KCNH2, the hERG-gene codes for a protein labeled Kv11.1, the alpha subunit of a potassium channel. The hERG potassium channels are essential for normal electrical activity in the heart. Inherited LQTS is associated with mutations in the hERG gene predisposing individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a large number of diverse cardioactive agents which has caused disappointing results for many preclinical drug safety studies.

The origin of the label ‘Ether-à-go-go’ denoting the hERG-gene is interesting. According to Wikipedia, The hERG gene is the human homolog of the Ether-a-go-go gene found in the Drosophila fly and named in the 1960s by William D. Kaplan. When flies with mutations in this gene are anaesthetized with ether, their legs start to shake, like the legs of the dancers at the then popular ‘Whisky A Go-Go’ nightclub in West Hollywood.

Arrhythmias related to abnormal repolarization are commonly caused by mutations in genes encoding K⁺-channels. Mutations in hHERG-gene and in gene encoding KvLQT1 cause the majority of Romano-Ward syndromes, autosomal dominant LQTS. Quinidine, procainamide, and disopyramide are examples of drugs that block K⁺-channel prolonging QT and in some setups causing TdP. Antiarrhythmic drugs have lost their appeal because of serious side effects although they are important in the management of patients with recurrent AF. IKur channel is a new target for search of new drugs for AF after discovery of atrial-specific distribution of IKur.

Verapamil and diltiazem are examples of class IV drugs blocking open and inactivated Ca²⁺– channels. The sudden cardiac death syndrome combining ECG features of the Brugada syndrome including short QT associated with a loss of function of the L-type Ca2 α1- or β2b subunit of the channel has been described by Antzelevitch et al. [5].

This channel has been targeted in search for agents (ivabradine etc.) which slow down heart rate without negative inotropic effect or hypotension which is the disadvantage of β-blockers. These drugs have been found effective in management of patients with stable angina pectoris. Newer findings include mutations of hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 or HCN4 associated with idiopathic sinus bradycardia and chronotrophic incompetence in one family [6] and severe bradycardia, QT prolongation, and torsade de pointes in another family [5]. If expression is upregulated in cardiac hypertrophy and congestive heart failure and may contribute to the arrhythmias observed in these disease conditions.

A variety of formulas with substantial differences in functional form have been introduced in ECG literature for QT adjustment for heart rate variation [7, 8]. QT rate sensitivity in women is higher than in men (the slope coefficient in linear regression of QT vs. RR interval is larger in women than in men) and the rate sensitivity decreases with age in both gender groups. The formulas by Bazett [9] and Fridericia [10] introduced in 1920 continue to be most commonly used for QT rate adjustment in clinical applications. Bazett’s formula (QTcBz) leaves a large bias in rate-adjusted QT at high and low heart rates by overcorrecting at higher heart rates and undercorrecting at low heart rates. This increases the proportion of false negative QT prolongations at high heart rates and false positives at low heart rates. The bias with Fridericia’s formula (QTcFr) is in opposite direction to that with QTcBz although the bias is smaller in magnitude. Both of these two formulas ignore the gender difference in QT rate sensitivity. Another problem with many QT rate adjustment formulas is that they may produce a satisfactory rate adjustment of the mean or median QT but do not properly adjust upper limits of QT distribution [8].

Newer formulas introduced labeled QTcLogLin and QTcMod in Table 9.2 may reduce the problems noted above [8]. This table provides a framework for categorization of QTc formulas as linear and inverse based on their generic form and QT prediction function. Rate-adjusted upper normal limits are strongly age- and gender-dependent.