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The effects of stroke and delirium on postdischarge cognition and patient-centered health outcomes after surgical aortic valve replacement (SAVR) are not well characterized. Here, we assess the impact of postoperative stroke and delirium on these health outcomes in SAVR patients at 90 days.Patients (N = 383) undergoing SAVR (41% received concomitant coronary artery bypass graft) enrolled in a randomized trial of embolic protection devices underwent serial neurologic and delirium evaluations at postoperative days 1, 3, and 7 and magnetic resonance imaging at day 7. Outcomes included 90-day functional status, neurocognitive decline from presurgical baseline, and quality of life.By postoperative day 7, 25 (6.6%) patients experienced clinical stroke and 103 (28.5%) manifested delirium. During index hospitalization, time to discharge was longer in patients experiencing stroke (hazard ratio, 0.62; 95% confidence interval [CI], 0.42-0.94; P = .02) and patients experiencing delirium (hazard ratio, 0.68; 95% CI, 0.54-0.86; P = .001). At day 90, patients experiencing stroke were more likely to have a modified Rankin score2 (odds ratio [OR], 5.9; 95% CI, 1.7-20.1; P = .01), depression (OR, 5.3; 95% CI, 1.6-17.3; P = .006), a lower 12-Item Short Form Survey physical health score (adjusted mean difference -3.3 ± 1.9; P = .08), and neurocognitive decline (OR, 7.8; 95% CI, 2.3-26.4; P = .001). Delirium was associated with depression (OR, 2.2; 95% CI, 0.9-5.3; P = .08), lower 12-Item Short Form Survey physical health (adjusted mean difference -2.3 ± 1.1; P = .03), and neurocognitive decline (OR, 2.2; 95% CI, 1.2-4.0; P = .01).Stroke and delirium occur more frequently after SAVR than is commonly recognized, and these events are associated with disability, depression, cognitive decline, and poorer quality of life at 90 days postoperatively. These findings support the need for new interventions to reduce these events and improve patient-centered outcomes.

Background Patients at intermediate risk (IR) according to The Society of Thoracic Surgeons risk score are today frequently oriented toward the transfemoral aortic valve replacement (TAVR) option. Our goal was to evaluate the best treatment strategies for IR patients with severe aortic stenosis. Methods Of a consecutive series of 1,144 surgical aortic valve replacements (AVRs) performed in our institution between 2008 and 2014, we reviewed the early and late outcomes of two different groups: a low-risk (LR) group of 470 patients, and an IR group of 620. We eliminated from the analysis 54 high-risk patients who were currently candidates for TAVR. All patients underwent surgical AVR with or without concomitant coronary artery bypass grafting. Social Security database interrogation provided long-term information. Results The early mortality rate (30 days) between LR and IR patients was similar (1.70% vs 2.74%, p = 0.25) and both lower than predicted mortality rates. However, cumulative 5-year survival was significantly higher in LR patients (86.3%) than in IR patients (75.4%; p = 0.0007 by log-rank test), although excellent in IR group. Comparing IR survivors and nonsurvivors, ages at operation were 69.5 ± 12.7 years for survivors vs 75.4 ± 9.6 years for those experiencing late deaths ( p = 0.002). Risk factors for late deaths after multivariate analysis were age, hemodialysis, and chronic lung disease. Conclusions Most IR patients today should undergo surgical AVR, but because of survival rates combined with still unavailable late structural deterioration rates in TAVR valves, patients in the IR group with high Society of Thoracic Surgeons scores and known risk factors may be better served with TAVR as data regarding late percutaneous valve function accrue.

Higher mortality in women than in men after isolated coronary artery bypass graft (CABG) procedures has been historically accepted. We have reviewed our continuous series of isolated CABG performed in a single institution providing all coronary interventions in a geographically isolated region

Background Therapeutic ultrasound as an alternative to the maze procedure was evaluated in this large US experience. Safety and efficacy were assessed at 6-, 12-, and 18-month visits with systematic 24-hour Holter monitoring. Methods From February 2005 to February 2007, 220 patients were prospectively enrolled in a single center study, and among them 129 patients with concomitant cardiac surgery and at least 6-month follow-up were reviewed. Primary procedures were mitral surgery in 50% of the cases, coronary bypass in 32%, and aortic surgery in 16%. Atrial fibrillation was permanent in 66 (51.1%), paroxysmal in 43 (33.3%), and persistent in 20 (15.5%) patients. An epicardial and circumferential left atrial encircling line was created on the beating heart. Routinely a mitral isthmus line was also created from the left atrium epicardium using an ultrasonic handheld device. Results No morbidity or mortality was device-related. There were four (2.33%) early deaths and six late extra-cardiac deaths. Follow-up ranged from 6 to 670 days with a mean follow-up of 358.5 days, median 340 days with two patients lost to follow-up. Freedom from atrial fibrillation or left-sided flutter was 83.2%, 84.4%, and 86.2% at 6, 12, and 18 months, respectively. A pacemaker was implanted in seven patients (5.4%). Male gender and left atrial dimension were significant risk factors for failure. Conclusions The study confirms the excellent safety record of the technology, and the efficacy at the level reported in a previous European multicenter study. Efficacy is also maintained at longer (12 and 18 months) follow-up.

Relationships between interstitial transudate adenosine and coronary flow and between global adenosine formation and cytosolic metabolism were examined in constant-pressure perfused guinea pig hearts during norepinephrine (NE) stimulation and adenosine antagonism with 10 microM 8-phenyltheophylline. Basal coronary flow was 5.7 ml.min-1 x g-1, and transudate and venous adenosine levels were approximately 0.26 and 0.06 microM, respectively. During 10 min of NE stimulation (15 nM), coronary flow and adenosine levels increased, the phosphocreatine-to-inorganic phosphate ratio ([PCr]/[Pi]) declined, and ATP and pH remained stable. Despite phasic release of adenosine, coronary flow correlated dose dependently with transudate adenosine, and adenosine release was inversely related to [PCr]/[Pi] under all conditions. 8-Phenyltheophylline infusion attenuated functional hyperemia by approximately 40%, enhanced the fall in [PCr]/[Pi], and potentiated elevations in transudate and venous adenosine. Similar results and correlations were obtained in hearts perfused at a constant-flow of 5.7 ml.min-1 x g-1, although stimulated adenosine levels and metabolic changes were greater and contractile responses smaller. These data indicate that: 1) endogenous adenosine plays a primary role in functional hyperemia in perfused guinea pig heart; 2) global adenosine formation appears related to phosphorylation status; and 3) adenosine receptor antagonism enhances metabolic disturbances during adrenergic stimulation and markedly potentiates adenosine release, indicating that the functional effects of antagonists may significantly underestimate the dilatory role of endogenous adenosine.

This study was designed to evaluate the relative response of myocardial efficiency to reduced oxygen supply (hypoxia and ischemia) in immature and mature isolated rabbit hearts. Hearts were subjected to either 15 min of hypoxia (60% or 30% O2) or reductions in coronary flow to 75%, 50%, 25%, and 15% of basal flow followed by 12 min of total global ischemia and 15 min of reperfusion. In order to examine changes in cardiac efficiency, we utilized the ratio of isovolumic contractile function (rate-pressure product) to myocardial oxygen consumption (RPP/MVO2). Under basal conditions, immature hearts displayed lower aortic pressure. RPP, coronary resistance and RPP/MVO2. Moderate hypoxia (60% O2) resulted in similar reductions in RPP and MVO2 in both age groups, with RPP/MVO2 remaining unchanged. During severe hypoxia, RPP/MVO2 increased significantly in mature hearts but not in immature hearts (P < 0.05). Underperfusion produced greater reductions in RPP and heart rate, whereas reperfusion after ischemia resulted in greater recovery of RPP, dP/dt and MVO2 in immature compared to mature hearts. When oxygen supply was limited by reductions in coronary perfusion. RPP/MVO2 tended to increase in mature hearts, whereas the ratio declined significantly in immature hearts. These data demonstrate that, in this model, a reduction in oxygen supply by hypoxia or hypoperfusion decreases efficiency in immature hearts, but increases efficiency in mature hearts under the same conditions.

We employed an isolated guinea-pig heart model perfused at constant pressure (70 cmH2O) to test the hypothesis that inhibition of adenosine metabolism increases interstitial adenosine concentrations (as measured with epicardial discs) and coronary flow. Iodotubercidin (ITU, 1 microM) and EHNA (erythro-9-[2-hydroxy-3-nonyl] adenine, 5 microM) were used to inhibit adenosine kinase and deaminase, respectively during control conditions and during metabolic stimulation with 1 microM isoproterenol. The adenosine receptor blocker 8-phenyltheophylline (8-PT) was used during control conditions to assess whether the response seen was adenosine specific. ITU plus EHNA decreased heart rate (202 +/- 10 to 136 +/- 11 beats/min) and increased coronary flow (8.2 +/- 0.3 to 12.4 +/- 0.9 ml/min/g) without a change in MVO2, developed pressure or dP/dt. ITU plus EHNA increased adenosine concentrations in epicardial fluid (0.24 +/- 0.07 microM to 1.02 +/- 0.09 microM) and venous effluent (40 +/- 3 nM to 262 +/- 32 nM) during control conditions, and adenosine release increased from 389 +/- 96 pmols/min/g to 3480 +/- 365 pmols/min/g. 8-PT infusion reversed the effects on heart rate and coronary flow and resulted in a persistent elevation of epicardial fluid adenosine concentrations. During metabolic stimulation with 1 microM isoproterenol, ITU plus EHNA significantly limited the increase in heart rate and ventricular developed pressure and dP/dt while coronary flow increased to a significantly greater extent. Myocardial oxygen consumption was similar during metabolic stimulation between the two groups (vehicle vs. ITU plus EHNA). Epicardial fluid adenosine concentration in the vehicle-treated group increased from 0.17 +/- 0.3 microM to 0.34 +/- 0.02 microM at 15 min of isoproterenol stimulation whereas it increased from 1.10 +/- 0.02 microM to 2.90 +/- 0.46 microM in the ITU plus EHNA-treated group. Inhibition of adenosine metabolism during metabolic stimulation significantly increased venous adenosine concentrations and adenosine release and reduced inosine and hypoxanthine release proportionately. The release of adenosine+inosine+hypoxanthine was unchanged. Inhibition of adenosine metabolism provides evidence supporting the hypothesis that adenosine plays a role in regulating coronary vascular resistance as well as influencing heart rate and ventricular inotropy.

Interest in minimally invasive coronary artery bypass grafting (CABG) continues to grow, and the techniques evolve. Our study examines the technical strategies of port-access (PA) CABG and compares results between PA CABG and conventional CABG.Two hundred and twenty-nine consecutive patients underwent PA CABG from December 1996 through July 1998. Postoperative complications were compared with a matched cohort of conventional access patients. Operative technique and times were reviewed in the PA group.The average Society of Thoracic Surgeons (STS) risk assessment was 1.3 in both groups. Observed mortality was 0.9%. Complications of stroke, perioperative myocardial infarction, and atrial fibrillation were not significantly different between the two groups. Reoperation for bleeding was more likely in the PA group, while infections were more likely in the sternotomy group (p0.05). Transfusion requirements and postoperative length of stay were lower in the PA group (p0.05).Early results were similar between these two low-risk cohort groups. These findings support continued careful use of port-access revascularization in low-risk patients. Close follow-up of outcomes is essential to define the appropriateness of port-access techniques in patients requiring surgical revascularization.

Background— Surgical therapy of atrial fibrillation concomitant to coronary bypass grafting using epicardial Ultrasound technology was assessed after a minimum 6-month follow-up. Methods and Results— A cohort of 98 consecutive patients with a mean age of 72±7.58 years and a primary diagnosis of ischemic heart disease had surgery for structural disease. Coronary artery bypass grafting was isolated (n=51) or associated (n=47) with various combinations of aortic, mitral, tricuspid, and left ventricular restoration surgery. Atrial fibrillation duration ranged from 6 to 360 months (mean 71 months) and was permanent in 47 patients, paroxysmal in 34, and persistent in 17. Left atrial mean diameter was 48±6.71 mm. A circumferential ablation was performed off-pump, before the concomitant procedure, and was always associated with an epicardial mitral line lesion using the same technology. At 3-, 6-, and 12-month visits, patients were routinely evaluated by physical examination, ECG, chest X-ray, and 24-hour Holter. There were 1 early death (1%) and 4 extracardiac late deaths. A pacemaker was implanted in 4 patients. Mean follow-up time was 325 days, 2 patients being lost to follow-up. Freedom from atrial fibrillation and flutter at the 6-month visit was 84% for the entire population, 76% in patients with permanent, and 91% in patients with paroxysmal atrial fibrillation. At the 1-year visit, 85% were free from atrial fibrillation or flutter. Conclusion— Epicardial beating heart ablation using therapeutic ultrasound is safe, reliable, and can easily treat atrial fibrillation in a difficult surgical population of patients with primary ischemic heart disease.

We examined metabolic effects of "supply" and "demand" ischemia in immature and mature rabbit hearts. Moderate supply ischemia was produced by a 50% reduction in coronary flow (to approximately 5.0 ml min-1 g-1 giving a 50-55% rise in O2 extraction and a 35% drop in O2 supply/demand). Demand ischemia was produced by stimulation of workload and O2 demand with 30 microM norepinephrine at constant coronary flow (55-60% rise in O2 extraction, 35-40% fall in O2 supply/demand). Basal energy state ([ATP]/[ADP].[Pi]) was lower in immature compared to mature hearts, primarily due to reduced [PCr]. Despite a lower energy state, basal purine efflux was lowest in immature hearts. During supply ischemia reductions in [ATP]/[ADP]. [Pi] and elevations in [H+] were greatest in mature compared to immature hearts (P < 0.05). Despite this depressed energy state purine efflux did not increase significantly during supply ischemia. In contrast, during demand ischemia reductions in energy state were greatest in immature compared to mature hearts. Moreover, purine efflux increased more than 30-fold in immature and only four-fold in mature hearts, resulting in two-fold greater purine washout in immature hearts. The data indicate that: (i) maturation increases basal energy state and, paradoxically, purine efflux, (ii) in immature hearts demand ischemia has a greater impact on energy state than supply ischemia, whereas there are minimal differences in the metabolic effects of supply and demand ischemia in mature hearts, (iii) consequently while maturation is associated with a reduction in metabolic/bioenergetic resistance to supply ischemia it is associated with increased resistance to demand ischemia, (iv) markedly reduced purine wash-out from mature myocardium may contribute to this increased resistance during demand ischemia, and (v) control of adenosine formation and purine efflux changes with maturation, and appears to involve mechanisms unrelated to cytosolic energy metabolism.

Adenosine is released from the myocardium in response to a decrease in the oxygen supply/demand ratio, as is seen in myocardial ischemia; its protective role is manifested by coronary and collateral vessel vasodilation that increase oxygen supply and by multiple effects that act in concert to decrease myocardial oxygen demand (i.e., negative inotropism, chronotropism, and dromotropism). During periods of oxygen deprivation, adenosine enhances energy production via increased glycolytic flux and can act as a substrate for purine salvage to restore cellular energy charge during reperfusion. Adenosine limits the degree of vascular injury during ischemia and reperfusion by inhibition of oxygen radical release from activated neutrophils, thereby preventing endothelial cell damage, and by inhibition of platelet aggregation. These effects help to preserve endothelial cell function and microvascular perfusion. Long-term exposure to adenosine may also induce coronary angiogenesis.

An isolated, isovolumetrically contracting rat heart preparation, perfused at constant flow, was used to test the hypothesis that adenosine treatment (100 μM) throughout the experiment could enhance the repletion of adenosine triphosphate and the recovery of ventricular function following 10 minutes of global, normothermic (37° C) ischemia. Left ventricular developed pressure was measured with an intraventricular balloon, and myocardial adenine nucleotides were measured from freeze-clamped tissues in a parallel series of experiments. The adenosine triphosphate level in the adenosine-treated hearts was not different from that of the untreated control hearts at the end of 30 minutes of equilibration but was significantly (p

The purine precursor AICAR (5-amino-4-imidazolecarboxamide) has been advocated as a substrate for myocardial adenine nucleotide repletion during postischemic reperfusion. The purpose of this study was to investigate the acute effects of this agent on adenine nucleotides, inosine monophosphate, and postischemic ventricular function in an isolated rat heart preparation. The hearts were perfused at constant flow, either continuously for 90 minutes or for a 30 minute period followed by 10 minutes of global normothermic (37° Q ischemia. The ischemic hearts were then reperfused for 15, 30, and 60 minutes. Both groups were treated with AICAR in a concentration of 100 μmol/L throughout the perfusion protocols. In the nonischemic time control group there was no effect on the levels of adenosine nucleotides or developed pressure over 90 minutes of perfusion. In contrast, AICAR treatment increased tissue inosine monophosphate content fourfold and sevenfold at 60 and 90 minutes, respectively (p

Coronary blood flow responds uniquely to changes in myocardial demand, regardless of the stimulus. If adenosine mediates this response, interstitial fluid adenosine concentration should also change in parallel with myocardial oxygen consumption and coronary blood flow during alterations of cardiac work. We tested this hypothesis by measuring coronary blood flow, myocardial oxygen consumption, and the concentration of adenosine in pericardial infusates, an index of interstitial fluid adenosine concentration, during six experimental conditions and control states in anesthetized, open-chest dogs. Significant alterations of myocardial oxygen consumption and coronary blood flow during aortic constriction, vagal stimulation, atrial pacing, or intravenous infusion of calcium chloride, norepinephrine, or isoproterenol were accompanied by significant alterations in pericardial infusate adenosine concentration. Significant linear relationships were determined among myocardial oxygen consumption, coronary blood flow, and pericardial infusate adenosine concentration for each of the experimental stimuli and their paired control values. There were no significant differences among the six different conditions for any of these relationships. In addition, these relationships were not altered by beta-blockade in five dogs subjected to aortic constriction and calcium infusion. Although beta-blockade may alter the effects of a stimulus, myocardial oxygen consumption, coronary blood flow, and adenosine all are affected proportionately. The results suggest that adenosine production responds to alterations of myocardial oxygen consumption independently of the stimulus which produces the change in oxygen demand, and the resultant change in interstitial fluid adenosine concentration may initiate the change in coronary blood flow to maintain the balance between oxygen supply and demand.

Myocardial dysfunction after induced ischemic arrest is an important problem in cardiac surgery. Adenosine-5’-triphosphate content in myocardial tissue remains depressed for days after ischemia, perhaps because of reperfusion washout of diffusable purine substrates. Left ventricular function is also depressed after ischemia, but its relationship to absolute tissue adenosine triphosphate content is unclear. We tested the hypothesis that arresting hearts with a cardioplegic solution containing adenosine, hypoxanthine, and ribose would result in improved tissue adenosine triphosphate content and left ventricular function after 1 hour of normothermic global ischemia in dogs supported by cardiopulmonary bypass. Animals with ischemic arrest initiated with a crystalloid cardioplegic solution containing adenosine 100 μmol/L, hypoxanthine 100 μmol/L, and ribose 2 mmol/L demonstrated significant improvement (p

The hypothesis that endogenously released adenosine plays an important role in maintaining patency of the fetal lamb ductus arteriosus was tested. The design of the study was (1) to determine the effect, if any, of exogenous adenosine on blood flow through the ductus arteriosus and (2) to evaluate the relationship among the partial pressure of oxygen in arterial blood, circulating endogenous plasma adenosine concentration, and the rate of blood flow through the ductus. When exogenous adenosine (5 mumoles) was administered during oxygen-induced ductal constriction, ductal blood flow increased from 101 +/- 6 ml/min to 153 +/- 4 ml/min (p less than 0.01). When fetal blood adenosine concentrations were measured during nonventilation and ventilation with 100% oxygen, endogenous adenosine concentrations fell to less than one-half of the preventilation levels, i.e., from 1.12 +/- 0.17 to 0.49 +/- 0.03 microM (p less than 0.01). Finally, when fetal lambs were ventilated with increasing concentrations of oxygen (0%, 10%, 20%, 60%, and 100%) and measurements obtained simultaneously at each level, there was a significant monoexponential relationship among the rise in PO2, the fall in plasma adenosine concentration, and the decrease in ductal blood flow. These data suggest that: (1) adenosine is a potent vasodilator of the lamb ductus arteriosus during oxygen-induced vasoconstriction; (2) fetal endogenous plasma adenosine levels fall significantly when PO2 is increased; and (3) the fall in adenosine concentrations parallels a decrease in ductal blood flow. The findings suggest that the endogenous vasodilator adenosine plays an important role in maintaining ductal patency in utero.

Adenosine may be an important metabolic regulator of coronary blood flow during active hyperemia in the newborn. In this study, the adenosine uptake blocker dipyridamole (DPY) and receptor antagonist theophylline (THEO) were used to assess the role of adenosine in the reactive hyperemic response of the neonatal heart. Eighteen anesthetized, open-chest lambs were instrumented with aortic and coronary sinus catheters as well as an extracorporeal shunt to the circumflex coronary artery incorporating a 2.0-mm electromagnetic flow transducer. Ten-second occlusions of the circumflex coronary artery catheter were performed, and the resulting reactive hyperemia was used to determine peak hyperemic blood flow (PHF), duration of hyperemia, and the blood flow repayment. These values were determined prior to treatment and 30 min following administration of a saline vehicle, DPY (0.2 mg/kg) or THEO (5 mg/kg). DPY resulted in increases in PHF from 220 +/- 12 to 247 +/- 14 ml/min/100 g heart tissue (P less than 0.05), durations of hyperemia from 29 +/- 2 to 38 +/- 2 sec (P less than 0.01), and blood flow repayments from 65 +/- 2 to 102 +/- 4 ml/100 g (P less than 0.001). THEO resulted in decreases in PHF from 224 +/- 15 to 198 +/- 12 ml/min/100 g (P less than 0.05), durations of hyperemia from 28 +/- 2 to 22 +/- 2 sec (P less than 0.05), and blood flow repayments from 64 +/- 2 to 46 +/- 2 ml/100 g (P less than 0.01). The data indicate that DPY enhances reactive hyperemia while antagonism of adenosine with THEO attenuates it. These results suggest that adenosine plays a role in mediating reactive hyperemia in the newborn heart.

A conscious dog model was employed to evaluate the relationship among myocardial oxygen consumption (MVO2), myocardial adenosine release and coronary blood flow (CNF) during graded treadmill exercise. Two methods were utilized simultaneously as indexes of changes in interstitial adenosine concentrations, (1) a pericardial infusate technique and (2) to measurement of arterial-coronary sinus plasma adenosine concentration differences. Graded exercise was associated with graded increases in MVO2, CBF, pericardial infusate adenosine concentration (PI Ado) and adenosine washout in coronary plasma. Regression analysis demonstrated significant linear relationships for MVO2 v. CBF (r = 0.78, P less than 0.01), MVO2 v. PI Ado (r = 0.52, P less than 0.01), and PI Ado v. CBF (r = 0.76, P less than 0.01). Coronary plasma adenosine arterio-sinus differences, sinus plasma concentrations, and net washout of adenosine also increased with graded exercise, however, a significant inter-animal variance was noted. These data suggest that the plasma adenosine assay is capable of detecting directional (qualitative) changes associated with changes in cardiac metabolism, however, it may not be reliable as a quantitative indicator of interstitial adenosine concentrations due to multiple factors which may influence the plasma adenosine pool. The pericardial infusate technique, which presumably represents a model of diffusion, is relatively invariant by comparison. The results demonstrate a significant correlation among MVO2, PI Ado and CBF, and thereby provide support to the hypothesis that adenosine is a major factor in the coupling of myocardial oxygen demand to oxygen supply under physiological conditions.

Although it has long been recognized that adenosine is a potent vasodilator, only during the past 20 years has serious consideration been given to its possible role in the local regulation of blood flow. Prior to that time other potential mediators of regional blood flow regulation, such as reduced PO2, increased PCO2, or decreased pH were often suggested, but definitive experimental proof for a physiological role for these agents was lacking. In more recent years, more evidence has appeared in support of a reduced pH, and additional substances such as potassium ions, inorganic phosphate, and increased osmolarity have been suggested with varying degrees of acceptance. In all likelihood, several factors, including a myogenic response, are involved in local blood flow regulation, but adenosine appears to be the primary factor. Since most of the studies on adenosine have been focused on its mediation of the control of coronary, cerebral, and skeletal muscle blood flow, in that order, discussion will be limited to these three tissues. This in no way means that adenosine does not act similarly in several other tissues. In the kidney, however, adenosine induces vasoconstriction, a subject considered in detail by Dr. Osswald in Chapter 25.

Allopurinol, a competitive inhibitor of xanthine oxidase, has been shown to have a protective effect on ischemic myocardium, but its mechanism of action remains controversial. We used an isolated rat heart preparation to test the hypothesis that allopurinol could restore adenosine triphosphate (ATP) levels and improve the recovery of left ventricular function after global myocardial ischemia. Hearts were equilibrated for 30 min, subjected to 10 min of global, normothermic (37 degrees C) ischemia, and reperfused for 15, 30, and 60 min. Hearts treated with allopurinol (100 microM) exhibited greater ATP levels and improved function during reperfusion than did untreated control hearts. Hearts treated with hypoxanthine (100 microM), the substrate for xanthine oxidase, also showed increased ATP and functional recovery compared with controls. These results suggest that allopurinol may protect the globally ischemic myocardium by enhancing the salvage of hypoxanthine for reincorporation into adenine nucleotides.

It has been demonstrated that resting coronary vascular resistance is elevated with chronic hypertension and concomitant cardiac hypertrophy. The present study employed a model of 6-week, one-kidney, one wrapped Page hypertension to determine if the ability of the heart to match an increase in oxygen demand with an increase in oxygen supply (coronary blood flow) is impaired, and to determine if these vasoregulatory abnormalities are attributable to inadequate adenosine release. Studies were performed in a pentobarbital anesthetized, open-chest canine preparation using a pericardial infusate method to determine adenosine release. Results showed that dobutamine (a beta-receptor agonist) induced increases in myocardial oxygen consumption (MVO2) over a physiological range (8-30 ml O2 X min-1 X 100 g-1) that were accompanied by an increase in coronary blood flow (CBF) with no change in oxygen extraction. The relationship between MVO2 and CBF was not different between the normotensive (NTC) and hypertensive (RHT) animals. Pericardial infusate adenosine (PI ADO) concentrations were not different for the same MVO2 and CBF, and the relationships for MVO2 vs PI ADO as well as PI ADO vs CBF were unaltered by hypertension. However, the relationship between PI ADO and coronary vascular resistance (CVR) was altered in the RHT group such that a given PI ADO concentration was associated with a significantly higher CVR. These data suggest that, over the range of MVO2 studied, there are no limitations in metabolic regulation of the coronary circulation of RHT animals, and that the higher CVR encountered in the RHT group is not the result of a reduced release of the endogenous vasodilator, adenosine.

1. Eight mongrel dogs were anaesthetized with sodium thiamylal and chloralose-urethane, ventilated, vagotomized and heparinized. Five Poland-China pigs were anaesthetized with sodium thiamylal and nitrous oxide, ventilated, vagotomized and heparinized. 2. Extracorporeal perfusion of the right coronary artery at constant pressure (100 mmHg) was instituted. A lung from a donor animal was interposed in the coronary perfusion circuit to effect changes in CO2 and O2 tensions in the coronary arterial blood while systemic blood gases were maintained at normal levels. 3. Local hypoxia (PO2 range 17-22 mmHg) produced a 25-75% decrease in coronary vascular resistance (P less than 0.05) and a 0-24% (not significant) decrease in right ventricular dP/dt. 4. Local changes in PCO2 over the range 8-105 mmHg were associated with a 17-58% decrease in coronary vascular resistance (P less than 0.05), a 19-24% decrease in right ventricular dP/dt (P less than 0.05) with no change in right ventricular end-diastolic pressure, and a 1-18% (not significant) decrease in heart rate. 5. These studies suggest that local decreases in O2 or increases in CO2 tensions produce decreases in right coronary vascular resistance that are in the opposite direction to those that would be expected from the observed changes in heart rate and contractility (two primary determinants of myocardial oxygen consumption). 6. These data support the hypothesis that CO2 and O2 are locally vasoactive in the coronary circulation.

Dipyridamole, a vasodilator that potentiates the actions of exogenous adenosine, is known to inhibit cellular uptake of adenosine, but its effects on cellular adenosine release, and thus interstitial adenosine levels, are disputed. We used the accumulation of adenosine in pericardial infusates (PCI) as an index of interstitial adenosine concentration and observed the effects of dipyridamole on relationships among coronary blood flow (CBF), myocardial oxygen consumption (MVO2), and PCI adenosine concentrations during steady-state alterations of cardiac work. Dipyridamole increased CBF and PCI adenosine concentration without altering MVO2. The relationship between PCI adenosine and CBF was unaltered, supporting a cause and effect relationship between interstitial adenosine concentration and CBF. In addition, we determined that unlike previous studies in isolated perfused hearts the washout of adenosine by coronary plasma was unaffected by dipyridamole. The results support previous suggestions that, whereas dipyridamole inhibits adenosine uptake, it does not alter cellular adenosine release, and therefore interstitial adenosine levels are increased. The constant relationship between PCI adenosine and CBF supports hypotheses that attribute the hyperemias associated with increased cardiac work or with dipyridamole to increased interstitial adenosine.

In certain forms of congenital heart disease, patency of the ductus arteriosus is critical for survival. Since the administration of prostaglandin is associated with adverse side effects, this study was undertaken to evaluate the effects of nitroglycerin and nitroprusside on ductal blood flow during oxygen-induced ductal closure. Fifteen near-term fetal lambs were instrumented acutely. Ductal blood flow and pre- and post-ductal pressures were monitored continuously. After obtaining control data, intravenous bolus injections of nitroglycerin (250 micrograms), nitroprusside (250 micrograms), or prostaglandin E1 (5 micrograms) were administered during ventilation with either 100% nitrogen or 100% oxygen. All three agents significantly increased ductal blood flow during nitrogen ventilation (PO2 = 15 +/- 1 mm Hg). When the lambs were ventilated with 100% oxygen, the arterial PO2 increased to 107 +/- 14 mm Hg, and this was associated with a marked decrease in ductal blood flow from 275 +/- 44 to 83 +/- 11 ml/min (P less than 0.05). When nitroglycerin was administered during oxygen-stimulated ductal closure, ductal blood flow increased 184%, from 79 +/- 18 to 225 +/- 18 ml/min (P less than 0.05); nitroprusside increased ductal blood flow 126%, from 86 +/- 20 to 195 +/- 25 ml/min (P less than 0.05); prostaglandin E1 increased ductal blood flow 110%, from 84 +/- 18 to 178 +/- 17 ml/min (P less than 0.05). These data demonstrate that both nitroglycerin and nitroprusside are potent vasodilators of the ductus arteriosus and, like prostaglandin E1, can markedly attenuate the oxygen-induced ductal vasoconstriction. These results imply that nitroglycerin and nitroprusside may be useful clinically in maintaining ductal patency.

The idea that intracoronary injection of adenosine deaminase should destroy interstitial fluid adenosine and abolish regulation of coronary blood flow has sparked a number of controversial studies. In some studies adenosine deaminase infusion failed to block vascular responses attributed to endogenous adenosine, but in others it depressed them. Such results are to be expected because the amount of adenosine deaminase calculated from direct measurements of enzyme kinetics (in the adenosine concentration range of 10−8-1(10−3 M) necessary to destroy adenosine in the myocardial interstitial fluid is considerably greater than that used by investigators who have used this approach.

This study was designed to evaluate the effects of the sympathetic nervous system on right ventricular and right coronary hemodynamics in the anesthetized vagotomized dog and pig during constant-pressure coronary perfusion. Carotid occlusion in the dog resulted in an increase in heart rate, aortic pressure, right ventricular dP/dt, and a sustained 13% decrease in right coronary artery blood flow and a 14% increase in coronary vascular resistance. This coronary vasoconstriction was not modified during beta-blockade with propranolol but was prevented by alpha- blockade with phentolamine. Similar hemodynamic data was obtained in the pig and, in addition, it was found that the O2 consumption of the right ventricle is low (4.8 +/- 0.4 ml O2.min-1.100 g-1) and is only slightly increased (5.l5 +/- 0.8 ml.min-1.100 g-1) during carotid occlusion. These data suggest that baroreflex-mediated sympathetic stimulation to the heart evokes only a minor increase in metabolic activity in the right ventricular myocardium so that the direct neural (alpha-vasoconstrictor) effect predominates over the metabolic vasodilator mechanism.

The role of adenosine in matching myocardial oxygen supply to demand by regulating coronary blood flow has been the subject of intensive study. The present experiments were designed to determine the relationship among myocardial oxygen consumption, coronary blood flow, and adenosine production as estimated by pericardial adenosine accumulation under several physiological conditions in the same animal. Conscious chronically instrumented dogs were used to measure changes in coronary blood flow, myocardial oxygen consumption, and pericardial adenosine accumulation during two levels of treadmill exercise, excitement caused by loud noises, and feeding (the presentation and consumption of a meal). The results show significant increases in the adenosine production with all experimental procedures and significant linear correlations between myocardial oxygen consumption and coronary blood flow (r = 0.78), myocardial oxygen consumption and adenosine production (r = 0.73), and adenosine production and coronary blood flow (r = 0.88). These data show that increases in adenosine production by the normally oxygenated myocardium can be the physiological mechanism for matching oxygen supply to increased oxygen demand in the conscious dog.