QT Risk Research Articles

Structural and functional basis for the long QT syndrome: relevance to veterinary patients.

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).

Dispersion of the corrected QT interval in the electrocardiogram of the ex-prisoners of war

The study of electrocardiograms (ECGs) was performed in a subgroup of 181 men, ex-prisoners of war with mean age 35.8±11.0 years and mean duration of imprisonment 164.5±87.1 days, chosen at random from the total sample of released prisoners ( N=1458). The control group was pair-matched. The analysis of ECGs was done according to the Minnesota code, and Bazett’s formula gave the values of the corrected QT interval (QT c). The dispersion of the QT c interval is determined by the difference between the longest and the shortest measured QT c interval in each ECG lead. The results of descriptive statistics in the group of ex-prisoners showed the range of QT c dispersion of 8.0–122.0 ms (mean 52.4±21.6 ms), while in the control group the range was 6.0–72.0 ms (mean 30.4±13.8 ms) (df=360, t=11.536; P<0.001). The QT c interval from 422.0 to 480.0 ms had 60.2% ex-prisoners and 30.4% controls, while a QT c interval over 480.0 ms had 19.3% ex-prisoners and 1.10% controls ( P<0.0001). In the ex-prisoners group, the QT c dispersion over 50 ms was present in 51.4%; of those, a dispersion of 95 ms and more was found in 3.9%, while in the controls a QT c dispersion over 50 ms was found in 8.3%, but a dispersion of 95 ms and more was not recorded ( P<0.0001). The odds ratio estimated for the prolonged QT c interval was 8.467 and for enlarged QT c dispersion it was 11.695 in the ex-prisoners versus controls ( P<0.001). In conclusion, persons exposed to long-term maltreatment in detention camps have significantly greater QT c dispersion, as well as a higher relative risk of prolonged QT c interval and greater QT c dispersion than a control group.

RR interval variation, the QT interval index and risk of primary cardiac arrest among patients without clinically recognized heart disease.

Autonomic tone influences RR interval variation (RRV) and the heart rate-corrected QT interval index (QTI). Together, QTI and RRV may improve characterization of sympathovagal control and estimation of risk of primary cardiac arrest. We therefore examined effects of QTI and short-term RRV from standard, 12-lead electrocardiograms on risk of primary cardiac arrest among persons without clinically recognized heart disease. We analysed data from a case-control study of risk factors for primary cardiac arrest among enrollees in a large health plan. Cases (n=505) were enrollees aged 18 to 79 years without history of heart disease who had primary cardiac arrest between 1980 and 1994. Controls (n=529) were a demographically similar, stratified random sample of enrollees. We determined enrollee characteristics from ambulatory medical records, QTI and RRV from standard, 12-lead electrocardiograms, and medication use from automated pharmacy files. Low and high values of QTI and RRV were designated as the first and fifth quintiles of QTI (96% and 107%) and RRV (35 ms and 120 ms) among controls. In a model adjusting for clinical predictors of primary cardiac arrest, RRV modified the association between QTI and risk of primary cardiac arrest (P=0.05). Compared to high RRV and low QTI, the risk of primary cardiac arrest (odds ratio [95% CI]) was 0.95 [0.73-1.23] at low RRV and QTI, 1.23 [0.97-1.57] at high RRV and QTI, and 1.55 [1.16-2.06] at low RRV and high QTI. Risk remained elevated after adjustment for other electrocardiographic predictors and medication use. Autonomic dysfunction, characterized by high QTI and low RRV on the standard, 12-lead electrocardiogram, is associated with an increased risk of primary cardiac arrest among persons without clinically recognized heart disease.

QT dispersion and risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy

This study examines the relation of QT dispersion (QTd) on a surface electrocardiogram (ECG) to clinical features and established risk factors of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HC). One hundred fifty-six consecutive patients with HC (91 men, mean age 41 ± 15 years, range 7 to 79) and 72 normal subjects (41 men, mean age 39 ± 9 years, range 20 to 60) were studied. Standard 12-lead ECGs were recorded from each subject using a MAC VU electrocardiograph. Patients with nonsinus rhythm, atrioventricular conduction block, QRS duration >120 ms, age <15 years, and low amplitude T waves were excluded from the analysis (n = 51). Another 22 patients who were receiving amiodarone and/or sotalol therapy were also excluded. QT interval and QTd were measured using automated analysis in the remaining 83 patients (46 men, age 40 ± 14 years, range 16 to 76). QT interval (406 ± 38 ms), QTc interval (432 ± 27 ms), and QTd (43 ± 25 ms) were significantly greater in patients with HC than in normal controls (386 ± 31 ms, 404 ± 16 ms, 26 ± 16 ms, respectively) (p <0.0001). QTd was significantly greater in patients with HC with chest pain compared with asymptomatic or mildly symptomatic patients (50 ± 28 ms vs 37 ± 20 ms, p = 0.02). Increased QTd was found in patients with dyspnea New York Heart Association functional classes II/III than in those with dyspnea New York Heart Association functional class I (50 ± 27 ms vs 38 ± 22 ms, p = 0.04). QTd was weakly correlated with maximum left ventricular wall thickness (r = 0.228, p = 0.038). No significant association was found between QTd and any risk factors for SCD. Thus, patients with HC have increased QTd. The QTd correlates with symptomatic status. Assessment of QTd might provide complementary clinical characterization of patients with HC but its relation to SCD remains uncertain.

QT interval prolongation and risk of life-threatening arrhythmias during toxoplasmosis prophylaxis with spiramycin in neonates

We recently reported two cases of QT interval prolongation and cardiac arrest in newborns receiving antibiotic therapy with spiramycin, a macrolide agent extensively used for toxoplasmosis prophylaxis. In this study we assessed the effects of this drug on ventricular repolarization and on the potential risk of lethal arrhythmias in eight newborn infants in whom toxoplasmosis prophylaxis after birth was necessary. Electrocardiograms (ECGs) and echocardiograms were recorded during spiramycin therapy (350,000 IU/kg/day) and after its withdrawal. In a control group of eight healthy newborns matched for age and sex, no differences were found between two ECGs analogously recorded. The QT interval corrected for heart rate (QTc) was longer during spiramycin therapy than after drug withdrawal (448 ± 32 msec vs 412 ± 10 msec, +9%, p = 0.021). QTc dispersion, expressed as the difference between the longest and the shortest value in 12 different leads (QTc max − min ), was also higher during spiramycin therapy (60 ± 32 msec vs 34 ± 8 msec, +76%, p = 0.021), mainly because of a major lengthening of the longest QTc (QTc max ). QTc and QTc dispersion were markedly increased in the two newborns who experienced cardiac arrest after beginning treatment compared with the six neonates who had no drug-induced symptoms. During therapy seven of eight newborns had a rare abnormality in the thickening of the left ventricular posterior wall similar to that observed in patients with congenital long QT syndrome. This abnormality disappeared after drug withdrawal. Thus antibiotic therapy with spiramycin in the neonatal period may induce QT interval prolongation and increase QT dispersion. When this effect on ventricular repolarization is more marked, it may favor the occurrence of torsades des pointes and lead to cardiac arrest. (Am Heart J 1997;133:108-11.)

Terfenadine-associated ventricular arrhythmias and QT c interval prolongation : A retrospective cohort comparison with other antihistamines among members of a health maintenance organization

This study compared the occurrence of syncope, ventricular arrhythmias, and corrected QT interval (QT c) prolongation over a 2 1 2 -year period in persons prescribed terfenadine versus other prescription antihistamines among 265,000 members of the Harvard Community Health Plan (HCHP), the largest staff-model health maintenance organization in New England. HCHP maintains an automated medical record system with coded diagnoses for each ambulatory and hospital visit, and a similar automated pharmacy system with information for each member on all prescriptions filled at its pharmacies. Among 0.86 million exposure days of terfenadine and 1.04 million exposure days of other antihistamines, we found no excess risk of either clinical/arrhythmia events (odds ratio (OR), 0.86; 95% confidence interval (CI), 0.52 to 1.44) or QT c prolongation (OR, 1.00; 95% CI, 0.64 to 1.57) during courses of terfenadine versus those of other antihistamines. Joint courses of antihistamines and oral erythromycin were associated with an increased risk of QT c prolongation (OR, 2.33; 95% CI, 1.31 to 4.15), and there was a trend for this to be observed more frequently with terfenadine (OR, 2.37; 95% CI, 0.73 to 7.51; P = 0.14).

Expression of vascular permeability factor (vascular endothelial growth factor) by human corpus luteal cells: Possible role in corpus luteum development

The purpose of conducting cardiovascular safety pharmacology studies is to investigate the pharmacological profiles of new molecular entities (NMEs) and provide data that can be used for optimization of a possible new drug, and help make a selection of NMEs for clinical development. An anaesthetised dog preparation has been used for more than two decades by our department to measure multiple cardiovascular and respiratory parameters and to evaluate different scientific models, leading to more in-depth evaluation of drug-induced cardiovascular effects.An anaesthetic regime developed in house (induction with lofentanil, scopolamine and succinylcholine, and maintenance with fentanyl and etomidate) gives us a preparation free of pain and stress, with minimal effects on the cardiovascular system. This anaesthetic regime had minimal influences on circulating catecholamine levels, on the baroreflex sensitivity, and on all measured basal parameters compared to conscious dogs. All parameters were stable for at least 3 h, with acceptable tolerance intervals, evaluated over 99 safety studies with 3 vehicle treatments (saline, 10% and 20% hydroxypropyl-beta-cyclodextrin). This translates into a highly sensitive model for detecting possible drug-induced effects of NMEs with different mechanisms of action such as: Ca-, Na-, IKr-, IKs-channel blockers, K- and Ca-channel activators, α1- and β-agonists, and muscarinic antagonists. Fentanyl in combination with etomidate is a successful anaesthetic regime in humans [Stockham, R.J., Stanley, T.H., Pace, N.L., King, K., Groen, F. & Gillmor, S.T. (1987). Induction of anaesthesia with fentanyl or fentanyl plus etomidate in high-risk patients. Journal of Cardiothoracic Anesthesia. 1(1), 19–23.]. In the anaesthetised dog, QT correction factors (Van de Water correction and body temperature correction) and risk factors (total, short-term and long-term instability) have been evaluated, using this regime [Van de Water, A., Verheyen, J., Xhonneux, R. & Reneman, R. (1989). An improved method to correct the QT interval of the electrocardiogram for changes in heart rate. Journal of Pharmacological Methods, 22, 207–217.; van der Linde, H.J., Van Deuren, B., Teisman, A., Towart, R. & Gallacher, D.J. (2008). The effect of changes in core body temperature on the QT interval in beagle dogs: A previously ignored phenomenon, with a method for correction. British Journal of Pharmacology, 154, 1474–1481.; van der Linde, H.J., Van de Water, A., Loots, W., Van Deuren, B., Lu, H.R., Van Ammel, K., et al. (2005) A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anaesthetised dogs. Journal of Pharmacological and Toxicological Methods, 52, 168–177.]. Furthermore, this anaesthetic protocol has been used to create different scientific models (long QT, short QT) with different specific end-points (ventricular fibrillation, adrenergic- or pause-dependent TdP) and also their specific precursors: e.g. aftercontractions, phase 2 EADs, phase 3 EADs, DADs, T-wave morphology changes, T-wave alternans, R-on-T, transmural and interventricular dispersion [Gallacher, D.J., Van de Water, A., van der Linde, H.J., Hermans, A.N., Lu, H.R., Towart, R., et al. (2007). In vivo mechanisms precipitating torsade de pointes in canine model of drug-induced long QT1 syndrome. Cardiovascular Research, 76–2, 247–256.]. This paper gives a brief overview of the stability, reproducibility, sensitivity and utility of a well-validated anaesthetised dog model.

Prolonged QT interval and risk of sudden death in South-East Asian men

Sudden death in sleep occurs in substantial numbers among young men in South-East Asia. The frequencies of electrocardiographic abnormalities were measured in groups with varying risks of such sudden death. The mean heart-rate-corrected QT interval (QTc) was significantly (p<0·05) greater among 123 Laotian refugees in Thailand at high risk (405 [95% confidence interval 397-413] ms) than in 77 Laotian refugees in the United States at lower risk (364 [359-369] ms) and 199 non-Asian US residents at negligible risk (358 [354-362] ms). Among refugees in Thailand, prolonged QTc interval was associated with poor thiamine status and a history of seizure-like episodes in sleep. Thiamine deficiency may be a cause of prolonged QT interval and sudden death in this region.