The heart has an electrical system that allows it to contract in a rhythm. A key aspect of this electrical system is depolarization and repolarization. The electrical activity is conducted through the sinoatrial (SA) node and atrioventricular (AV) node and into the ventricles. This electrical activity is clearly outlined on an electrocardiogram (ECG) with P waves, the QRS complex, and T waves. The P wave represents the electrical activity of the atrium. The QRS complex shows the depolarization of the ventricles. Lastly, the T wave shows the repolarization of the ventricles.[1][2]

The focus of this article is on the QT interval. It is measured from the Q wave until the T wave, and the QT interval clinically represents the repolarization of the ventricles. When measured on an ECG, the QT interval lengthens when the heart is beating slower and shortens when the heart is beating faster. That is why an adjusted version of the QT interval is used: QTc. This allows for an accurate QT interval at lower and higher heart rates. There are different formulas used to obtain the QTc interval.[3][4]

• Bazett
• Fridericia
• Framingham

Bazett is the most commonly used formula and is done by dividing the QT interval by the square root of the R-R interval.[5] Fridericia is a similar formula, except it uses the cube root of the R-R interval.[6][7] Framingham is a more complex formula, but the literature has shown it may be the most superior formula. Bazett's is automatically calculated on most ECG machines, and its limitations are underestimation and overestimation of the QTc in the cases of bradycardia and tachycardia, respectively. Its accuracy is largely limited to heart rates of 60 to 100 beats per minute, and clinicians must factor in the heart rate when assessing the QTc.[8]

A normal QTc in a male is 440 ms or less, and in a female, it is 460 ms or less. Those with prolonged QT are at risk for one of the potentially deadly arrhythmias known as torsades de pointes. It is the most common form of polymorphic ventricular tachycardia, an unstable cardiac rhythm. This rhythm may cease on its own and go into sinus rhythm, or it may degenerate into ventricular fibrillation. The most common symptom is syncope. Patients with torsade are administered a 2-4g bolus of magnesium sulfate and must undergo cardioversion if hemodynamically unstable. Isoproterenol can also be used to increase the heart rate, thereby decreasing the absolute QT interval. It is generally accepted that QT prolongation past 500 ms carries an increased risk of torsades de pointes; however, if the QT prolongation is severely prolonged, ventricular fibrillation is a certainty.

Prolonged QT Etiologies

• Pharmacological
• Long QT syndrome
• Jervell and Lange-Neilson syndromes[9]
• Romano-Ward syndrome
• Hypocalcemia
• Hypokalemia
• Hypomagnesemia
• Hypothyroidism
• Hypothermia

Literature has shown that people who have diabetes and those suffering from certain inflammatory diseases may suffer from mildly prolonged QT. This is also true in those with heart disease. No major evidence in the general population indicates changes in mortality are associated with QT prolongation. However, subsets of cardiac patients may have an increased risk of mortality if they suffer from QT prolongation.[10]

Pharmacological agents are the most common cause of QT prolongation given the broad range of medications that may induce it. As well, torsade, which is drug-induced, is reversible by the discontinuation of the offending drug. 

QT-Prolonging Medications

Antipsychotics: Haloperidol, ziprasidone, quetiapine, thioridazine, olanzapine, risperidone  

Antiarrhythmics: Amiodarone, sotalol, dofetilide, procainamide, quinidine, flecainide

Antibiotics: Macrolides, fluoroquinolones

Antidepressants: Amitriptyline, imipramine, citalopram, amitriptyline

Others: Methadone, sumatriptan, ondansetron, cisapride

A vast number of medications prolong the QT interval. They are preferably classified based on the degree of QT prolongation they induce. This is specifically medication dependent. Caution is advised when combining QT-prolonging medications or when using these medications in those with electrolyte abnormalities.

Many commonly used medications, such as diphenhydramine and azithromycin, exhibit QT-prolonging effects. However, the degree of QT prolongation is not severe enough to warrant caution in healthy patients. These medications bind to the human ether-related gene (hERG) channels and reduce electrical conduction through the potassium ion channels. This results in delayed repolarization of the heart.[11]

The QT interval is measured from the beginning of the QRS complex to the end of the T wave. Mechanisms that prolong the action potential duration can prolong the QT interval. Specifically, this occurs via delaying the third phase of repolarization. When the hERG channels are altered, there are changes made to the potassium ion channels. This causes an impairment of the channel's ability to conduct electrical activity. The result is prolonged cardiac repolarization.

This mechanism can occur via genetic changes to hERG and/or drug-binding to these channels. Different drugs will induce changes in the hERG channels to variable degrees. Hence, different medications induce different levels of QT prolongation.[11][12][13]

QT prolongation increases the risk of torsades de pointes, a potentially lethal arrhythmia. Torsades de pointes is the most common form of polymorphic ventricular tachycardia; it is initiated when a premature ventricular contraction occurs in the setting of a prolonged QT interval. This is known as the "R on T" phenomenon.[14] It may cease on its own and return to sinus rhythm, or it may degenerate into ventricular fibrillation.

The clinical feature of this arrhythmia is often syncope. However, it can be asymptomatic. If it degenerates into ventricular fibrillation, death is the likely outcome if there is no intervention.[15][16][17]

Patients diagnosed with long QT syndrome or any genetic causation of prolonged QT syndrome should use these medications with caution. Patients with hypokalemia, hypomagnesemia, and hypocalcemia should be put on QT-prolonging medications with caution. Certain electrolyte derangements prolong QT, which would be further exacerbated by these medications.[18]

Medication interactions are another form of dangerous contraindication. Certain QT-prolonging medications are substrates of the cytochrome P450 (CYP450) system. If a patient is using a CYP450 inhibitor medication at the same time, there is a risk of significantly greater QT prolongation.