Andrew S. Wechsler

Glucagon. Its enhancement of cardiac performance in the cat and dog and persistence of its inotropic action despite beta-receptor blockade with propranolol.

The action of glucagon on cardiac performance was studied in 21 isolated cat papillary muscle preparations, in 13 spontaneously beating cat atria, in 15 intact dog hearts, and in 4 isolated perfused dog hindlimbs. In each papillary muscle preparation, addition of glucagon produced marked increases in maximal developed tension, averaging 36±4.2% (SEM) (P < 0.01), and shifted the force-velocity curve upwards and to the right, indicating that contractility was augmented. Glucagon always increased the rate of the spontaneously beating atrium, the rise averaging 28.8±5.5 contractions/min (P < 0.01). In the dog, myocardial performance was markedly augmented by the administration of glucagon, 50 μg/kg iv, as indicated by an average increase of 72.2±18.4% (P < 0.01) in the left ventricular peak dP/dt and of 58.9±12.8% (P < 0.01) in force recorded by a strain gauge arch, despite an average decrease of 3.8±1.2 cm H2O (P < 0.02) in left ventricular end-diastolic pressure. Heart rate rose an average of 38.7±10.9 beats/min (P < 0.02). Small but significant decreases in peripheral vascular resistance were produced. Single intravenous injections produced effects lasting 15 to 20 minutes. Propranolol did not prevent the inotropic responses in either the cat or dog preparations but markedly decreased the chronotropic effects.

Myocardial Blood Flow Distribution in Concentric Left Ventricular Hypertrophy

Regional myocardial blood flow during both control conditions and ischemia-induced vasodilatation was studied in eight chronically instrumented awake dogs. Seven of these animals had coarctation-banding of the ascending aorta performed at 6 wk of age, and the other dog had congenital subvalvular aortic stenosis. The mean left ventricular weight for the group was 157+/-7.6 g, and the left ventricular body weight ratio was 8.76+/-0.47 g/kg. None of the animals exhibited signs of congestive heart failure. During the control state, the mean left ventricular systolic pressure was 249+/-12 mm Hg and the left ventricular end-diastolic pressure was 11.5+/-0.5 mm Hg. The aortic diastolic pressure was 74+/-6 mm Hg. Mean left circumflex coronary artery blood flow was 71+/-6 cm(3)/min. In the animals with coarctation-banding, 52+/-6% of the flow occurred during systole. In the dog with congenital subvalvular aortic stenosis, 5% of the coronary flow was systolic. Mean transmural blood flow during resting conditions was 0.97+/-0.08 cm(3)/min per g, and the ratio of endocardial to epicardial flow (endo/epi) was 0.88+/-0.07. During reactive hyperemia, the mean transmural blood flow increased to 3.5+/-0.30 cm(3)/min per g; however, the endo/epi decreased to 0.52+/-0.06.THESE STUDIES DOCUMENT A DIFFERENCE IN TRANSMURAL BLOOD FLOW DISTRIBUTION BETWEEN THE NORMAL AND THE HYPERTROPHIED LEFT VENTRICLE: during resting conditions, in the normal ventricle, the highest flow occurs in the endocardial layer, whereas in the hypertrophied ventricle, the highest flow is in the middle layers with the endocardial flow less than the epicardial flow. During ischemia-induced vasodilatation, the abnormal endo/epi becomes accentuated markedly. These data demonstrate that, in situations requiring high flow, the endocardial layer of a heart with marked concentric left ventricular hypertrophy may not be perfused adequately.

Surgical management of chronic pulmonary embolism.

The clinical course of most patients with pulmonary embolism is one of gradual resolution with re-establishment of flow in the pulmonary arteries. In a small but definite group of patients, the emboli do not resolve and a state of chronic pulmonary embolism ensues. The primary thrombotic process in the systemic venous system may persist, and in some instances may be unrecognized. Such patients experience recurrent showers of emboll which may ultimately occlude a large part of the pulmonary arterial circulation with development of severe respiratory insufficiency. Six patients with this syndrome are described, and in each there was a history of dyspnea, cyanosis, and exercise intolerance associated with a low arterial Po2, right ventricular hypertrophy, and pulmonary hypertension. Pulmonary scans and arteriograms demonstrated that more that half of the major pulmonary arteries were occluded and, in addition, smaller vessels were also obstructed. Pulmonary embolectomy was performed in each patient. Five of the 6 obtained a highly gratifying response, including relief of the dyspnea and cyanosis, an increase in arterial Po2, and a decrease in pulmonary arterial pressure. In each of the five in whom improvement occurred, the back-bleeding from the pulmonary artery at the time of embolectomy was quite good. In the sixth patient, the back-bleeding was very poor, and despite embolectomy, the vessel thrombosed postoperatively with no improvement in the patients clinical course. Follow-up studies in these patients range up to 8 years with demonstration of continued patency of the pulmonary arteries as well as continued improvement in clinical symptoms and in the arterial Po2.

Reflex Cardiovascular Depression Produced By Stimulation Of Pulmonary Stretch Receptors In The Dog

To study the possible reflex effects of stimulation of pulmonary stretch receptors on the cardiovascular system, experiments were designed that would allow separate assessment of the responses of the heart, the total peripheral vascular resistance, and the resistance of the innervated hindlimb that was perfused at a constant flow rate. In every experiment, inflation of the lungs to a positive pressure of 20 mm Hg produced significant negative inotropic and chronotropic effects. Heart rate fell an average of 22.3+/-3.8% (SEM) (P < 0.01), pressure recorded from within an isovolumic balloon in animals on total cardiopulmonary bypass fell an average of 14.3+/-4.6% (P < 0.05), dp/dt recorded from within the balloon declined an average of 31.4 +/- 6.0% (P < 0.01), and contractile force measured with a Walton-Brodie strain gauge arch fell an average of 18.6 +/-2.2% (P < 0.01). Similarly, a depressor response to inflation of the lungs was noted in the periphery as manifested by an average decrease in total peripheral vascular resistance of 21.9+/-2.5% in the animals on total cardiopulmonary bypass (P < 0.01), and by an average decrease in perfusion pressure in the isolated hindlimb of 26.0 +/-3.8% (P < 0.01). After bilateral cervical vagotomy, the cardiovascular responses to inflation of the lungs were either abolished or markedly lessened. Thus, sudden expansion of the lungs activates the afferent arm of a depressor reflex, which produces negative inotropic and chronotropic responses, in addition to arterial vasodilation. The receptors are sensitive to stretch and the afferent pathway runs predominantly in the vagus nerves.

Coronary Flow and Regional Function before and after Supraarterial Myotomy for Myocardial Bridging

Myocardial bridges have been associated with clinical and metabolic evidence of ischemia, although the mechanism for this is unclear. We measured coronary blood flow and segmental function at different heart rates prior to and after release of a myocardial bridge involving the left anterior descending coronary artery in a patient with angina. Before lysis of the bridge, atrial pacing was associated with a decreased systolic flow/total flow, increased duration of systole, a lag in diastolic flow, and functional deterioration. After release of the bridge, pacing was associated with increased systolic flow/total flow and systolic interval, no diastolic flow lag, and no functional deterioration. These data imply that before bridge division, systolic flow and the initiation of diastolic flow were impeded. Functional abnormalities resulting from the flow discrepancies at heart rates of 120 to 150 beats per minute may have accounted for this patients symptoms.

Single Versus Multiple Internal Mammary Artery Grafting for Coronary Artery Bypass 15-Year Follow-Up of a Clinical Practice Trial

Background—The long-term clinical advantages of using routine multiple internal mammary artery (IMA) grafts for coronary artery bypass (CAB) are not clear. This study was designed to test the hypothesis that multiple IMA grafts would provide better 15-year outcomes when compared with single IMA and vein grafts. Methods and Results—Between 1984 and 1987, 1067 consecutive patients undergoing isolated CAB were referred to 1 surgeon practicing primarily single and another surgeon maximizing multiple IMA grafts (clinical practice trial). A 207-patient subset with multiple IMAs underwent postoperative graft angiography at 1 to 32 weeks to define initial IMA patency. Patients were followed-up yearly, and the groups were analyzed as (I) surgical strategy (surgeon operating) (single=413 versus multiple=654), (II) ultimate operation performed (single=418 versus multiple=449), or (III) single versus multiple coronary systems revascularized with IMAs (single=490 versus multiple=377). Advantages of this study design were that an entire referral population was examined, multiple IMAs were applied to the entire spectrum of baseline patient risk, 15-year follow-up provided a complete prognostic picture, and the subgroups were potentially comparable at baseline. In all 3 analyses, single and multiple groups were statistically similar with respect to baseline, operative, and immediate postoperative variables. Early IMA patency was 98.5% (333/338 grafts patent), validating the quality of IMA procedures. Unadjusted and adjusted 15-year outcome analyses for I, II, and III for death, myocardial infarction, percutaneous coronary intervention, redo coronary bypass, and the composite of all events identified multiple versus single as a significant predictor of outcome for the composite end point in adjusted analysis III (hazard ratio=0.808; 95% CI, 0.689 to 0.948; P=0.009), because of a 5% to 10% absolute reduction in each of the outcome variables at 15 years. Moreover, >50% reduction in reoperation rate was observed at 15 years in every analysis. Conclusions—At 15-year follow-up, multiple IMA grafting was associated with a 19.2% adjusted risk reduction in death and cardiac events, caused by decreases in all adverse end points and fewer reoperations. These data indicate that the clinical advantages of maximizing IMA conduits are significant. Based on this information, it is suggested that multiple IMA grafting to 2 coronary systems should be applied liberally to patients with noncardiac risk profiles predictive of long-term survival.

The Effects of Hypothermia on Myocardial Oxygen Consumption and Transmural Coronary Blood Flow in the Potassium-arrested Heart

Hypothermia remains the primary adjunct employed to lower cellular metabolism during various cardiac procedures. In these experiments, left ventricular myocardial oxygen consumption (MVO2) and transmural blood flow (TBF) were measured during cardiopulmonary bypass with the range of temperatures used clinically. Determinations were made in empty beating normothermic hearts and after potassium cardioplegia at 37, 32, 28, 22, 18, and 15° (K+ = 15–37 meq/L: Hct 25 volumes %). Oxygen content of the total coronary sinus collection was compared with a large volume arterial sample using a Lex-O2-Con-TL analyzer (vs Van Slyke, R = 0.98). Transmural blood flow was measured at each temperature using microspheres (8μ), and perfusion was maintained at 80 mmHg. Asystole (37°) alone decreased MVO2 from 5.18 ± 0.55 to 1.85 ± 0.20 ml O2/min/100 g of left ventricle or approximately 65% (p < 0.001). With progressive cooling to 15° an additional 82% decrement in oxygen uptake occurred during asystole (p < 0.001). During asystole at 37° the decrease in MVO2 was reflected mainly by a large decrement (p < 0.01) in TBF (1.27 ± 0.19 to 0.74 ± 0.17 ml/min/g of mean left ventricular flow). However, with cooling below 32°, the arteriovenous oxygen difference narrowed progressively (p < 0.001) while TBF paradoxically returned to control levels. Endocardial/epicardial flow ratios were not altered by cooling. These data not only confirm earlier reports describing a sequential drop in MVO2 with incremental myocardial cooling, but also establish MVO2 levels for perfused hearts arrested by potassium at lower temperatures (18–15°). Moreover, as transmural blood flow becomes independent of metabolic necessity during hypothermia, coronary autoregulation appears to be impaired, possibly affecting detrimental tissue over perfusion.

Augmentation and Redistribution of Myocardial Blood Flow During Acute Ischemia by Intraaortic Balloon Pumping

Abstract Regional coronary blood flow (CBF) in the acutely ischemic, normotensive ventricle was evaluated using radionuclide-labeled microspheres. Intraaortic balloon pumping (IABP) significantly increased CBF to myocardium made ischemic by either total or partial coronary artery occlusion. Both subendocardial and myocardial CBF in the ischemic area were increased by IABP, associated with a slight but not significant decrease in CBF to normally perfused areas of myocardium. The heart in this setting appears to autoregulate local CBF in response to IABP.

Enflurane Enhances Postischemic Functional Recovery in the Isolated Rat Heart

Enflurane is a direct myocardial depressant and may act as a myocardial protective agent during ischemia. The authors studied the effects of enflurane on myocardial high-energy phosphates and tolerance to ischemia in the normothermic, isolated rat heart. After isolation and perfusion with Krebs-Henseleit buffer, the hearts were perfused with either buffer (control) or buffer gassed with 2% enflurane for 10 minutes. Thereafter, hearts were made globally ischemic and elapsed times to initiation of ischemic contracture (IC) were determined. ATP and creatine phosphate (CP) were measured at the conclusion of control and enflurane administration and at IC. Ten hearts per group were reperfused with buffer following IC for 20 min; peak pressure and ATP and CP were determined. Administration of 2% enflurane significantly decreased peak pressure by 20% but did not alter baseline high-energy phosphate levels nor did it prolong time to IC. However, enflurane-treated hearts exhibited significantly greater (P < 0.01) recovery of function as defined by per cent return of peak pressure (67%±3%) when compared with those hearts not treated with enflurane preischemically (44%±5%). Also, enflurane-treated hearts had significantly higher (P < 0.01) ATP levels at the conclusion of reperfusion than hearts not perfused with enflurane (12.2±.8 μmol/g dry weight vs. 9.0·0.8 μmol/g dry weight). These findings suggest that enflurane administered prior to an ischemic interval enhances postischemic myocardial recovery.

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.