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Biomedical subjects

Peter Taggart

Publications and source records attributed to Peter Taggart.

11 recordsLinked to original sources
PubMed2006

Evidence for multiple mechanisms in human ventricular fibrillation.

BACKGROUND: The mechanisms that sustain ventricular fibrillation (VF) in the human heart remain unclear. Experimental models have demonstrated either a periodic source (mother rotor) or multiple wavelets as the mechanism underlying VF. The aim of this study was to map electrical activity from the entire ventricular epicardium of human hearts to establish the relative roles of these mechanisms in sustaining early human VF. METHODS AND RESULTS: In 10 patients undergoing cardiac surgery, VF was induced by burst pacing, and 20 to 40 seconds of epicardial activity was sampled (1 kHz) with a sock containing 256 unipolar contact electrodes connected to a UnEmap system. Signals were interpolated from the electrode sites to a fine regular grid (100x100 points), and dominant frequencies (DFs) were calculated with a fast Fourier transform with a moving 4096-ms window (10-ms increments). Epicardial phase was calculated at each grid point with the Hilbert transform, and phase singularities and activation wavefronts were identified at 10-ms intervals. Early human VF was sustained by large coherent wavefronts punctuated by periods of disorganized wavelet behavior. The initial fitted DF intercept was 5.11 +/- 0.25 (mean +/- SE) Hz (P < 0.0001), and DF increased at a rate of 0.018 +/- 0.005 Hz/s (P < 0.01) during VF, whereas combinations of homogeneous, heterogeneous, static, and mobile DF domains were observed for each of the patients. Epicardial reentry was present in all fibrillating hearts, typically with low numbers of phase singularities. In some cases, persistent phase singularities interacted with multiple complex wavelets; in other cases, VF was driven at times by a single reentrant wave that swept the entire epicardium for several cycles. CONCLUSIONS: Our data support both the mother rotor and multiple wavelet mechanisms of VF, which do not appear to be mutually exclusive in the human heart.

Aged↗
PubMed2006

Hepatic expression of heme oxygenase-1 and antioxidant response element-mediated genes following administration of ethinyl estradiol to rats.

Heme oxygenase-1 (HO-1) is one of several enzymes induced by hepatotoxicants, and is thought to have an important protective role against cellular stress during liver inflammation and injury. The objective of the present study was to evaluate the role of HO-1 in estradiol-induced liver injury. A single dose of ethinyl estradiol (500 mg/kg, po) resulted in mild liver injury. Repeated administration of ethinyl estradiol (500 mg/kg/day for 4 days, po) resulted in no detectable liver injury or dysfunction. Using RT-PCR analysis, we demonstrate that HO-1 gene expression in whole liver tissue is elevated (>20-fold) after the single dose of ethinyl estradiol. The number and intensity of HO-1 immunoreactive macrophages were increased after the single dose of ethinyl estradiol. HO-1 expression was undetectable in hepatic parenchymal cells from rats receiving Methocel control or a single dose of ethinyl estradiol, however cytosolic HO-1 immunoreactivity in these cells after repeated dosing of ethinyl estradiol was pronounced. The increases in HO-1 mRNA and HO-1 immunoreactivity following administration of a single dose of ethinyl estradiol suggested that this enzyme might be responsible for the observed protection of the liver during repeated dosing. To investigate the effect of HO-1 expression on ethinyl estradiol-induced hepatotoxicity, rats were pretreated with hemin (50 micromol/kg, ip, a substrate and inducer of HO-1), with tin protoporphyrin IX (60 micromol/kg, ip, an HO-1 inhibitor), or with gadolinium chloride (10 mg/kg, iv, an inhibitor/toxin of Kupffer cells) 24 h before ethinyl estradiol treatment. Pretreatment with modulators of HO-1 expression and activity had generally minimal effects on ethinyl estradiol-induced liver injury. These data suggest that HO-1 plays a limited role in antioxidant defense against ethinyl estradiol-induced oxidative stress and hepatotoxicity, and suggests that other coordinately induced enzymes are responsible for protection observed with repeated administration of high doses of this compound.

Animals↗
PubMed2006

Whole heart action potential duration restitution properties in cardiac patients: a combined clinical and modelling study.

Steep action potential duration (APD) restitution has been shown to facilitate wavebreak and ventricular fibrillation. The global APD restitution properties in cardiac patients are unknown. We report a combined clinical electrophysiology and computer modelling study to: (1) determine global APD restitution properties in cardiac patients; and (2) examine the interaction of the observed APD restitution with known arrhythmia mechanisms. In 14 patients aged 52-85 years undergoing routine cardiac surgery, 256 electrode epicardial mapping was performed. Activation-recovery intervals (ARI; a surrogate for APD) were recorded over the entire ventricular surface. Mono-exponential restitution curves were constructed for each electrode site using a standard S1-S2 pacing protocol. The median maximum restitution slope was 0.91, with 27% of all electrode sites with slopes<0.5, 29% between 0.5 and 1.0, and 20% between 1.0 and 1.5. Eleven per cent of restitution curves maintained slope>1 over a range of diastolic intervals of at least 30 ms; and 0.3% for at least 50 ms. Activation-recovery interval restitution was spatially heterogeneous, showing regional organization with multiple discrete areas of steep and shallow slope. We used a simplified computer model of 2-D cardiac tissue to investigate how heterogeneous APD restitution can influence vulnerability to, and stability of re-entry. Our model showed that heterogeneity of restitution can act as a potent arrhythmogenic substrate, as well as influencing the stability of re-entrant arrhythmias. Global epicardial mapping in humans showed that APD restitution slopes were organized into regions of shallow and steep slopes. This heterogeneous organization of restitution may provide a substrate for arrhythmia.

Action Potentials↗
PubMed2005

Regional differences in APD restitution can initiate wavebreak and re-entry in cardiac tissue: a computational study.

BACKGROUND: Regional differences in action potential duration (APD) restitution in the heart favour arrhythmias, but the mechanism is not well understood. METHODS: We simulated a 150 x 150 mm 2D sheet of cardiac ventricular tissue using a simplified computational model. We investigated wavebreak and re-entry initiated by an S1S2S3 stimulus protocol in tissue sheets with two regions, each with different APD restitution. The two regions had a different APD at short diastolic interval (DI), but similar APD at long DI. Simulations were performed twice; once with both regions having steep (slope > 1), and once with both regions having flat (slope < 1) APD restitution. RESULTS: Wavebreak and re-entry were readily initiated using the S1S2S3 protocol in tissue sheets with two regions having different APD restitution properties. Initiation occurred irrespective of whether the APD restitution slopes were steep or flat. With steep APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms with S1S2 of 250 ms, to 75 ms (S1S2 180 ms). With flat APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms (S1S2 250 ms), to 21 ms (S1S2 340 ms) and then 11 ms (S1S2 400 ms). CONCLUSION: Regional differences in APD restitution are an arrhythmogenic substrate that can be concealed at normal heart rates. A premature stimulus produces regional differences in repolarisation, and a further premature stimulus can then result in wavebreak and initiate re-entry. This mechanism for initiating re-entry is independent of the steepness of the APD restitution curve.

Action Potentials↗
PubMed2004

Mental stress and sudden cardiac death: asymmetric midbrain activity as a linking mechanism.

Patients with specific neurological, psychiatric or cardiovascular conditions are at enhanced risk of cardiac arrhythmia and sudden death. The neurogenic mechanisms are poorly understood. However, in many cases, stress may precipitate cardiac arrhythmia and sudden death in vulnerable patients, presumably via centrally driven autonomic nervous system responses. From a cardiological perspective, the likelihood of arrhythmia is strongly associated with abnormalities in electrical repolarization (recovery) of the heart muscle after each contraction. Inhomogeneous and asymmetric repolarization, reflected in ECG T-wave abnormalities, is associated with a greatly increased risk of arrhythmia, i.e. a proarrhythmic state. We therefore undertook a study to identify the brain mechanisms by which stress can induce cardiac arrhythmia through efferent autonomic drive. We recruited a typical group of 10 out-patients attending a cardiological clinic. We simultaneously measured brain activity, using H2(15)O PET, and the proarrhythmic state of the heart, using ECG, during mental and physical stress challenges and corresponding control conditions. Proarrhythmic changes in the heart were quantified from two ECG-derived measures of repolarization inhomogeneity and were related to changes in magnitude and lateralization of regional brain activity reflected in regional cerebral blood flow. Across the patient group, we observed a robust positive relationship between right-lateralized asymmetry in midbrain activity and proarrhythmic abnormalities of cardiac repolarization (apparent in two independent ECG measures) during stress. This association between stress-induced lateralization of midbrain activity and enhanced arrhythmic vulnerability provides empirical support for a putative mechanism for stress-induced sudden death, wherein lateralization of central autonomic drive during stress results in imbalanced activity in right and left cardiac sympathetic nerves. A right-left asymmetry in sympathetic drive across the surface of the heart disrupts the electrophysiological homogeneity of ventricular repolarization, predisposing to arrhythmia. Our findings highlight a proximal brain basis for stress-induced cardiac arrhythmic vulnerability.

Aged↗
PubMed2004

Intercellular coupling through gap junctions masks M cells in the human heart.

OBJECTIVES: M cells have been described in many mammalian species. They are thought to be relevant for the genesis of long QT intervals, afterdepolarizations and for dispersion in action potential duration and in repolarization time. Their role in the human heart is subject to debate. METHODS: We simulated action potential propagation in a strand of transversally oriented myocytes running from endocardium towards epicardium through the left ventricular free wall. The characteristics of the myocytes were either based on the Priebe-Beuckelmann ventricular cell model or on the Luo-Rudy ventricular cell model. The former model is based on the latter and includes adaptations in order to mimic the human ventricular myocyte. The amount and location of M cells as well as the intercellular coupling through gap junctions were varied. Also, we assessed action potential duration in a Langendorff-perfused explanted human heart and in a wedge preparation obtained from such a heart. RESULTS: At low, but physiological intercellular coupling conductance, the inclusion of M cells leads to a much longer 'QT interval' in the simulations than in the in vivo or isolated human heart. Dispersion in repolarization time becomes unphysiologically large when M cells are included in the strand and is also substantially larger than in the in vivo or isolated human heart. At stronger intercellular coupling this effect disappears. CONCLUSIONS: The manifestation of M cells is absent in the human heart, probably by effective intercellular coupling, turning them functionally "invisible".

Action Potentials↗
PubMed2003

Effect of adrenergic stimulation on action potential duration restitution in humans.

BACKGROUND: Enhanced sympathetic activity facilitates complex ventricular arrhythmias and fibrillation. The restitution properties of action potential duration (APD) are important determinants of electrical stability in the myocardium. Steepening of the slope of APD restitution has been shown to promote wave break and ventricular fibrillation. The effect of adrenergic stimulation on APD restitution in humans is unknown. METHODS AND RESULTS: Monophasic action potentials were recorded from the right ventricular septum in 18 patients. Standard APD restitution curves were constructed at 3 basic drive cycle lengths (CLs) of 600, 500, and 400 ms under resting conditions and during infusion of isoprenaline (15 patients) or adrenaline (3 patients). The maximum slope of the restitution curves was measured by piecewise linear regression segments of sequential 40-ms ranges of diastolic intervals in steps of 10 ms. Under control conditions, the maximum slope was steeper at longer basic CLs; eg, mean values for the maximum slope were 1.053+/-0.092 at CL 600 ms and 0.711+/-0.049 at CL 400 ms (+/-SEM). Isoprenaline increased the steepness of the maximum slope of APD restitution, eg, from a maximum slope of 0.923+/-0.058 to a maximum slope of 1.202+/-0.121 at CL 500 ms. The effect of isoprenaline was greater at the shorter basic CLs. A similar overall effect was observed with adrenaline. CONCLUSIONS: The adrenergic agonists isoprenaline and adrenaline increased the steepness of the slope of the APD restitution curve in humans over a wide range of diastolic intervals. These results may relate to the known effects of adrenergic stimulation in facilitating ventricular fibrillation.

Action Potentials↗
PubMedDate not supplied

Electrotonic cancellation of transmural electrical gradients in the left ventricle in man.

Myocardial cells isolated from different depths of the ventricular wall show substantial differences in action potential duration. Whether these electrophysiological differences are present in vivo when the cells are well coupled is a subject of ongoing controversy. This article provides a brief review and includes experimental evidence derived from patients undergoing cardiac surgery.

Action Potentials↗
PubMedDate not supplied

The effect of mental stress on the non-dipolar components of the T wave: modulation by hypnosis.

OBJECTIVE: Mental or emotional stress-induced ventricular arrhythmias and sudden cardiac death are thought to be mediated by the autonomic nervous system and ischemia. In the absence of ischemia, increased inhomogeneity of repolarization is thought to be important. We tested the hypotheses that in the absence of ischemia, mental stress may modulate repolarization by changing autonomic balance; and mental relaxation induced by hypnosis may offset the potentially adverse effects of stress on the cardiac electrophysiology. METHODS: Twelve healthy volunteers (6 male, age 18-35, mean 25 years) experienced a series of different emotions intended to induce a wide range of autonomic response (42 test epochs) on two separate occasions, with and without hypnosis, with continuous electrocardiogram recording. Low- (LF) and HF (high-frequency) heart rate variability was measured and ventricular repolarization was assessed using the relative T-wave residua (proportion of nondipolar components of the T wave) calculated for the T-onset - T peak (TWR-peak T), T peak -T end (TWR-end T), and the whole T wave (TWR). RESULTS: Emotionally induced changes in LF and LF/HF ratio correlated with changes in TWR, e.g., (R = 0.51, p < .001; R = 0.59, p < .0001; and R = 0.59, p < .0003, for LF/HF versus TWR, TWR-Peak T, and TWR-end T, respectively. Mental relaxation induced by hypnosis increased LF power (1,205 ms2) versus 624 ms2, p < .003 for hypnotized versus nonhypnotized state), HF power (1,619 ms2 versus 572 ms2), p < .0004), and reduced LF/HF ratio (1.0 versus 1.5, p = .052) and was associated with a marked reduction in the changes in repolarization in response to emotion, e.g., 10.7 x 10(-6) versus 5.0 x10(-6), p < .03 for TWR. CONCLUSIONS: a) Mental stress in the absence of ischemia altered repolarization inhomogeneity via change in the autonomic balance. b) Mental relaxation induced by hypnosis greatly reduced the effect of mental stress on repolarization. c) These findings may have implications for arrhythmogenesis.

Adolescent↗