Structural and Functional Basis for the Long QT Syndrome: Relevance to Veterinary Patients

Abstract

Long QT syndrome (LQTS) is a condition characterized by prolongation of ventricular repolarization and is manifested clinically by lengthening of the QT interval on the surface ECG. Whereas inherited forms of LQTS associated with mutations in the genes that encode ion channel proteins are identified only in humans, the acquired form of LQTS occurs in humans and companion animal species. Often, acquired LQTS is associated with drug-induced block of the cardiac K+ current designated I(Kr). However, not all drugs that induce potentially fatal ventricular arrhythmias antagonize I(Kr), and not all drugs that block I(Kr), are associated with ventricular arrhythmias. In clinical practice, the extent of QT interval prolongation and risk of ventricular arrhythmia associated with antagonism of I(Kr) are modulated by pharmacokinetic and pharmacodynamic variables. Veterinarians can influence some of the potential risk factors (eg, drug dosage, route of drug administration, presence or absence of concurrent drug therapy, and patient electrolyte status) but not all (eg, patient gender/genetic background). Veterinarians need to be aware of the potential for acquired LQTS during therapy with drugs identified as blockers of HERG channels and I(Kr).

Assessment of temperature‐induced hERG channel blockade variation by drugs

“…The screening of commonly used human and veterinary drugs on the hERG channel has been suggested by Finley et al (2003). Golden et al (2011) suggested that the CHO cell line is suitable for the automated patch clamp and can also be used for screening of hERG liability of clinical compounds (Walker et al, 1999;Polonchuk, 2012).…”

“…Such individuals and animals may be influenced by an acquired form of long QT syndrome with multiple influencing factors such as gender, heart rate and hypokalemia (Ayad et al, 2010). However, it is possible that these animals are also susceptible to the aforementioned adverse effects, through iatrogenic influence (drug dosage, route of drug administration and electrolyte status of patients) (Finley et al, 2003).…”

Influence of estrous stages on electrocardiography, clinical pathology and ovarian weight of experimental beagle dogs: a retrospective analysis

“…Recording of ECG has a particular importance on cardiac repolarization during preclinical assessment of drugs. Dog shares certain similarities with the human electrical conduction system and hence used to evaluate the potential risk of arrhythmia in humans (Hammond et al 2001;Finley et al 2003), which cannot be assessed by other methods and have no morphological correlates visible in histopathological examination (Detweiler, 1981). Owing to association with Torsades de Pointes, drug-induced QT interval prolongation has been and remains a significant hurdle to the development of safe and effective drug.…”

“…The canine estrous cycle consists of 4 phases: proestrus, estrus, diestrus and assigned to same group potentially leading to erroneous interpretation of drug-induced effects on the electrocardiography, clinical pathology and reproductive organ weight when the test chemical being tested has either direct or indirect effect on the female reproductive system/hormones. Recording of ECG in non-rodents has a particular importance during preclinical assessment of drugs: to extrapolate the potential cardiovascular risk in humans (Hammond et al, 2001;Finley et al, 2003). Multiple factors have been described to affect the ECG parameters (De Ponti et al, 2002;Luo et al, 2004).…”

Doctoral Dissertation

“…The transmural difference in early repolarization is reflected on the transmural ECG as a J-wave ( Figure 10). 50,87 Cardiac action potentials from other animals, such as pig, 100,102 cow 107 and horse 104,105 do not exhibit the spikeand-dome morphology and there appear to be minor/no differences in action potential shape from endo-, mid-and epicardial cells (Table 2 and Figure 11). cAMP binds directly to HCN channels as well as other channels but most of its actions are due to activation of protein kinase A (PKA).…”