James W. Covell

Bio: James W. Covell is an academic researcher from University of California, San Diego. The author has contributed to research in topics: Ventricle & Diastole. The author has an hindex of 73, co-authored 163 publications receiving 16199 citations. Previous affiliations of James W. Covell include University of California, Los Angeles & Boston University.

Factors Influencing Infarct Size Following Experimental Coronary Artery Occlusions

Abstract: The purpose of this study was the determination of whether hemodynamic and pharmacologic factors influence the extent and severity of myocardial necrosis produced by coronary occlusion. In 48 dogs, 10 to 14 epicardial leads were recorded on the anterior surface of the left ventricle in the distribution and vicinity of the site of occlusion of a branch of the left anterior descending coronary artery. The average S-T segment elevation for each animal was determined at 5-min intervals after occlusion. This elevation was used as an index of the presence and severity of myocardial ischemic injury. The number of sites showing this elevation provided an additional measure of the size of the injured area. Occlusion alone raised the average S-T segment elevation from 0.22 ± 0.04 to 3.32 ± 0.37 mv (SEM). Isoproterenol, ouabain, glucagon, bretylium, and tachycardia given prior to a repeated occlusion increased the severity and extent of ischemic injury, while propranolol decreased it. Elevation of arterial pressure ...

Effects of changes in preload, afterload and inotropic state on ejection and isovolumic phase measures of contractility in the conscious dog.

Abstract: Despite much investigation, the usefulness of various indexes employed clinically for detecting alterations in ventricular contractility in the intact circulation remains controversial. The effects of acute preload, afterload and contractility changes on both ejection and isovolumic phase measures of left ventricular function were analyzed in normal, trained conscious dogs instrumented with micromanometers and endocardial ultrasonic diameter gauges. Rapid volume overload increased the excursion of the left ventricular diameter (Δ LVD) by 7 percent above the control level, but mean velocity of circumferential shortening (V CF ) did not change significantly; peak rate of left ventricular pressure rise (dP/dt) increased by 11 percent and (dP/dt)/DP40 (DP = developed pressure) was augmented by 10 percent, but maximal [(dP/dt)/LVP], or "V pm " decreased by 20 percent. Pressure overload by phenylephrine infusion decreased Δ LVD by 15 percent and mean V CF fell by 26 percent; peak dP/dt and (dP/dt)/DP40 remained unaltered, but V pm was reduced by 37 percent. Isoproterenol augmented peak dP/dt by 55 percent, and (dP/dt)/DP40, V pm and mean V CF were increased comparably. Propranolol decreased these measures equally by about 16 percent. Therefore, in the conscious animal in the steady state, isovolumic phase indexes were mildly influenced by acute volume loading, whereas ejection phase indexes were not. Acute increases in aortic pressure markedly reduced ejection phase measures, whereas the isovolumic indexes were unaffected. All of the indexes studied were comparably sensitive to acute alterations in contractility, but we conclude that no single measure can always be used for defining an acute contractility change in the intact circulation.

Transmural myocardial deformation in the canine left ventricle. Normal in vivo three-dimensional finite strains.

Abstract: To examine transmural finite deformation in the wall of the canine left ventricle, closely spaced columns of lead beads were implanted at a single site on the left ventricular free wall. The three-dimensional coordinates of these myocardial markers were obtained with high-speed biplane cineradiography. Any four noncoplanar markers forming small tetrahedral volumes (less than or equal to 0.1 cc) were used to calculate finite normal and shear strains with respect to a cardiac coordinate system at end diastole. Due to the symmetry of the finite strain tensor, the algebraic eigenvalue problem could be solved to compute principal strains and the directions of the principal axes of deformation with respect to the reference coordinates. An examination of the principal strains in a number of tetrahedra in five animals indicates that deformation increases with depth beneath the epicardium. For example, the transmural variation of principal shortening strain averages -0.014 +/- 0.009 per 10% increment in thickness from epicardium to endocardium. Furthermore, shortening and thickening strains at midwall and deeper are too large (0.10 to 0.40) to be described accurately by infinitesimal theory. These strains are often accompanied by substantial in-plane and transverse shears which are not predicted by typical membrane or shell theories, indicating that these theories must be applied with caution when computing indices of regional ventricular performance. The directions of the principal axes of shortening vary substantially less than the fiber direction varies across the wall (20 degrees - 40 degrees compared with 100 degrees - 140 degrees for fiber direction), supporting the concept that there are substantial interactions between neighboring fibers in the left ventricular wall.

Dependence of ventricular distensibility on filling of the opposite ventricle.

Abstract: TAYLOR, ROGER R., JAMES W. COVELL, EDMUND H. SONNENBLICK, AND JOHN Ross, JR. Dependence of ventricular distensibility on jilling of the opposite ventricle. Am. J. Physiol. 2 13 (3) : 7 1 l-7 18. 1967.-The influence of filling one ventricle on distensibility of the opposite ventricle was examined in dogs. Distensibility of the left or right ventricle was consistently decreased in proportion to the filling of the opposite chamber. To quantify the effect of right ventricular (RV) filling on left ventricular (LV) distensibility in the intact circulation the coexisting LV and RV end-diastolic pressures (EDP) were determined over a wide range of ventricular filling induced by blood infusion. LV pressure-volume relations were then obtained in the arrested heart and each level of LV filling pressure was matched with the RV filling pressure found to coexist in vivo. The effect of RV filling on the LV volume when LVEDP was low (3 mm Hg) was not discernible. The effect was apparent when LVEDP was 5 mm Hg with the appropriate RV filling, the LV volume being decreased by 1.8 =t 1.2 (SD) ml. At an LVEDP of 20 mm Hg the reduction was 3.9 & 2.4 ml or 7.1 it 4.7 (35 of LV volume; LV volume at an LVEDP of 20 mm Hg therefore was 7.1 y0 smaller with the RV full than with the RV empty. This effect is considered to result from the sharing of a common septum and fiber bundles. The effect should be considered when the passive diastolic pressurevolume relation is compared with that in the beating heart and whenever ventricular function is examined over a range of cardiac filling pressures. It may also play an important role when either ventricle is acutely distended in disease states.

Precordial S-T segment elevation mapping: An atraumatic method for assessing alterations in the extent of myocardial ischemic injury

Abstract: A noninvasive technique for evaluating the extent of myocardial ischemic injury after experimental coronary artery occlusion was devised and applied to study alterations in the extent of injury produced by hemodynamic and pharmacologic interventions. The technique was then extended to the assessment of myocardial ischemic injury in patients with acute myocardial infarction. In 7 closed chest dogs, electrocardiograms were recorded from 15 sites on the chest wall before and after intermittent occlusions of the left anterior descending coronary artery. There was no S-T segment elevation before the occlusion; 15 minutes after occlusion the sum of S-T segment elevations (ΣS-T) averaged 15.0 ± 3.0 mm (SEM, 1 mm deflection = 0.1 mv), and an average of 4.2 ± 0.6 sites exhibited elevations exceeding 0.1 mv (NS-T). Occlusions occurring during administration of isoproterenol (0.25 μg/kg per min) increased ΣS-T to 51.0 ± 9.0 mm and NS-T to 10.6 ± 0.9, whereas occlusions occurring after administration of propranolol (1 mg/kg) decreased ΣS-T to 3.0 ± 1.5 mm and NS-T to 0.2 ± 0.2. In 8 dogs the extent of ischemic injury, manifested by S-T segment changes, was decreased by propranolol and norepinephrine and increased by hemorrhagic hypotension and isoproterenol, applied up to 6 hours after occlusion. Reproducible S-T segment maps, using 35 surface electrodes, were obtained in 19 patients with acute myocardial infarction. In 15 patients studied serially, ΣS-T decreased from 54.25 ± 7.00 to 38.50 ± 6.30 mm and NS-T from 18.7 ± 2.5 to 12.3 ± 2.8, respectively, during a 24 hour period. However, in 3 patients in whom ventricular fibrillation, arterial hypotension and further ischemic pain occurred, ΣS-T and NS-T increased whereas in another patient propranolol decreased ΣS-T and NS-T. Thus, precordial mapping, both in dogs and patients, shows changes parallel to those measured by the epicardial technique and should provide a useful clinical tool for determining acute changes in the extent of ischemic injury.

Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications.

Abstract: An acute myocardial infarction, particularly one that is large and transmural, can produce alterations in the topography of both the infarcted and noninfarcted regions of the ventricle. This remodeling can importantly affect the function of the ventricle and the prognosis for survival. In the early period, infarct expansion has been recognized by echocardiography as a lengthening of the noncontractile region. The noninfarcted region also undergoes an important lengthening that is consistent with a secondary volume-overload hypertrophy and that can be progressive. The extent of ventricular enlargement after infarction is related to the magnitude of the initial damage to the myocardium and, although an increase in cavity size tends to restore stroke volume despite a persistently depressed ejection fraction, ventricular dilation has been associated with a reduction in survival. The process of ventricular enlargement can be influenced by three interdependent factors, that is, infarct size, infarct healing, and ventricular wall stresses. A most effective way to prevent or minimize the increase in ventricular size after infarction and the consequent adverse effect on prognosis is to limit the initial insult. Acute reperfusion therapy has been consistently shown to result in a reduction in ventricular volume. The reestablishment of blood flow to the infarcted region, even beyond the time frame for myocyte salvage, has beneficial effects in attenuating ventricular enlargement. The process of scarification can be interfered with during the acute infarct period by the administration of glucocorticosteroids and nonsteroidal antiinflammatory agents, which result in thinner infarcts and greater degrees of infarct expansion. Modification of distending or deforming forces can importantly influence ventricular enlargement. Even short-term augmentations in afterload have deleterious long-term effects on ventricular topography. Conversely, judicious use of nitroglycerin seems to be associated with an attenuation of infarct expansion and long-term improvement in clinical outcome. Long-term therapy with an angiotensin converting enzyme inhibitor can favorably alter the loading conditions on the left ventricle and reduce progressive ventricular enlargement as demonstrated in both experimental and clinical studies. With the former therapy, this attenuation of ventricular enlargement was associated with a prolongation in survival. The long-term clinical consequences of long-term angiotensin converting enzyme inhibitor therapy after myocardial infarction is currently being evaluated. Although studies directed at attenuating left ventricular remodeling after infarction are in the early stages, it does seem that this will be an important area in which future research might improve long-term outcome after infarction.

The wavefront phenomenon of ischemic cell death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs.

Abstract: Irreversible ischemic myocardial cell injury developes in an increasing number of cells as the duration of coronary occlusion is prolonged. The present study quantitates myocardial necrosis produced by 40 minutes, 3 hours, or 6 hours of temporary circumflex coronary occlusion (CO) followed by 2 to 4 days of reperfusion, or by 24 or 96 hours of permanent circumflex ligation in pentobarbital anesthetized open chest dogs. After 40 minutes of ischemia, myocyte necrosis was subendocardial but with increasing duration of coronary occlusion, irreversible injury progressed as a wavefront toward the subepicardium. Transmural necrosis was 38 +/- 4% after 40 min, 57 +/- 7% after 3 hours, 71 +/- 7% after 6 hours and 85 +/- 2% after 24 hours of ischemic injury. These results document the presence of a subepicardial zone of ischemic but viable myocardium which is available for pharmacologic or surgical salvage for at least three and perhaps six hours following circumflex occlusion in the dog.

Left Ventricular Remodeling After Myocardial Infarction Pathophysiology and Therapy

Abstract: Left ventricular remodeling is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors.1 2 Remodeling may be physiological and adaptive during normal growth or pathological due to myocardial infarction, cardiomyopathy, hypertension, or valvular heart disease (Figure 1⇓). This article will review postinfarction remodeling, pathophysiological mechanisms, and therapeutic intervention. Figure 1. Diagrammatic representation of the many factors involved in the pathophysiology of ventricular remodeling. ECM indicates extracellular matrix; RAAS, renin-angiotensin-aldosterone system; CO, cardiac output; SVR, systemic vascular resistance; LV, left ventricular; and AII, angiotensin II. ### Postinfarction Left Ventricular Remodeling The acute loss of myocardium results in an abrupt increase in loading conditions that induces a unique pattern of remodeling involving the infarcted border zone and remote noninfarcted myocardium. Myocyte necrosis and the resultant increase in load trigger a cascade of biochemical intracellular signaling processes that initiates and subsequently modulates reparative changes, which include dilatation, hypertrophy, and the formation of a discrete collagen scar. Ventricular remodeling may continue for weeks or months until the distending forces are counterbalanced by the tensile strength of the collagen scar. This balance is determined by the size, location, and transmurality of the infarct, the extent of myocardial stunning, the patency of the infarct-related artery, and local tropic factors.1 3 The myocardium consists of 3 integrated components: myocytes, extracellular matrix, and the capillary microcirculation that services the contractile unit assembly. Consideration of all 3 components provides important insights into the remodeling process and a rationale for future therapeutic strategies. The cardiomyocyte is terminally differentiated and develops tension by shortening. The extracellular matrix provides a stress-tolerant, viscoelastic scaffold consisting of type I and type III collagen that couples myocytes and maintains the spatial relations between the myofilaments and their capillary microcirculation.4 5 The collagen framework couples adjacent myocytes by intercellular struts that …

Negative inotropic effects of cytokines on the heart mediated by nitric oxide

Abstract: The direct effects of pro-inflammatory cytokines on the contractility of mammalian heart were studied. Tumor necrosis factor alpha, interleukin-6, and interleukin-2 inhibited contractility of isolated hamster papillary muscles in a concentration-dependent, reversible manner. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) blocked these negative inotropic effects. L-Arginine reversed the inhibition by L-NMMA. Removal of the endocardial endothelium did not alter these responses. These findings demonstrate that the direct negative inotropic effect of cytokines is mediated through a myocardial nitric oxide synthase. The regulation of pro-inflammatory cytokines and myocardial nitric oxide synthase may provide new therapeutic strategies for the treatment of cardiac disease.