Criteria for arrhythmogenicity in genetically-modified Langendorff-perfused murine hearts modelling the congenital long QT syndrome type 3 and the Brugada syndrome.
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ABSTRACT:
SUBMITTER: Sabir IN
PROVIDER: S-EPMC2082651 | biostudies-other | 2008 Jan
REPOSITORIES: biostudies-other
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Project description:Acute effects of heptanol (0.1 to 2 mM) on atrial electrophysiology were explored in Langendorff-perfused mouse hearts. Left atrial bipolar electrogram or monophasic action potential recordings were obtained during right atrial stimulation. Regular pacing at 8 Hz elicited atrial activity in 11 out of 11 hearts without inducing atrial arrhythmias. Programmed electrical stimulation using a S1S2 protocol provoked atrial tachy-arrhythmias in 9 of 17 hearts. In the initially arrhythmic group, 2 mM heptanol exerted anti-arrhythmic effects (Fisher's exact test, P < 0.05) and increased atrial effective refractory period (ERP) from 26.0 ± 1.9 to 57.1 ± 2.5 ms (ANOVA, P < 0.001) despite increasing activation latency from 18.7 ± 1.1 to 28.9 ± 2.1 ms (P < 0.001) and leaving action potential duration at 90% repolarization (APD90) unaltered (25.6 ± 1.2 vs. 27.2 ± 1.2 ms; P > 0.05), which led to increases in ERP/latency ratio from 1.4 ± 0.1 to 2.1 ± 0.2 and ERP/APD90 ratio from 1.0 ± 0.1 to 2.1 ± 0.2 (P < 0.001). In contrast, in the initially non-arrhythmic group, heptanol did not alter arrhythmogenicity, increased AERP from 47.3 ± 5.3 to 54.5 ± 3.1 ms (P < 0.05) and activation latency from 23.7 ± 2.2 to 31.3 ± 2.5 ms and did not alter APD90 (24.1 ± 1.2 vs. 25.0 ± 2.3 ms; P > 0.05), leaving both AERP/latency ratio (2.1 ± 0.3 vs. 1.9 ± 0.2; P > 0.05) and ERP/APD90 ratio (2.0 ± 0.2 vs. 2.1 ± 0.1; P > 0.05) unaltered. Lower heptanol concentrations (0.1, 0.5 and 1 mM) did not alter arrhythmogenicity or the above parameters. The present findings contrast with known ventricular pro-arrhythmic effects of heptanol associated with decreased ERP/latency ratio, despite increased ERP/APD ratio observed in both the atria and ventricles.
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Project description:Spontaneous Raman spectroscopy, which senses changes in cellular contents of reduced cytochrome c, could be a powerful tool for label-free evaluation of ischemic hearts. However, undetermined is whether it is applicable to evaluation of myocardial viability in ischemic hearts. To address this issue, we investigated sequential changes in Raman spectra of the subepicardial myocardium in the Langendorff-perfused rat heart before and during ligation of the left coronary artery and its subsequent release and re-ligation. Under 532-nm wavelength excitation, the Raman peak intensity of reduced cytochrome c at 747 cm-1 increased quickly after the coronary ligation, and reached a quasi-steady state within 30 min. Subsequent reperfusion of the heart after a short-term (30-min) ligation that simulates reversible conditions resulted in quick recovery of the peak intensity to the baseline. Further re-ligation resulted in resurgence of the peak intensity to nearly the identical value to the first ischemia value. In contrast, reperfusion after prolonged (120-min) ligation that assumes irreversible states resulted in incomplete recovery of the peak intensity, and re-ligation resulted in inadequate resurgence. Electron microscopic observations confirmed the spectral findings. Together, the Raman spectroscopic measurement for cytochrome c could be applicable to evaluation of viability of the ischemic myocardium without labeling.
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Project description:BackgroundTime-domain and non-linear methods can be used to quantify beat-to-beat repolarization variability but whether measures of repolarization variability can predict ventricular arrhythmogenesis in mice have never been explored.MethodsLeft ventricular monophasic action potentials (MAPs) were recorded during constant right ventricular 8 Hz pacing in Langendorff-perfused mouse hearts, in the presence or absence of the gap junction and sodium channel inhibitor heptanol (0.1, 0.5, 1 or 2 mM).ResultsUnder control conditions, mean action potential duration (APD) was 39.4 ± 8.1 ms. Standard deviation (SD) of APDs was 0.3 ± 0.2 ms, coefficient of variation was 0.9 ± 0.8% and the root mean square (RMS) of successive differences in APDs was 0.15 ± 0.14 ms. Poincaré plots of APDn+1 against APDn revealed ellipsoid morphologies with a SD along the line-of-identity (SD2) to SD perpendicular to the line-of-identity (SD1) ratio of 4.6 ± 2.1. Approximate and sample entropy were 0.61 ± 0.12 and 0.76 ± 0.26, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.49 ± 0.27 and 0.81 ± 0.36, respectively. Heptanol at 2 mM induced ventricular tachycardia in five out of six hearts. None of the above parameters were altered by heptanol during which reproducible electrical activity was observed (KW-ANOVA, P > 0.05). Contrastingly, SD2/SD1 decreased to 2.03 ± 0.41, approximate and sample entropy increased to 0.82 ± 0.12 and 1.45 ± 0.34, and short-term fluctuation slope decreased to 0.82 ± 0.19 during the 20-s period preceding spontaneous ventricular tachy-arrhythmias (n = 6, KW-ANOVA, P < 0.05).ConclusionMeasures of repolarization variability, such as SD2/SD1, entropy, and fluctuation slope are altered preceding the occurrence of ventricular arrhythmogenesis in mouse hearts. Changes in these variables may allow detection of impending arrhythmias for early intervention.
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Project description:Background: Beat-to-beat variability in action potential duration (APD) is an intrinsic property of cardiac tissue and is altered in pro-arrhythmic states. However, it has never been examined in mice. Methods: Left atrial or ventricular monophasic action potentials (MAPs) were recorded from Langendorff-perfused mouse hearts during regular 8 Hz pacing. Time-domain, frequency-domain and non-linear analyses were used to quantify APD variability. Results: Mean atrial APD (90% repolarization) was 23.5 ± 6.3 ms and standard deviation (SD) was 0.9 ± 0.5 ms (n = 6 hearts). Coefficient of variation (CoV) was 4.0 ± 1.9% and root mean square (RMS) of successive differences in APDs was 0.3 ± 0.2 ms. The peaks for low- and high-frequency were 0.7 ± 0.5 and 2.7 ± 0.9 Hz, respectively, with percentage powers of 39.0 ± 20.5 and 59.3 ± 22.9%. Poincaré plots of APDn+1 against APDn revealed ellipsoid shapes. The ratio of the SD along the line-of-identity (SD2) to the SD perpendicular to the line-of-identity (SD1) was 8.28 ± 4.78. Approximate and sample entropy were 0.57 ± 0.12 and 0.57 ± 0.15, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.80 ± 0.15 and 0.85 ± 0.29, respectively. When compared to atrial APDs, ventricular APDs were longer (ANOVA, P < 0.05), showed lower mean SD and CoV but similar RMS of successive differences in APDs and showed lower SD2 (P < 0.05). No difference in the remaining parameters was observed. Conclusion: Beat-to-beat variability in APD is observed in mouse hearts during regular pacing. Atrial MAPs showed greater degree of variability than ventricular MAPs. Non-linear techniques offer further insights on short-term and long-term variability and signal complexity.
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Project description:As progressive organ shortage in cardiac transplantation demands extension of donor criteria, effort is needed to optimize graft survival. Reactive oxygen and nitrogen species, generated during organ procurement, transplantation, and reperfusion, contribute to acute and late graft dysfunction. The combined application of diverse substances acting via different molecular pathways appears to be a reasonable approach to face the complex mechanism of ischemia reperfusion injury. Thus, an antioxidant solution containing ?-ketoglutaric acid, 5-hydroxymethylfurfural, N-acetyl-L-methionine, and N-acetyl-selenium-L-methionine was combined with endogenous angiotensin-(1-7). Its capacity of myocardial protection was investigated in isolated Langendorff-perfused rat hearts subjected to warm and cold ischemia. The physiological cardiac parameters were assessed throughout the experiments. Effects were evaluated via determination of the oxidative stress parameters malondialdehyde and carbonyl proteins as well as immunohistochemical and ultrastructural tissue analyses. It was shown that a combination of 20% (v/v) antioxidant solution and 220?pM angiotensin-(1-7) led to the best results with a preservation of heart tissue against oxidative stress and morphological alteration. Additionally, immediate cardiac recovery (after warm ischemia) and normal physiological performance (after cold ischemia) were recorded. Overall, the results of this study indicate substantial cardioprotection of the novel combination with promising prospective for future clinical use.
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Project description:BackgroundIncreased variability of QT interval (QTV) has been linked to arrhythmias in animal experiments and multiple clinical situations. Congenital long QT syndrome (LQTS), a pure repolarization disease, may provide important information on the relationship between delayed repolarization and QTV.Methods and resultsTwenty-four-hour Holter monitor tracings from 78 genotyped congenital LQTS patients (52 females; 51 LQT1, 23 LQT2, 2 LQT5, 2 JLN, 27 symptomatic; age, 35.2±12.3 years) were evaluated with computer-assisted annotation of RR and QT intervals. Several models of RR-QT relationship were tested in all patients. A model assuming exponential decrease of past RR interval contributions to QT duration with 60-second time constant provided the best data fit. This model was used to calculate QTc and residual "intrinsic" QTV, which cannot be explained by heart rate change. The intrinsic QTV was higher in patients with long QTc (r=0.68; P<10(-4)), and in LQT2 than in LQT1/5 patients (5.65±1.28 vs 4.46±0.82; P<0.0002). Both QTc and intrinsic QTV were similar in symptomatic and asymptomatic patients (467±52 vs 459±53 ms and 5.10±1.19 vs 4.74±1.09, respectively).ConclusionsIn LQTS patients, QT interval adaptation to heart rate changes occurs with time constant ?60 seconds, similar to results reported in control subjects. Intrinsic QTV correlates with the degree of repolarization delay and might reflect action potential instability observed in animal models of LQTS.
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Project description:The clinical effects of hypokalemia including action potential prolongation and arrhythmogenicity suppressible by lidocaine were reproduced in hypokalemic (3.0 mM K(+)) Langendorff-perfused murine hearts before and after exposure to lidocaine (10 muM). Novel limiting criteria for local and transmural, epicardial, and endocardial re-excitation involving action potential duration (at 90% repolarization, APD(90)), ventricular effective refractory period (VERP), and transmural conduction time (Deltalatency), where appropriate, were applied to normokalemic (5.2 mM K(+)) and hypokalemic hearts. Hypokalemia increased epicardial APD(90) from 46.6 +/- 1.2 to 53.1 +/- 0.7 ms yet decreased epicardial VERP from 41 +/- 4 to 29 +/- 1 ms, left endocardial APD(90) unchanged (58.2 +/- 3.7 to 56.9 +/- 4.0 ms) yet decreased endocardial VERP from 48 +/- 4 to 29 +/- 2 ms, and left Deltalatency unchanged (1.6 +/- 1.4 to 1.1 +/- 1.1 ms; eight normokalemic and five hypokalemic hearts). These findings precisely matched computational predictions based on previous reports of altered ion channel gating and membrane hyperpolarization. Hypokalemia thus shifted all re-excitation criteria in the positive direction. In contrast, hypokalemia spared epicardial APD(90) (54.8 +/- 2.7 to 60.6 +/- 2.7 ms), epicardial VERP (84 +/- 5 to 81 +/- 7 ms), endocardial APD(90) (56.6 +/- 4.2 to 63.7 +/- 6.4 ms), endocardial VERP (80 +/- 2 to 84 +/- 4 ms), and Deltalatency (12.5 +/- 6.2 to 7.6 +/- 3.4 ms; five hearts in each case) in lidocaine-treated hearts. Exposure to lidocaine thus consistently shifted all re-excitation criteria in the negative direction, again precisely agreeing with the arrhythmogenic findings. In contrast, established analyses invoking transmural dispersion of repolarization failed to account for any of these findings. We thus establish novel, more general, criteria predictive of arrhythmogenicity that may be particularly useful where APD(90) might diverge sharply from VERP.
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Project description:The prevalence of genetic arrhythmogenic diseases is unknown. For the long-QT syndrome (LQTS), figures ranging from 1:20 000 to 1:5000 were published, but none was based on actual data. Our objective was to define the prevalence of LQTS.In 18 maternity hospitals, an ECG was performed in 44 596 infants 15 to 25 days old (43 080 whites). In infants with a corrected QT interval (QTc) >450 ms, the ECG was repeated within 1 to 2 weeks. Genetic analysis, by screening 7 LQTS genes, was performed in 28 of 31 (90%) and in 14 of 28 infants (50%) with, respectively, a QTc >470 ms or between 461 and 470 ms. A QTc of 451 to 460, 461 to 470, and >470 ms was observed in 177 (0.41%), 28 (0.06%), and 31 infants (0.07%). Among genotyped infants, disease-causing mutations were found in 12 of 28 (43%) with a QTc >470 ms and in 4 of 14 (29%) with a QTc of 461 to 470 ms. One genotype-negative infant (QTc 482 ms) was diagnosed as affected by LQTS on clinical grounds. Among family members of genotype-positive infants, 51% were found to carry disease-causing mutations. In total, 17 of 43 080 white infants were affected by LQTS, demonstrating a prevalence of at least 1:2534 apparently healthy live births (95% confidence interval, 1:1583 to 1:4350).This study provides the first data-based estimate of the prevalence of LQTS among whites. On the basis of the nongenotyped infants with QTc between 451 and 470 ms, we advance the hypothesis that this prevalence might be close to 1:2000. ECG-guided molecular screening can identify most infants affected by LQTS and unmask affected relatives, thus allowing effective preventive measures.
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