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Biomedical subjects

Gary F Mitchell

Publications and source records attributed to Gary F Mitchell.

25 records · Page 2Linked to original sources
PubMed2004

Attenuation of I(K,slow1) and I(K,slow2) in Kv1/Kv2DN mice prolongs APD and QT intervals but does not suppress spontaneous or inducible arrhythmias.

Overexpression of a truncated Kv1.1 or Kv2.1 channel polypeptide in the heart (Kv1DN or Kv2DN) resulted in mice with a prolonged action potential duration (APD) due to marked attenuation of rapidly activating, slowly inactivating K+ current (I(K,slow1)) or slowly inactivating outward K(+) current (I(K,slow2)) in ventricular myocytes. ECG monitoring, optical mapping, and programmed electrical stimulation of Kv1DN mice revealed spontaneous and inducible reentrant ventricular tachycardia due to spatial dispersion of repolarization and refractoriness. Recently, we demonstrated upregulation of I(K,slow2) in apical cardiomyocytes derived from Kv1DN mice. We therefore hypothesized that the selective upregulation of Kv2.1-encoded currents underlies the apex-to-base dispersion of repolarization and the reentrant arrhythmias. To test this hypothesis, the Kv1DN line was crossbred with the Kv2DN line to produce Kv1/Kv2DN lines. Whole cell voltage-clamp recordings from left ventricular cells of Kv1/Kv2DN confirmed that the 4-aminopyridine- and tetraethylammonium-sensitive components of IK,slow were eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, and Kv2DN cells. Telemetric ECG recordings revealed prolongation of the corrected QT in Kv1/Kv2DN compared with Kv1DN and Kv2DN mice. However, attenuation of Kv2.1-encoded currents in Kv1DN mice did not suppress the arrhythmias. Thus, the elimination of I(K,slow2) prolongs APD and the QT intervals, but does not have an antiarrhythmic effect.

Action Potentials↗
PubMed2003

Determinants of elevated pulse pressure in middle-aged and older subjects with uncomplicated systolic hypertension: the role of proximal aortic diameter and the aortic pressure-flow relationship.

BACKGROUND: Elevated pulse pressure (PP) is associated with increased cardiovascular risk and is thought to be secondary to elastin fragmentation with secondary collagen deposition and stiffening of the aortic wall, leading to a dilated, noncompliant vasculature. METHODS AND RESULTS: By use of calibrated tonometry and pulsed Doppler, arterial stiffness and pulsatile hemodynamics were assessed in 128 subjects with uncomplicated systolic hypertension (supine systolic pressure > or =140 mm Hg off medication) and 30 normotensive control subjects of comparable age and gender. Pulse-wave velocity was assessed from tonometry and body surface measurements. Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Effective aortic diameter was assessed by use of the water hammer equation. Hypertensives were heavier (P<0.001) and had higher PP (P<0.001), which was attributable primarily to higher Zc (P<0.001), especially in women. Pulse-wave velocity was higher in hypertensives (P=0.001); however, this difference was not significant after adjustment for differences in mean arterial pressure (MAP) (P>0.153), whereas increased Zc remained highly significant (P<0.001). Increased Zc in women and in hypertensive men was attributable to decreased effective aortic diameter, with no difference in wall stiffness at comparable MAP and body weight. CONCLUSIONS: Elevated PP in systolic hypertension was independent of MAP and was attributable primarily to elevated Zc and reduced effective diameter of the proximal aorta. These findings are not consistent with the hypothesis of secondary aortic degeneration, dilation, and wall stiffening but rather suggest that aortic function may play an active role in the pathophysiology of systolic hypertension.

Adult↗
PubMed2003

Relation between conduit vessel stiffness (assessed by tonometry) and endothelial function (assessed by flow-mediated dilatation) in patients with and without coronary heart disease.

Endothelial dysfunction and large artery stiffness occur in patients with risk factors for coronary artery disease (CAD) and in those with established CAD. We evaluated the relation between endothelial function and conduit vessel distensibility in normal subjects, in patients with documented stable CAD, and in patients demonstrating only risk factors but no overt atherosclerosis. Endothelium-dependent dilatation was evaluated by way of flow-mediated dilatation of the brachial artery using high-resolution ultrasound. Large artery stiffness was assessed using tonometry. After adjusting for age and intergroup differences, percent flow-mediated dilatation showed statistically significant correlations with several measures of stiffness, including central pulse pressure (r = -0.457, p = 0.019), central systolic pressure (r = -0.442, p = 0.024), peripheral pulse pressure (r = -0.393, p = 0.039), peripheral systolic pressure (r = -0.398, p = 0.036), and proximal aortic compliance (r = 0.390, p = 0.049). Measures of arterial stiffness correlate significantly with those of endothelial function. An increase in large conduit vessel stiffness may represent either a cause or consequence of endothelial dysfunction and may explain why elevated pulse pressure is a new cardiovascular risk factor.

Adult↗
PubMed2003

In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype.

Mutations in cardiac voltage-gated K+ channels cause long QT syndrome (LQTS) and sudden death. We created a transgenic mouse with a long QT phenotype (Kv1DN) by overexpression of a truncated K+ channel in the heart and investigated whether the dominant negative effect of the transgene would be overcome by the direct injection of adenoviral vectors expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. End points at 3-10 days included electrophysiology in isolated cardiomyocytes, surface ECG, programmed stimulation of the right ventricle, and in vivo optical mapping of action potentials and repolarization gradients in Langendorff-perfused hearts. Overexpression of Kv1.5 reconstituted a 4-aminopyridine-sensitive outward K+ current, shortened the action potential duration, eliminated early afterdepolarizations, shortened the QT interval, decreased dispersion of repolarization, and increased the heart rate. Each of these changes is consistent with a physiologically significant primary effect of adenoviral expression of Kv1.5 on ventricular repolarization of Kv1DN mice.

4-Aminopyridine↗
PubMed2002

Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study.

BACKGROUND: Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension. METHODS AND RESULTS: We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n=87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor omapatrilat 80 mg daily (n=80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be > or =160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Z(c)), a direct measure of the stiffness of the central aorta, was calculated from the ratio of changes in carotid pressure and aortic flow in early systole. Omapatrilat compared with enalapril produced greater reductions in peripheral (-8.2+/-12.2 versus -4.0+/-12.2 mm Hg, P<0.05) and central (-10.2+/-16.2 versus -3.2+/-16.9 mm Hg, P<0.01) pulse pressures and Z(c) (237+/-83 to 208+/-70 versus 225+/-87 to 231+/-94 dyne x s/cm(5), P<0.001); the latter remained significant (P<0.05) after adjusting for change in mean pressure. CONCLUSIONS: Greater reductions in pulse pressure and Z(c) in hypertensive subjects treated with omapatrilat compared with enalapril suggest that aortic stiffness is maintained by specific, partially reversible mechanisms and underscore a potential role for pharmacological modulation of natriuretic peptides in the treatment of hypertension.

Adult↗