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Biomedical subjects

W M Lester

Publications and source records attributed to W M Lester.

At least 19 recordsLinked to original sources
PubMed2000

Dispersion of ventricular repolarization and ventricular fibrillation in left ventricular hypertrophy: influence of selective potassium channel blockers.

This study tested the hypothesis that combination ion channel blockers of the transient outward current (I(to)) and the rapid component of the delayed rectifying current (I(Kr)) would produce greater prolongation of the ventricular action potential duration (APD) and increased dispersion of the APD in hypertrophied hearts compared with control hearts. Isolated rabbit hearts were studied 48 +/- 5 days postabdominal aortic banding. Left ventricular endocardial and epicardial APDs were significantly greater at baseline in the hypertrophied group than in controls (P <.05). The magnitude of APD prolongation induced by the I(to) blocker 4-aminopyridine (4-AP) and combination 4-AP and the I(Kr) blocker dofetilide was greater in the hypertrophied hearts than in the normal hearts (P <.01). Mean APD dispersion was significantly greater in the hypertrophied group than in the control hearts at baseline (P <.05). 4-AP increased APD dispersion by a similar magnitude in the hypertrophied hearts (10 +/- 10 ms) and the control hearts (8 +/- 8 ms, P = NS), whereas the combination 4-AP and dofetilide increased APD dispersion by a greater magnitude in the hypertrophied hearts (41 +/- 28 ms) than the control hearts (21 +/- 11 ms, P <.05). Ventricular fibrillation occurred spontaneously in four hypertrophied hearts (40%) during combination drug perfusion and in none of the control hearts (P <.05). Thus, combination I(to) and I(Kr) blockers cause greater prolongation APD and increased APD dispersion in left ventricular hypertrophy, and this is associated with the development of ventricular fibrillation.

4-Aminopyridine↗
PubMed1998

Dispersion of ventricular repolarization in left ventricular hypertrophy: influence of afterload and dofetilide.

INTRODUCTION: Increased dispersion of ventricular repolarization is observed in cardiac hypertrophy and is associated with sudden cardiac death. At present, there is little information about the effects of cardiac hemodynamics and antiarrhythmic drugs on dispersion of repolarization in disease states. We compared the effects of increasing afterload and the Class III antiarrhythmic drug, dofetilide, on dispersion of ventricular repolarization in hypertrophied rabbit hearts to normal rabbit hearts. METHODS AND RESULTS: Cardiac hypertrophy was induced in rabbits by abdominal aortic banding. Isolated hearts were studied 49+/-4 days postsurgery in the working heart mode using a blood-buffer perfusate. The action potential duration (APD) was measured from eight sites on the epicardium of the heart at low (50+/-7 mmHg) afterload and high afterload (97+/-12 mmHg) at baseline and during dofetilide perfusion. APD dispersion, determined as the difference between the maximal and minimal APD, was greater in hypertrophied hearts (42+/-8 msec) compared with control hearts (26+/-8 msec, P < 0.05) at baseline and low afterload. Increasing afterload caused a decrease in APD dispersion in hypertrophied hearts (P < 0.05) but not in control hearts, and APD dispersion was similar in hypertrophied hearts (31+/-9 msec) compared with control hearts (30+/-9 msec, P = NS). During dofetilide perfusion, APD dispersion remained greater in hypertrophied hearts (60+/-39 msec) compared with control hearts (30+/-13 msec, P < 0.05) at low afterload but not high afterload. Increasing afterload caused shortening of the APD in most regions of the control hearts, whereas APD did not shorten significantly in hypertrophied hearts at baseline and tended to increase during dofetilide perfusion. During dofetilide perfusion, the maximal change in APD recorded from the posterior wall of the left ventricle following an increase in afterload was -18+/-21 msec in control hearts and 7+/-21 ms in hypertrophied hearts (P < 0.05). CONCLUSION: Epicardial APD dispersion decreases in hypertrophied hearts following an increase in afterload, and this response is mediated in part by the absence of afterload-induced shortening of the APD. This effect may be due in part to altered responses of the delayed rectifying current to cardiac loading conditions in the setting of cardiac hypertrophy.

Action Potentials↗
PubMed1998

The effects of barium, dofetilide and 4-aminopyridine (4-AP) on ventricular repolarization in normal and hypertrophied rabbit heart.

The density of potassium channels, including the inward rectifying current (IK1), the delayed rectifying current and the transient outward current have been reported to be decreased in cardiac hypertrophy. However, it is not known whether the effects of specific ionic channel blockers are altered in this setting. The effects of barium chloride, which inhibits IK1, of dofetilide, which inhibits the rapidly activating component of the delayed rectifying current, and 4-aminopyridine, which inhibits the transient outward current, were studied in isolated perfused working rabbit hearts. Cardiac hypertrophy was induced in rabbits by aortic banding. Hearts were removed 43 +/- 8 days after surgery, and electrophysiologic parameters were measured at low (30 cm H2O) and high (100 cm H2O) afterload at base line and during perfusion of barium, dofetilide or 4-aminopyridine. The hearts from banded rabbits weighed more (13.0 +/- 2.3 g) than those from the sham controls (10.0 +/- 1.6 g; P < .001). The action potential duration at 90% repolarization (APD90) was greater in hypertrophied hearts (198 +/- 16 msec) at base line than in control hearts (182 +/- 20 msec; P < .01). Barium (0.025 mM) caused greater prolongation of APD90 in hypertrophied hearts than in control hearts at both low afterload (214 +/- 9 msec vs. 195 +/- 20 msec) and high afterload (200 +/- 10 msec vs. 166 +/- 22 msec, P < .01). This interaction of barium's effects on APD90 and hypertrophy was highly statistically significant (P < .001). In contrast, dofetilide (15 nM) and 4-aminopyridine (1.0 mM) caused similar changes in APD90 in hypertrophied hearts and in control hearts at low afterload and high afterload (P = NS). In isolated ventricular myocytes, IK1 and transient outward densities, but not the rapidly activating component of the delayed rectifying current were decreased in hypertrophied cells compared with control cells (P < .05). Thus the increased effects of barium on prolongation of APD in hypertrophy are probably due to the decreased density of IK1 in hypertrophy and perhaps, in part, to a change in the balance of repolarizing currents that occurs in hypertrophy.

4-Aminopyridine↗
PubMed1996

Hypomagnesemia: characterization of a model of sudden cardiac death.

OBJECTIVES: We sought to compare the incidence of sudden death in rats treated with magnesium-deficient and control diets and to address the electrophysiologic characteristics associated with these end points. BACKGROUND: Although magnesium deficiency is associated with an increased incidence of sudden cardiac death in patients, there has been no clear cause and effect relation because of a number of covariables, including diuretic use, hypokalemia, digitalis use and left ventricular dysfunction. METHODS: Hypomagnesemic rats and their paired control rats underwent in vivo electrophysiologic studies and measurements of the total calcium and magnesium content of their cardiac ventricles RESULTS: Serum magnesium levels were 0.5 +/- 0.3 mEq/liter (mean +/- SD) in hypomagnesemic animals and 1.2 +/- 0.9 mEq/liter in control animals. A modest but significant prolongation of the repolarization time was seen at the apical epicardial site (83 +/- 8 ms in hypomagnesemic rats vs. 68 +/- 13 ms in control rats, p < 0.05), but not at the other sites studied. Bradyarrhythmias and tachyarrhythmias were observed in 82% of the hypomagnesemic rats during the in vivo electrophysiologic studies, compared with 0% in the control group. During these studies, sudden, unexpected asystolic deaths were observed in 4 of 11 hypomagnesemic rats and 0 of 8 control rats. Polymorphic nonsustained ventricular tachycardia was provoked by rapid pacing in 5 to 11 hypomagnesemic rats and 0 of 8 control rats. Three of six hypomagnesemic rats exposed to auditory stimuli developed seizures, followed immediately by sudden deaths-two due to asystole and one due to ventricular fibrillation-although no end points occurred in the control animals. CONCLUSIONS: In this model, magnesium deficiency results in sudden cardiac death. The presence of startle induction of sudden death preceded by seizures suggests that sudden cardiac death results from a neurologic trigger.

Animals↗
PubMed1996

Quinidine pharmacodynamics in normal and isoproterenol-induced hypertrophied blood-perfused working rabbit hearts.

Ventricular hypertrophy is associated with several electrophysiologic abnormalities. However, little is known about the pharmacodynamics of antiarrhythmic drugs in the setting of ventricular hypertrophy. We studied the myocardial accumulation and pharmacodynamics of quinidine in 10 control rabbit hearts and 10 with isoproterenol-induced hypertrophy. Hearts were perfused in the working heart configuration. Electrophysiologic measurements were made at low afterload (30 cm H2O) and high afterload (60 cm H2O) at baseline and during quinidine perfusion (972 ng/ml). The myocardial quinidine concentration measured at the end of each experiment was significantly lower in the hypertrophied hearts (25.0 +/- 11.7 micrograms/g) as compared with the control hearts (51.2 +/- 12.7 micrograms/g, p < 0.001). The left ventricular (LV) monophasic action potential (MAP) duration was significantly shorter in the hypertrophied hearts as compared with control hearts at low afterload (166 +/- 27 vs. 192 +/- 24 ms, p < 0.01) and at high afterload (141 +/- 7 vs. 171 +/- 24 ms, p < 0.01). Quinidine prolonged MAP duration to a similar extent in both hypertrophied and control hearts; the MAP prolongation occurred at both low (192 +/- 21 vs. 223 +/- 25 ms, p < 0.02) and high afterloads (179 +/- 15 vs. 216 +/- 20 ms, p < 0.01) in the hypertrophied and control hearts, respectively. However, the ratios of the changes in electrophysiologic parameters to quinidine myocardial concentrations were greater in the hypertrophied hearts than in control hearts (p < 0.05). Therefore, AP duration (APD) is significantly shortened in isoproterenol-induced hypertrophy. The magnitude of quinidine effects on MAP duration and ventricular effective refractory period (VERP) are similar in hypertrophied hearts and control hearts, but the myocardial concentration-effect relations are increased significantly in hypertrophied hearts.

Action Potentials↗
PubMed1993

Interstitial cells from the atrial and ventricular sides of the bovine mitral valve respond differently to denuding endocardial injury.

The mitral valve has atrial and ventricular sides, each lined by endocardial cells. The valve stroma contains alpha smooth muscle actin positive interstitial cells, collagen, glycosaminoglycans, and elastic tissue. To eliminate the effect of endocardium on wound repair in bovine mitral valve organ culture, the endocardium was removed from both sides of the valve. At 6 days, organ cultures of these preparations revealed surface cells on the ventricular side but not in the atrial side. Ventricular surface cells were negative for Factor VIII-related antigen, and positive for alpha smooth muscle actin. Immunoperoxidase staining for proliferating cell nuclear antigen/cyclin, a marker for cell proliferation, revealed a positive labeling index of (mean +/- standard deviation) 0.08 +/- 0.16% for interstitial cells from the atrial side and 0.14 +/- 0.19% for ventricular side interstitial cells in uncultured preparations (not significant), and 0.44 +/- 0.69% for atrial side interstitial cells and 2.25 +/- 1.64% for ventricular side interstitial cells in the cultured preparations (significant, P < 0.0006). The results suggest that in organ culture, interstitial cells from the ventricular side of the mitral valve respond to a denuding endocardial injury by proliferating and migrating onto the adjacent surface whereas interstitial cells from the atrial side do not. This difference in the response to injury of interstitial cells from the atrial and ventricular sides of the valve may reflect differences in phenotype or may be due to effects of extracellular matrix on interstitial cell behavior. The latter is possible because of differences in the extracellular matrix of the atrial and ventricular sides of the valve.

Actins↗
PubMed1992

Bovine mitral valve organ culture: role of interstitial cells in repair of valvular injury.

The atrial and ventricular surfaces of the mitral valve are lined by endothelial cells termed endocardial cells, while the valve stroma contains interstitial cells. Bovine mitral valve organ cultures were immunoperoxidase-stained for Factor VIII RAg, alpha smooth muscle actin, and PCNA/cyclin in order to identify the cell types involved in mitral valve wound repair. Factor VIII RAg is a well-characterized endothelial cell marker, alpha smooth muscle actin is an indicator of smooth muscle differentiation and PCNA/cyclin is a marker for S phase. Bovine mitral valve endocardium was Factor VIII RAg positive and remained positive after culturing for 6 days (n = 7). Mitral valve interstitial cells were Factor VIII RAg negative and positive for alpha smooth muscle actin. By 6 days in culture, the lateral edges of the preparations, where the tissue was originally dissected from the mitral valve leaflet, were covered by multiple layers of cells. These cells were Factor VIII RAg negative (n = 7), and hence not endocardial, but were alpha smooth muscle actin positive like interstitial cells. Interstitial cells subjacent to the lateral edges were negative for PCNA/cyclin in uncultured preparations (n = 5), but positive in 12 out of 15 specimens cultured for 6 days. The results suggest that mitral valve interstitial cells are responsible for the repair process seen in the lateral edges of mitral valve organ cultures.

Animals↗
PubMed1992

Left main coronary artery dissection during cardiac catheterization.

A 70-year-old man with a downward sloping origin of the left main coronary artery developed left main dissection at coronary angiography and died despite emergency coronary by-pass surgery. Autopsy showed that the left main coronary artery had an acute angle take off and dissection had originated at the junction of the superior wall of the left main and the aorta. The combination of left main stenosis secondary to dissection and severe right coronary atherosclerosis had caused circumferential subendocardial left ventricular infarction. The left main coronary artery had mild atherosclerosis and lacked cystic medial necrosis. An angulated left main coronary artery may be a risk factor for dissection at angiography.

Aged↗
PubMed1991

Propafenone disposition and pharmacodynamics in normal and norepinephrine-induced cardiomyopathic rabbit hearts.

The myocardial disposition and pharmacodynamics of propafenone were studied in 10 normal and 10 norepinephrine-induced cardiomyopathic rabbit hearts. The left ventricular propafenone concentrations measured after perfusion of propafenone (0.3 microM) for 150 min were similar in the normal group (18 +/- 8 micrograms/g) compared to the cardiomyopathy group (20 +/- 5 micrograms/g, P = NS). However, the concentration of propafenone in cardiomyopathic left ventricular papillary muscle, which was always extensively involved in the inflammatory process, was significantly lower (11 +/- 2 micrograms/g) compared to normal papillary muscle (19 +/- 4 micrograms/g, P less than .05). During propafenone perfusion a significantly greater increment in ventricular conduction time was observed in the cardiomyopathy group (17 +/- 6 msec) compared to the normal group (12 +/- 3 msec, P less than .05). The propafenone myocardial concentration-effect relationships describing changes in QRS duration were shifted to the left in the cardiomyopathy group. Furthermore, the slopes of these linear concentration-effect relationships were greater in the cardiomyopathy group (1.80 +/- 0.60 msec/micrograms/g) compared to the normal group (1.07 +/- 0.25 msec/micrograms/g, P less than .01). The ventricular effective refractory period was shorter at base line in the cardiomyopathy hearts (156 +/- 21 msec) compared to the normal group (176 +/- 23 msec, P less than .08). However, propafenone effects on changes in the ventricular effective refractory period were similar in the two groups. Thus, the myocardial accumulation of propafenone is reduced in areas of extensive necrosis observed in norepinephrine-induced cardiomyopathy. As well, cardiomyopathic tissue is more responsive to propafenone effects on ventricular conduction time.

Animals↗
PubMed1990

Human papillomavirus type 16 associated with oral squamous carcinoma in a cardiac transplant recipient.

Human papillomavirus type 16 (HPV 16) has been associated with a variety of squamous carcinomas, particularly those involving the anogenital tract. The authors report the development of an oropharyngeal carcinoma in a 43-year-old man approximately 20 months after cardiac transplantation while he was on a maintenance regimen of cyclosporine A and prednisone. The carcinoma was resistant to treatment, and he died of complications related to metastatic disease 3 years posttransplantation. Molecular biologic studies using nonisotopic-labeled viral DNA probes were done. In situ hybridization demonstrated the presence of HPV 16 DNA in the tumor cells. DNA dot blot analysis confirmed the presence of multiple copies of HPV 16 DNA within the tumor cells and their absence from adjacent normal-appearing tissue. Southern blot analysis suggested that the HPV 16 DNA was integrated into the tumor cell genome. With increasing recognition of the carcinogenicity of HPV type 16 infection, a role for this virus in the development of squamous cell malignancies in immunosuppressed organ transplant recipients is likely to be noted with increasing frequency.

Adult↗
PubMed1989

New perspectives on left ventricular hypertrophy: anatomy, physiology, and significance.

The advent of echocardiography has added an important and sensitive tool for assessment of left ventricular hypertrophy (increased left ventricular mass). Recent echocardiographic studies in large population-based samples suggest an epidemic of left ventricular hypertrophy. Preliminary data suggesting important prognostic importance for such left ventricular hypertrophy (independent of standard risk factors) has fueled interest in the development, determinants, and other features of the hypertrophy. Hemodynamic and neurohumoral factors are the most prominent stimuli to adaptive (physiologic) myocardial hypertrophy, which can progress to maladaptive (pathologic) hypertrophy. The overall blood pressure experience, overweight, the cardiovascular response to recurrent psychosocial stress and physical activity level are four important correlates and potential determinants of left ventricular mass in various urban-suburban populations. Determination of the relative contributions and interrelations of these and other factors (such as heredity) to various forms of left ventricular hypertrophy found in various demographic groups warrants intensive investigation.

Cardiomegaly↗
PubMed1988

Amiloride. Antiarrhythmic and electrophysiological activity in the dog.

Amiloride, a widely used diuretic, has multiple pharmacological actions, including inhibition of the sodium-hydronium ion and the sodium-calcium exchanger in heart. In terms of cardiac electrophysiology, amiloride prolongs action potential duration without alteration in upstroke velocity of phase 0 in Purkinje fibers. The antiarrhythmic efficacy of amiloride was assessed in a model of inducible sustained ventricular tachyarrhythmias in 16 dogs late after 2-hour occlusion-reperfusion of the left anterior descending coronary artery. Sixteen animals were studied: Four were randomly assigned to placebo, and 12 were assigned to amiloride treatment. Prolonged loading and maintenance infusions were designed to produce amiloride concentrations over the range achievable in humans. Animals were chronically instrumented to allow electrophysiological measures of conduction and refractoriness in the left ventricular infarct and border zones. Of the 12 animals treated with amiloride, six responded with inability to induce ventricular tachyarrhythmias, whereas of the four animals treated with placebo, none responded. The mean infarct size of the six animals responding to amiloride (12 +/- 5%) was significantly less than that of the six animals not responding to amiloride (20 +/- 8%). Overall, the only electrophysiological effect of amiloride observed in this study was prolongation of border zone ventricular refractoriness. This electrophysiological effect was accentuated in animals responding to amiloride. In addition, when animals were subdivided into responders, partial responders, or nonresponders, the border zone repolarization time was prolonged in responders and partial responders, whereas this measure shortened in nonresponding animals. Amiloride has antiarrhythmic activity in the suppression of sustained ventricular tachyarrhythmias in this postinfarction model.

Amiloride↗
PubMed1988

In vitro repair of the wounded porcine mitral valve.

An organ culture of the anterior leaflet of the porcine mitral valve was developed and characterized in order to study the early events in the repair of small endocardial wounds. A linear superficial denuding endocardial injury was made with a nylon filament attached to a stereo tonearm. The repair process was studied by scanning and transmission electron microscopy over a 6-day period. By day 2 in culture, flattened endocardial cells at the wound edge extended processes out onto the wound edge. By 4 and 6 days, the wound was bridged over by spindle-shaped cells although gaps still remained between cells. In some areas, multilayering of cells beneath the surface was present. The results indicate that the initial events in in vitro endocardial repair involve both surface endocardial cells and interstitial cells.

Animals↗