Simon W.H. Kendall

Myocardial β-Adrenergic Receptor Function and High-Energy Phosphates in Brain Death– Related Cardiac Dysfunction

BACKGROUND Cardiac failure remains an important problem after heart transplantation and may be associated with events that occur during brain death (BD) before transplantation. In this study, cardiac function is studied after BD, and biochemical evaluation of myocardial high-energy phosphates and the beta-adrenergic receptor system is presented. METHODS AND RESULTS The hearts of 17 mongrel dogs (23 to 31 kg) were instrumented with flow probes, micromanometers, and ultrasonic dimension transducers to measure ventricular pressure and volume relationships. In a validated canine BD model, systolic right and left ventricular (RV/LV) function was analyzed by load-insensitive measurements during caval occlusion (preload-recruitable stroke work, PRSW). The beta-adrenergic receptor (BAR) density, adenylate cyclase (AC) activity, and myocardial ATP and creatine phosphate (CP) were measured before and 6 to 7 hours after BD. Results are expressed as mean +/- SEM (*P < .05 versus baseline, paired two-tailed Students t test). Myocardial function deteriorated significantly from baseline PRSW (RV, 22 +/- 1 erg x 10(3); LV, 75 +/- 4 erg x 10(3)) by 37 +/- 10% for the RV (P < .001) and 22 +/- 7% for the LV (P < .001). BAR density increased from 282 +/- 42 to 568 +/- 173 fmol/mg for the RV and from 291 +/- 64 to 353 +/- 56 fmol/mg for the LV. Isoproterenol-stimulated AC activity was also significantly enhanced after BD. ATP and CP, however, remained unchanged after BD compared with baseline values before BD. CONCLUSIONS BD causes significant systolic biventricular dysfunction. The loss of ventricular function after BD was more prominent in the right ventricle and may contribute to early postoperative RV failure in the recipient. These injuries occurred despite BAR system upregulation after BD. Global myocardial ischemia is unlikely, since ATP and CP remained normal before and after BD.

Right ventricular function in the donor heart

OBJECTIVES Early morbidity and mortality post cardiac transplantation is frequently caused by right ventricular failure; this is usually attributed to an elevated pulmonary vascular resistance in the recipient. Brain death in the donor is recognised as causing left ventricular dysfunction, but its effects on the right ventricle have not previously been studied. The aim of this study was to investigate right ventricular function following brain death, using a canine model. METHODS The hearts of 33 dogs were instrumented with micromanometers, flow probes and dimension transducers to measure minor/major axes, and right and left ventricular free wall to septal distances. Left ventricular volume was calculated according to the prolate ellipsoid model and right ventricular volume was calculated according to the shell subtraction method. Systolic function for left and right ventricles was analysed by plotting ventricular stroke work vs. end-diastolic volume during a caval occlusion (preload-independent recruitable stroke work PRSW). Brain death was instigated by inflation of a subdurally placed intracranial balloon; subsequently blood pressure was maintained with intravenous fluid whilst no inotropic medications were given. Data were collected at baseline, and at 2 and 4 h thereafter. A two-tailed paired Students t-test was applied to compare post-brain death data with baseline measurements. RESULTS All animals had an initial hyperdynamic response post brain death ensued by the development of diabetes insipidus. Brain stem death was validated by neuropathological examination at the termination of the experiments. Right and left ventricular systolic function had deteriorated significantly 2 h post brain death by 34.4% (+/- 5.1%, P < 0.001) and 20.4% (+/- 3.4%, P < 0.001), respectively, from baseline PRSW [RV = 23.6 erg.10(3) (+/- 1.5), LV = 76.2 erg.10(3) (+/- 3.5)]. This deterioration remained at 4 h post brain death (29.4% (+/- 4.9%, P < 0.001) and 21.2% (+/- 4.3%, P < 0.001), respectively). (The results are expressed as mean and S.E.M.). CONCLUSIONS Brain death causes a significant decrease in left and right ventricular function. The injury to the right ventricle is more prominent than the left ventricle, and at 2 h post brain death it is significantly greater. Failure of the right ventricle post transplantation in clinical practice may be related to this brain death induced injury. Further studies are required to investigate the mechanisms of this injury.

Myocardial performance after graft preservation and subsequent cardiac transplantation from brain-dead donors

BACKGROUND This study examined the effects of brain death and graft preservation on right and left ventricular function after subsequent cardiac transplantation. METHODS Seventy-eight dogs underwent 34 orthotopic complete atrioventricular transplantations using a validated brain-dead organ donor model, hypothermic cardiac preservation, and right and left ventricular function analysis (preload-independent recruitable stroke work). Four groups were studied: controls, transplantation from brain-dead organ donors, graft preservation without brain death, and donor brain death and graft preservation before transplantation. RESULTS Without brain death, cardiac arrest alone as well as the combination of cardiac arrest and preservation did not significantly decrease cardiac function after transplantation. After brain death alone, right ventricular and left ventricular function decreased significantly by 30% and 25%, respectively, but subsequent transplantation did not cause further cardiac dysfunction. Preservation after brain death led to a further significant decrease in right ventricular function after subsequent transplantation, and dopamine hydrochloride was required to wean 4 animals from cardiopulmonary bypass. CONCLUSIONS Brain death causes a significant loss of right and left ventricular function. These injuries are greater in the right ventricle and may contribute to early right ventricular failure after transplantation. Brain death and cardiac preservation interact significantly to impair right ventricular function further. Future studies of graft preservation should use brain-dead organ donors.

Mechanisms of transplant right ventricular dysfunction.

ObjectiveRight ventricular (RV) dysfunction remains the leading cause of early mortality after cardiac transplantation. The effect of brain death and subsequent hypothermia cardioplegic arrest and storage on subsequent post-transplant right ventricular function was examined. Summary Background DataRight ventricular dysfunction in the donor heart usually is attributed to failure of the donor right ventricle to adapt to the sudden increase in afterload (pulmonary vascular resistance) in the recipient. Strategies to improve ventricular mechanics in the postoperative period are aimed at reducing pulmonary vascular resistance with vasodilators or augmenting right ventricular contractility with inotropic agents. Events occurring in the donor heart (brain death, hypothermic cardioplegic arrest, and storage) also may be directly related to post-transplant RV dysfunction. MethodsA canine model of brain death and orthotopic cardiac transplantation was used. A dynamic pressure-volume analysis of RV mechanics was performed using micromanometers and sonomicrometric dimension transducers. Systolic function was assessed by measurement of preload recruitable stroke work (PRSW). Brain death was induced in 17 dogs by inflation of an intracranial balloon. Right ventricular function then was assessed serially to 6 hours (PRSW). Right ventricular adrenergic β receptor density and function was sampled at control and after 6 hours of brain death. The effect of cardioplegic arrest and hypothermic storage was assessed in a second group of 17 dogs, using the same instrumentation and method of RV analysis. ResultsA significant decrease in right ventricular PRSW occurred after brain death, with the average decrease being 37% ± 10.4% from the control. The RV myocardial β adrenergic receptor density did not significantly change (253 ± 34 fmol/ng control vs. 336 ± 54 fmol/ng after brain death). The adenylyl cyclase activity of the RV β receptor was assessed and was not altered by brain death. Orthotopic transplantation after cardioplegic arrest and hypothermic storage significantly decreased RV PRSW from 23.6 ± 2.0 X 103 erg to 13.5 ± 1.4 X 103 erg. ConclusionsThese data indicate that the donor right ventricle is exposed to factors significantly detrimental to its mechanical performance well before facing an increased afterload in the recipient. Strategies to reduce RV dysfunction associated with brain death and hypothermic storage could positively impact post-transplant survival.

Endocrine changes and metabolic responses in a validated canine brain death model

PURPOSE Endocrinologic and metabolic changes after brain death (BD) have not yet been investigated in a validated animal model. Therefore, the effects of BD on hormonal and metabolic function were studied in 10 dogs (23 to 31 kg). METHODS BD was induced by intracranial pressure increase and validated neuropathologically. Plasma concentrations of pituitary, thyroid, adrenal, and pancreatic hormones were measured pre/post BD. The results are expressed as mean (+/- SEM). RESULTS A Cushing reflex and diabetes insipidus occurred after BD. Elevated catecholamine levels were documented after 15 minutes whereas the pituitary gland hormones vasopressin and adrenocorticotrophic hormone (ACTH) decreased significantly after 15 and 45 minutes of BD respectively. Thyroxine, triiodothyronine, and glucagon decreased significantly (P < .01) from 0.58 ng/mL (+/- 0.05), 2.20 micrograms/dL (+/- 0.15), and 49.7 pg/mL (+/- 9.1) respectively to 0.34 ng/mL (+/- 0.03), 1.14 micrograms/dL (+/- 1.14), and 6.9 pg/mL (+/- 1.4) respectively 420 minutes after BD. The hematocrit increased significantly after BD and declined toward the end of all experiments. Metabolic acidosis occurred immediately after BD and at the end of the experiments. CONCLUSIONS In a simple, reproducible, and reliable animal model of BD, a catecholamine storm, vasopressin and ACTH cessation, and diabetes insipidus were consistent findings. The decrease in cortisol and vasopressin levels warrant consideration of hormonal therapy.

Complete atrioventricular cardiac transplantation: Improved performance compared with the standard technique

BACKGROUND There has been renewed clinical interest in an alternative technique to orthotopic cardiac transplantation involving six anastomoses: left pulmonary veins, right pulmonary veins, inferior vena cava, pulmonary artery, aorta, and superior vena cava (complete technique). In this study, the results of the complete technique are compared with those of the standard operation (ventricular transplantation with atrioplasty). METHODS Dogs were used for ten acute standard and ten acute complete atrioventricular transplantations. There were no significant differences in the baseline cardiac function (preload-independent right and left ventricular recruitable stroke work), bypass times, and cardiac ischemic times between the two groups. RESULTS After transplantation, sinus rhythm was preserved after all ten complete and after only one standard transplantation but no significant hemodynamic differences were observed. The right and left ventricular preload-independent recruitable stroke work in the complete group and the left ventricular preload-independent recruitable stroke work in the standard group were conserved after transplantation, but the right ventricular preload-independent recruitable stroke work decreased by 39% +/- 8% (p < 0.05) in the standard group. There was also a significant decrease in the rate of biventricular filling in the standard group after transplantation. CONCLUSIONS Complete atrioventricular transplantation is a feasible alternative technique and conserves normal sinus rhythm. The ischemic and bypass times are comparable for both methods. The insignificant change in the rate of biventricular filling in the dogs undergoing the complete technique indicates right and left ventricular diastolic function may be conserved after transplantation.

Nitric oxide in brain death related cardiovascular dysfunction

PURPOSE Nitric oxide (NO) is a major regulator of vascular tone, blood pressure, and blood flow, and plays a significant role in disease states associated with hemodynamic alterations. However, the role of NO in association with the effects of brain death (BD) has not yet been evaluated. METHODS In 17 mongrel dogs (23 to 31 kg), right atrial serum measurements of nitrite and L-arginine as well as NO ex vivo tissue nitrite extraction were performed at baseline (0), and 120, 240, and 360 minutes after BD. The hearts were instrumented with micromanometers, transonic flow probes, and ultrasonic dimension transducers to determine systolic function and to analyze the pulmonary vasculature flow characteristics by Fourier analysis. Brain death was induced by inflation of a subdurally placed balloon and validated neuropathologically. The results are expressed as mean and standard error of the mean (+/- SEM) (P < .05, paired t-test). RESULTS Right and left ventricular function deteriorated significantly (P < .001) by 37% (+/- 10) and 22% (+/- 7) respectively following BD. Pulmonary and systemic vascular resistance as well as pulmonary impedance decreased significantly over 6 hours after BD. Pulsatile flow, a potent stimulant of NO release, converted significantly to more steady flow. Myocardial NO extraction values remained unchanged after BD and serum L-arginine decreased from 12.84 mu g/L (+/- 0.60) to 11.77 mu g/L (+/- 0.55). CONCLUSIONS The decreases in pulmonary and systemic vascular resistance, pulmonary impedance, and cardiac function associated with BD are not related to major changes in the NO pathway. NO may not play a key role in the early changes after BD.