Alan G. Rose

Prevention of Myocardial Injury During Brain Death by Total Cardiac Sympathectomy in the Chacma Baboon

In a previous study, structural myocardial damage was found to occur in 60% of baboons after brain death had been induced by a rapid increase in intracranial pressure. In the present study, we attempt to clarify the causative mechanisms involved in the development of such injury. Three groups of baboons were subjected to brain death: group A, the control; group B, those with previous surgical or pharmacological cardiac sympathectomy or cardiac denervation; and group C, those with bilateral vagotomy, incomplete sympathectomy, or bilateral adrenalectomy. Electrocardiographic and hemodynamic responses to brain death were greatly modified in group B baboons compared with responses in groups A and C. Groups A and C showed a high incidence of myocardial necrosis, whereas no myocyte damage was seen in the hearts of group B baboons. The histological appearance of innervated hearts following brain death (groups A and C) may closely resemble that seen during an acute rejection episode following cardiac transplantation. We suggest that myocardial damage occurring during the process of dying may be related to endogenous catecholamine release (possibly resulting in increased calcium uptake by the myocardial cells), inducing various forms of myocyte necrosis. This may result in early failure in a donor heart following cardiac transplantation.

Pathophysiology of pulmonary edema following experimental brain death in the chacma baboon.

Systemic and pulmonary hemodynamics have been studied during the induction of brain death in the chacma baboon. In 11 animals brain death was induced by acute intracranial hypertension. Continuous recording of blood flow through both the pulmonary artery and the aorta was obtained by electromagnetic flow meters placed around these vessels. Mean arterial, central venous, pulmonary arterial, and left atrial pressures were recorded continuously. Systemic and pulmonary vascular resistances were calculated. During the agonal period marked sympathetic activity occurred, with significant increases in circulating catecholamines and systemic vascular resistance. The great increase in systemic resistance resulted in acute left ventricular failure. Mean left atrial or pulmonary capillary wedge pressure rose above the mean pulmonary arterial pressure in 9 animals. As the systemic vascular resistance rose, a significant difference between pulmonary artery and aortic blood flows occurred, leading to blood pooling within the lungs. A mean of 72% of the total blood volume of the animal accumulated within these organs. The increase of left atrial pressure to levels higher than pulmonary artery pressure indicated a state of pulmonary capillary blood flow arrest. This, associated with the blood pooling within the lungs, almost certainly resulted in disruption of the anatomic integrity of the pulmonary capillaries (blast injury); 4 animals developed pulmonary edema, with alveolar septal interstitial hemorrhage.

Injury of myocardial conduction tissue and coronary artery smooth muscle following brain death in the baboon

Experimental brain death was induced in 36 chacma baboons. In group A (n=17), brain death was induced with no pharmacologic or surgical manipulation. Group B (n=7) underwent bilateral vagotomy, unilateral left cardiac sympathectomy, or bilateral adrenalectomy before induction of brain death. Group C (n=7) underwent total cardiac sympathectomy. Group D (n=5) was pre-treated with verapamil hydrochloride. Following induction of brain death, group A animals were maintained on a ventilator for a mean of 12 hr and 6 hr for the remaining groups. At the end of the experiment, the heart was excised, and tissue blocks were examined with light microscopy at (A) the atriaventricular node-bundle of His; (B) the major coronary arteries; and (C) myocardial tissue from the ventricular septum or left ventricular wall. In group A, 41% of the hearts showed histologic features of injury to the conduction tissue, 70% presented contraction band necrosis of the smooth muscle of the coronary arteries, and an incidence of 100% of the groups showed myocyte injury, more evident in the subendocardial area. In group B animals, conduction tissue injury was seen in 6 animals; the coronary arteries were not examined in this group; the incidence of myocyte injury was seen in 80% of the animals. Animals in groups C and D show no histopathologic injury in the conduction tissue (group A vs. C P < 0.04), nor in the coronary arteries (group A vs. C P < 0.002; group A vs. D P < 0.01), preserving the myocytes (P < 0.001). The cathecholamine storm associated to acute increment of the endocranial pressure at the time of induction of brain death induces major histopathologic changes in the myocardium, as a result of endogenous cathecholamines released inducing calcium overflow injury, affecting the conduction tissue, the smooth muscle of the coronary arteries, and the contractile myocardium. This can be prevented by calcium blockers or cardiac denervtion.

Forty-eight hours hypothermic perfusion storage of pig and baboon hearts

A system has been developed for the continuous hypothermic perfusion of isolated hearts using a clear fluid perfusate. Myocardial viability has been maintained after periods of storage of up to 48 hr. Pig hearts stored in this way showed almost normal hemodynamic performance on subsequent functional testing. Orthotopic allotransplantation or autotransplantation of baboon hearts stored for 48 hr was followed by good immediate and long-term function. Baboons receiving allotransplants survived until rejection. Three of four of those autotransplanted survived until electively sacrificed at 1, 3, and 12 months; all showed normal hemodynamic function on cardiac catheterization and normal myocardial histology.

15-Deoxyspergualin for induction of graft nonreactivity after cardiac and renal allotransplantation in primates.

In order to assess the immunosuppressive potentials of 15-deoxyspergualine (15-DS) in a preclinical experiment, heterotopi cardiac (n=27, group I) and classic renal (n=25, group II) allotransplantations were performed in Chacma baboons. The following immunosuppressive regimens were applied: Groups IB and IIB were treated with 15-DS alone (4 mg/kg/day) for p.o. days 0–9. Groups IC and IIC were treated with cyclosporine A (10–40 mg/kg/day) for p.o. days 0–30. Groups ID and IID received a combination of 15-DS (for p.o. days 0–9) and CsA (for p.o. days 0–30). Groups IA and IIA served as control and received no medication. The mean graft survival was 11.0 days for group IA, 28.2 days for group IB (P<0.05; IB vs. IA), 32.4 days for group IC, and 43.1 days for group ID (P<0.025; ID vs. IA). After renal transplantation, the corresponding figures were 12.3 days for group IIA, 8.5 days for group IIB, 30.4 days for group IIC and 148.9 days for group IID (P<0.025; IID vs. IIA). After cardiac and renal transplantation, acute rejection was the main cause of graft failure. Treatment-related side effects, mainly gastrointestinal complications, were observed only in primates, who were treated with 15-DS alone. After cardiac transplantation, permanent graft non-reactivity was not achieved, but a delayed rejection occurred within a mean of 21.8 days after immuno-suppression had been stopped. Following renal transplantation, graft nonreactivity was also not achieved in groups IIB and IIC. In group IID, however, 4 of 8 animals (50%) were graft-tolerant 340, 256, 244, and 164 days after treatment discontinuation. Thus, the combination of 15-DS and CsA led to a significant prolongation of graft survival in both groups. Long-term nonreactivity was achieved only after renal transplantation, when initially treated with 15-DS and CsA.

Calcification of glutaraldehyde-fixed porcine xenograft.

The clinical and light and electron microscopic findings are reported in a 14-year-old patient who died 12 months after mitral valve replacement with a Hancock prosthesis. Severe cusp calcification had led to immobilisation of the valve and stenosis. Calcification involved the substance of the valve cusps. The cause of the calcification in this patient is unknown.

Prevention of myocardial injury by pretreatment with verapamil hydrochloride prior to experimental brain death: Efficacy in a baboon model

Systemic and pulmonary hemodynamics were studied in two groups of Chacma baboons following the induction of brain death. Group A was a control group of 11 animals who underwent brain death. They showed significant increments of mean systemic arterial, left atrial, and pulmonary arterial pressures; of systemic vascular resistance, heart rate, and pulmonary artery blood flow; and a reduction in aortic blood flow during the induction of brain death. As a result of increased sympathetic nervous system activity, areas of myocardial cell necrosis occurred in 73% of the animals and pulmonary edema in 36%. Group B consisted of five animals that were pretreated with verapamil hydrochloride infused over a period of 30 minutes prior to the induction of brain death (mean dosage, 0.26 mg/kg). Except for a rise in heart rate, no significant changes occurred in systemic or pulmonary hemodynamics, and no myocardial or pulmonary histopathological changes were seen. These findings would indicate that verapamil hydrochloride prevents both the peripheral and central hemodynamic changes that result from increased sympathetic activity associated with the induction of brain death, and thus prevents myocardial structural damage, which may be associated with increased calcium uptake by the myocyte.

An electron microscopic study of the giant cells in proliferative myositis

The fine structure of the giant cells in a case of proliferative myositis was examined by electron microscopy. These cells were found to contain numerous well formed filaments. Similar filaments have occasionally been observed in a variety of tumor cells of non‐myogenic origin. The present electron microscopic study has not resolved the uncertain origin of the giant cells in proliferative myositis. Cancer 33:1543–1547, 1974.

Pathology of the formalin-treated heterograft porcine aortic valve in the mitral position

The mitral valve was replaced by a pig aortic valve in 33 patients at Groote Schuur Hospital. Eleven of the failed heterograft aortic valves were examined at intervals of from 2 to 32 months after insertion. Fourteen control pig aortic valves were also examined. Electron microscopy was performed on two of the failed heterograft valves and three control pig valves. Failure of the heterograft was due to stretching and deformation of the cusps with resultant valvular incompetence. Stretching of the cusp was a result of reduction in the amount of its collagen content. The elastic tissue appeared little altered. A microscopic layer of fibrin thrombus was present on the surface of 8 of the 11 valves. Only 2 of the 11 valves showed invasion of the graft by immunologically competent cells. No valve showed any sign of infection or calcification. The denatured collagen of the heterograft has a low antigenicity and also, infortunately, a limited durability.

Extended Cardiopulmonary Preservation: University of Wisconsin Solution Versus Bretschneider's Cardioplegic Solution

Application of the University of Wisconsin cold storage solution has rapidly expanded to include medium-term to long-term preservation of virtually all intraabdominal organs. Its use in intrathoracic organ transplantation has also been suggested. We therefore examined the efficacy of the University of Wisconsin solution in a primate allotransplantation model for preservation of hearts, and as a simple single-solution system for static preservation of heart-lung blocks, for periods of ischemia ranging from 6 to 24 hours. For comparison, we employed the histidine-tryptophane-ketoglutarate cardioplegic solution of Bretschneider. University of Wisconsin solution provided superior results with regard to clinical outcome and hemodynamic recovery of hearts after ischemic periods of up to 16 hours. This was in contrast to Bretschneiders solution, which allowed storage of hearts for periods of only up to 10 hours. Heart-lung blocks were equally well preserved with either University of Wisconsin or Bretschneiders solution after 6 to 12 hours, although the University of Wisconsin solution group exhibited a more notable increase in pulmonary water content. This was in accordance with histological data, which suggested that, although hemodynamic recovery of hearts stored for periods longer than 10 hours was poor, preservation of pulmonary ultrastructure was far superior using Bretschneiders solution as compared with University of Wisconsin solution after an ischemic period of up to 16 hours.