Assessment of ventricular repolarization variability with the DeltaT50 method improves identification of patients with congenital long QT syndromes.

BACKGROUND: We analyzed ventricular repolarization variability in genotyped long QT syndrome (LQTS) patients and in healthy volunteers (HV). METHOD: The deltaT50, that is, the temporal variability of ventricular repolarization at 50% of the T-wave downslope, was analyzed every 15th minute on 175 and 390 Holter electrocardiogram (ECG) recordings from HV and genotyped LQTS patients, respectively. The average deltaT50 and QTcF were calculated in each subject. RESULTS: DeltaT50 was 2.26 ± 0.71 ms (mean ± SD) in the HV and 5.74 ± 2.30 ms in the LQTS population (P < 0.0001). The sensitivity and specificity of QTcF (cutoff value 450 ms) to discriminate between the LQTS patients and the HV were 51.5% and 98.9%, and for deltaT50 (cutoff value 3 ms) 93.9% and 88.6%, respectively. The combination of both variables improved the diagnosis of the LQTS patients even further. Subgroups of LQTS patients at higher risk of cardiac events (with LQTS3, JLN, QTc > 500 ms or symptoms) had higher deltaT50 than subgroups at lower risk (with LQTS1, QTc < 450 ms or without symptoms). The variation in deltaT50 between day and night was concordant with the risk of symptoms; patients with LQTS1 had higher deltaT50 in the daytime and patients with LQTS3 had higher deltaT50 during the night. CONCLUSION: DeltaT50 more accurately distinguished between LQTS patients and HV than QTcF and was higher in LQTS patients with a higher risk of cardiac events. DeltaT50 can be used together with QTcF to improve the diagnosis in patients with the LQTS phenotype and tentatively also be of value for risk assessment in such patients.

DeltaT50--a new method to assess temporal ventricular repolarization variability.

BACKGROUND: Increased beat-to-beat variability in cardiac repolarization time is a tentative risk marker of drug-induced torsades de pointes. We developed a new, automatic method based on the temporal variability of the T-wave down slope to assess this variability. METHOD AND RESULTS: Leads V(1) to V(6) of resting electrocardiograms were recorded in 42 healthy subjects (18-68 years, 22 men). The temporal variability at 50% of the T-wave down slope, deltaT50 (1.5 ± 0.41 milliseconds; range, 0.86-2.66 milliseconds), was measured with an accuracy of 1 millisecond on at least 9 pairs of electrocardiogram complexes with a signal-to-noise ratio more than 10 and changes in the R-R interval less than 150 milliseconds. The correlation between repeated measurements of deltaT50 was high. DeltaT50 was measured without corrections for age, sex, heart rate, T-wave amplitude, signal-to-noise ratio, R-R variability, and QTcF because none of these factors explained more than 4% of the within-subject deltaT50 variability. CONCLUSION: The beat-to-beat repolarization variability was measured with high fidelity with the deltaT50 method and was a robust measure in healthy volunteers.

Involvement of metabotropic glutamate 5 receptor in visceral pain.

Metabotropic glutamate 5 receptor (mGluR5) antagonists are effective in animal models of inflammatory and neuropathic pain. The involvement of mGluR5 in visceral pain pathways from the gastrointestinal tract is as yet unknown. We evaluated effects of mGluR5 antagonists on the colorectal distension (CRD)-evoked visceromotor (VMR) and cardiovascular responses in conscious rats, and on mechanosensory responses of mouse colorectal afferents in vitro. Sprague-Dawley rats were subjected to repeated, isobaric CRD (12 x 80 mmHg, for 30s with 5 min intervals). The VMR and cardiovascular responses to CRD were monitored. The mGluR5 antagonists MPEP (1-10 micromol/kg, i.v.) and MTEP (1-3 micromol/kg, i.v.) reduced the VMR to CRD dose-dependently with maximal inhibition of 52+/-8% (p<0.01) and 25+/-11% (p<0.05), respectively, without affecting colonic compliance. MPEP (10 micromol/kg, i.v.) reduced CRD-evoked increases in blood pressure and heart rate by 33+/-9% (p<0.01) and 35+/-8% (p<0.05), respectively. Single afferent recordings were made from mouse pelvic and splanchnic nerves of colorectal mechanoreceptors. Circumferential stretch (0-5 g force) elicited slowly-adapting excitation of action potentials in pelvic distension-sensitive afferents. This response was reduced 55-78% by 10 microM MTEP (p<0.05). Colonic probing (2g von Frey hair) activated serosal splanchnic afferents; their responses were reduced 50% by 10 microM MTEP (p<0.01). We conclude that mGluR5 antagonists inhibit CRD-evoked VMR and cardiovascular changes in conscious rats, through an effect, at least in part, at peripheral afferent endings. Thus, mGluR5 participates in mediating mechanically evoked visceral nociception in the gastrointestinal tract.

A method for heart rate-corrected estimation of baroreflex sensitivity.

OBJECTIVE: The relationship between the prevailing heart rate (HR) and the baroreflex sensitivity (BRS) is described in the present study together with a method for individual HR-corrected estimations of BRS. DESIGN: HR and BRS, determined with the sequence method, were measured in ten young healthy subjects during rest, stress, standing and bicycle exercise, i.e. at a wide range of HRs. RESULTS: BRS decreased exponentially with increasing HR. The relationship between the natural logarithm of BRS and HR was linear in each individual and could be described by the equation of a straight line. The equation describing the individual BRS-HR relationship could be derived either from BRS and HR measured during steady-state conditions or from the slope and average HR of the individual sequences occurring throughout the experimental protocol. The latter method was preferable since it did not require recordings during steady-state conditions. In order to eliminate the influence of differences in HR on BRS when comparing BRS between subjects, the equation describing the individual BRS-HR relationship was used to calculate BRS at a HR of 60 bpm, BRS(60), which ranged from 9.5 to 30.1 ms/mmHg for the 10 subjects. CONCLUSIONS: Considering the dramatic effect of a small difference in HR on BRS, especially at lower HRs, BRS should be estimated at a wide range of HRs in order to determine the HR-corrected BRS from the individual HR-BRS relationship. Otherwise, comparisons of BRS between different individuals, study groups or following drug treatment or other interventions would be highly dependent on differences in HR and thereby easily misinterpreted.