degree of lengthening is expected and is considered a measure of their antiarrhythmic effects on the heart tissue.[9] However, QT monitoring is most often recommended to prevent drugs from causing excessive prolongation -- this can induce potentially lethal arrhythmias (see below). Fortunately, for most drugs, this is an uncommon or even rare event. Understanding the pharmacologic basis for QT prolongation and drug-induced arrhythmias is important for identifying patients who are at risk for TdP.
Long QT syndrome refers to a clinical condition in which there is an abnormally long QT interval on the ECG. It is often associated with TdP; however, TdP may not be seen at the time QT prolongation is observed. The QT syndrome can be due to inherited genetic abnormalities of ion channels and other cardiac proteins; this case is called "congenital long QT." It can be also be "acquired," ie, induced by clinical conditions such as thyroid disease, a wide variety of prescribed drugs, or abnormally low electrolyte levels in the blood (potassium and magnesium).
TdP is a syndrome of polymorphic ventricular arrhythmia occurring in the setting of marked prolongation of the ECG QT interval. It occurs spontaneously in young individuals with congenital long QT syndrome. At least 7 different genetic subsets have been identified. Each subset is caused by mutations in different genes that control the expression of cardiac ion channels or related proteins. TdP is a common cause of sudden death in these individuals.
TdP also occurs as an adverse effect of drugs that prolong the QT interval by blocking cardiac potassium channels. Patients with TdP experience dizziness or loss of consciousness if the arrhythmia is brief. If it is sustained, TdP can be lethal. The QT interval is prolonged in the heart beats before the sudden onset of rapid and disorganized contractions of the heart (Figure 2). Because the heart muscle contracts in a rapid and disorganized manner during the arrhythmia, the heart is unable to pump blood effectively. This leads to the symptoms described above or to the death of the patient.
;)
EnlargeECG tracing of QT prolongation and torsades de pointes ventricular tachycardia. The tracing shows some evidence of the hallmark pattern of "twisting of the points."
;)