Gary L. Pellom

Quantification of the contractile response to injury: assessment of the work-length relationship in the intact heart.

We used a sonomicrometric determination of ventricular dimension to examine the effect of ischemia and reperfusion on the work-length relationship in the intact heart to develop a useful and precise variable of ventricular contractile response to injury. Twenty anesthetized dogs were instrumented with epicardial ultrasonic dimension transducers to record right ventricular free wall chord length and left ventricular minor-axis length, micromanometers to record ventricular pressures, and an electromagnetic probe to record pulmonary arterial (n = 8) or aortic (n = 7) flow. Dogs were subjected to either 20 min (n = 7) or 30 min (n = 13) of global cardiac ischemia supported by cardiopulmonary bypass. Data were acquired over a range of end-diastolic volumes produced by transient (5 to 10 sec) vena caval occlusion before and after ischemia. In both ventricles, systolic epicardial dimensional shortening correlated with flow probe-measured stroke volume (mean r = .969) and regional stroke work calculated as the integral of instantaneous ventricular pressure and epicardial dimension correlated with measured global stroke work (mean r = .960), confirming the validity of dimensional measurements. Regression analysis demonstrated a highly linear relationship between calculated regional stroke work and end-diastolic length in the right ventricle (mean r = .973) and left ventricle (mean r = .967), quantifiable by a slope (Mw) and x intercept (Lw). Change in afterload produced by pulmonary arterial or aortic constriction resulted in no significant changes in Mw or Lw in either ventricle. Ischemia and reperfusion decreased Mw and shifted Lw to the right in both ventricles. The decrease in Mw with 30 min ischemia exceeded the decrease with 20 min ischemia by 29% in the right ventricle and by 32% in the left (p less than .04) with up to 1 hr of reperfusion. Changes in Lw were not related to severity of injury. After ischemia, infusion of calcium increased Mw by 177% in the right ventricle and by 67% in the left (p less than .03) without significant changes in Lw. Independent of load conditions, the slope Mw, of the linear stroke work vs end-diastolic length relationship is a valid and precise index of right and left ventricular contractile response to global ischemia in the intact circulation. This variable may be useful in evaluating therapies designed to limit myocardial injury and enhance ventricular functional performance.

Myocardial depression by anesthetic agents (halothane, enflurane and nitrous oxide): quantitation based on end-systolic pressure-dimension relations.

The end-systolic pressure-diameter relation of the left ventricle was used to examine the effect of halothane, enflurane and nitrous oxide on left ventricular (LV) contractility in 10 dogs chronically instrumented with dimension transducers to measure LV diameter and micromanometers to measure LV transmural pressure. Contractility was assessed by the slope (EES) of the end-systolic pressure-diameter relation. A new index that identifies the dose of anesthetic necessary to depress the inotropic state by 20% (ID20) was calculated to be 0.63% for halothane and 1.55% for enflurane, indicating a greater apparent myocardial depressant effect of halothane than enflurane. However, when these agents were compared at equi-anesthetic concentrations by normalizing the ID20 to the minimal alveolar concentration of each drug, they had comparable degrees of myocardial depressant effects. This measurement technique was used in 7 patients undergoing coronary artery bypass grafting conducted under narcotic anesthesia showing that halothane induced a similar depression of contractility. The use of ID20 should allow reclassification of anesthetic agents according to their myocardial depressant effects.

The Effect of PEEP on Left Ventricular Diastolic Dimensions and Systolic Performance Following Myocardial Revascularization

To quantitate the alterations in left ventricular (LV) dimensions and performance at successive levels of positive end-expiratory pressure (PEEP), 16 patients undergoing coronary artery bypass grafting (CABG) underwent instrumentation with ultrasonic dimension transducers to measure the minor-axis diameter of the left ventricle. Matched micromanometers were placed to measure intracavitary LV pressure and intrathoracic pressure. LV pressure and dimension data were recorded and computer analyzed during continuous positive-pressure ventilation at 0, 5, 10, and 15 cm H2O of PEEP 4 to 8 hours postoperatively. Preload was determined by the end-diastolic minor-axis diameter, cardiac output was measured by thermodilution, and indices of LV contractility assessed included the maximal velocity of minor-axis shortening and the slope of the end-systolic pressure-diameter relationship. PEEP produced a progressive increase in intrathoracic pressure associated with a fall in cardiac output; this was associated with a decrease in LV end-diastolic diameter and no significant change in the maximal velocity of minor-axis shortening or the slope of the end-systolic pressure-diameter relationship. Our results indicate that PEEP of 10 cm H2O or greater will produce a significant fall in cardiac output in patients following CABG, due to a decrease in preload rather than impaired LV contractility.

An Improved Technique for Producing Ventricular Hypertrophy with a Subcoronary Valvular Aortic Stenosis Model

Although techniques for producing aortic valve stenosis proximal to the ostia of the coronary arteries have been described in experimental animals, only moderate left ventricular hypertrophy has been obtained. A technique for plicating the noncoronary sinus of Valsalva in puppies is presented that has enabled us to achieve levels of ventricular hypertrophy not previously reported with methods for subcoronary aortic stenosis.

Protection of mitochondrial function during ischemia by potassium cardioplegia: correlation with ischemic contracture.

The effect of potassium cardioplegia on mitochondrial function was evaluated in the ischemic isolated rat heart. Mitochondrial function as well as adenosine triphosphate (ATP) levels were determined at the initiation of ischemic contracture, at the completion of ischemic contracture, and 20 minutes following contracture completion. Group I received no cardioplegia prior to ischemia, while Group II received potassium cardioplegia prior to the onset of ischemia. The respiratory control index (RCI), which is the primary measure of the intactness of mitochondrial function, was calculated with both a NAD (nicotinamide adenine dinucleotide)-linked substrate and a FAD (flavin adenine dinucleotide)-linked substrate. Potassium cardioplegia significantly delayed ischemic contracture initiation and completion. Although the RCI and ATP levels decreased significantly at successive levels of contracture, there was no difference in the RCI or ATP content between Group I and Group II at contracture initiation or completion. Unlike previous investigations that have used a time-base to examine mitochondrial function and acute cardiac ischemic injury, we correlated mitochondrial function with the measurable physiologic event ischemic contracture. The data indicated that potassium cardioplegia preserved ATP content and mitochondrial function, and that contracture initiation and completion correlate well with specific ATP levels and mitochondrial respiratory control. The relationship between mitochondrial function and ATP content indicates that the beneficial effect of potassium cardioplegia on mitochondrial function may be secondary to the preservation of high-energy phosphate levels which provide energy for mitochondrial maintenance.

Assessment of the intrinsic contractile status of the heart during sepsis by myocardial pressure-dimension analysis.

The effect of sepsis on the intrinsic contractile status of the myocardium is best examined in the awake, closed-chest animal with intact circulation because anesthesia, open thoracotomy, and circulatory support are all known to affect hemodynamics. To fulfill these criteria, 18 adult dogs were chronically studied in the awake state after instrumentation with left ventricular high-fidelity pressure catheters and ultrasonic dimension transducers to measure left ventricular transmural pressure and minor axis dimension. This allowed computer assessment of the left ventricular end-systolic pressure-dimension relationship in the control state and at intervals following cecal ligation in one group of dogs. A second group of control animals was studied over variable time intervals without cecal ligation to evaluate the temporal stability and reproducibility of the animal model and the end-systolic pressure-dimension relationship. Evaluation of contractility by use of the end-systolic pressure-dimension relationship was essential because this relationship is a sensitive indicator of the intrinsic myocardial contractile state while remaining insensitive to the wide swings in preload and afterload that are commonly seen in sepsis. In the control group of dogs, the temporal consistency and stability of the end-systolic pressure-dimension relationship in this model was confirmed; no significant changes in the slope and dimension-axis intercept were demonstrated over the study interval. In the septic group of dogs, however, the intrinsic myocardial contractility significantly deteriorated as the mean slope of the end-systolic pressure-dimension relationship (mmHg/mm) decreased from 16.87 ± 0.85 to 12.79 ± 1.67 over 120 hours following cecal ligation. Intrinsic contractility of the heart during sepsis was therefore isolated for the first time from the widely variant loading conditions seen during sepsis by pressure-dimension analyses in the chronically instrumented, awake, closed-chest canine with intact circulation.

The Influence of Time on the Response to Dopamine after Coronary Artery Bypass Grafting: Assessment of Left Ventricular Performance and Contractility Using Pressure/Dimension Analyses

Pressure and dimension analyses were used to quantitate the changing cardiac response to dopamine over a 24-hour interval after coronary artery bypass grafting (CABG). Ultrasonic dimension transducers were utilized to measure the minor-axis diameter of the left ventricle, and matched micromanometers were inserted to measure intracavitary left ventricular pressure and intrathoracic pressure. Pressure and dimension data were recorded and analysed by computer during dopamine infusion at 0, 2.5, 5.0, and 10.0 micrograms per kilogram per minute, at periods designated as early (2 to 4 hours after CABG) and late (18 to 24 hours after CABG). Myocardial contractile responses to dopamine (peak velocity of minor-axis shortening, maximal excursion) were similar at each dose in the early and late studies. However, overall hydraulic performance, as reflected by cardiac outputs and the areas of the pressure/diameter work loops, had augmented late dose responses. This study suggests a major change in the relationship between the heart and peripheral control mechanisms that may partially explain diminishing inotropic requirements over time, in addition to the generally accepted occurrence of improvement in contractile state and functional reserve following cardiac operation.

Effect of B-15,000 (Iopamidol), A New Nonionic Contrast Agent, on Cardiac Function of the Isolated Rat Heart

The isolated rat heart model was used to examine the effect of a new nonionic contrast agent, B-15,000 (Iopamidol), on cardiac function. Comparative studies were performed with Amipaque, Renografin 60, Renografin 76, and Vascoray. The three ionic contrast agents had significantly greater detrimental effects on cardiac function than either nonionic agent. The results support the continued evaluation of the nonionic agents for use in coronary angiography.

Effects of Delay in Administration of Potassium Cardioplegia to the Isolated Rat Heart

Ischemic injury to the heart in the period between aortic cross-clamping and administration of cardioplegic solution was evaluated in the normothermic rat heart model. After isolation and control perfusion with oxygenated Krebs-Henseleit bicarbonate buffer, the hearts were given lactated Ringers cardioplegic solution (30 mEq of K+ per liter) for 2 minutes at three different intervals following aortic clamping: no delay, 2-minute delay, and 5-minute delay. Thereafter, the hearts were left unperfused and the time to initiation of ischemic contracture was recorded. Adenosine triphosphate (ATP) and creatine phosphate levels were measured in all groups prior to and at the conclusion of cardioplegia administration. A 2-minute delay in the administration of cardioplegic solution resulted in significantly lower (p less than 0.001) ATP levels that were restored after 2 minutes of cardioplegia administration. Contracture times were not significantly altered. A 5-minute delay resulted in significantly shorter (p less than 0.001) contracture times and significantly lower (p less than 0.001) ATP levels that were not restored to preischemic levels by 2 minutes of cardioplegia administration. The fate of the myocardium may be insensitive to events that occur during the earliest moments of ischemia provided that rapid administration of oxygenated potassium cardioplegia follows the ischemic period and restores preischemic high-energy phosphate stores. However, there is a critical ischemic time during the initial interval before cardioplegia that is associated with an impaired ability of the myocardium to tolerate subsequent ischemia.

The relationship of transmural myocardial blood flow to midwall function

Abstract The relationship of transmural myocardial blood flow to midwall function was evaluated in seven adult mongrel dogs anesthetized with morphine SO4 (3 mg/kg) and a-chloralose (80 mg/kg) and instrumented with catheters for measuring aortic and left ventricular end-diastolic pressures and dp/dt. Three pairs of miniature ultrasonic transducers (3 mm diameter) were positioned at midwall level of the left ventricle along the minor axis within each of the three regions: anterior, lateral, and posterior segments. Transmural blood flow in the epicardium and endocardium was measured utilizing 8- to 10-μm tracer microspheres before and after a 60-sec circumflex occlusion. Functional data for extent (ΔL) and rate (dl/dt) of systolic shortening were determined and systolic excursion was normalized to an initial end-diastolic length of 10 mm. Total circumflex occlusion for 1 min was associated with a severe flow imbalance to the posterior endocardium (endocardium/epicardium 0.2 ± 0.1) resulting in marked functional impairment (ΔL = -0.5 ± 0.2 mm, dl/dt = -1.6 ± 1.1 mm/sec) and holosystolic bulging. Flow within the lateral region was not as severely impaired (endocardium/epicardium 0.5 ± 0.1, P