Increase In Myocardial Oxygen Extraction Research Articles

Increased oxidative stress alters coronary microvascular tone in exercising swine with multiple comorbidities

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Cardiovascular Alliance Background/Objectives We have previously shown, in female swine that the combination of three cardiovascular risk factors (diabetes mellitus (DM), hypercholestolemia (HC) and chronic kidney disease (CKD)) induces systemic inflammation, oxidative stress, coronary endothelial dysfunction and impaired myocardial perfusion due to impaired nitric oxide (NO) bioavailability. In the present study we hypothesized that the reduced bioavailability of nitric oxide (NO) is the result of increased production of reactive oxygen species (ROS) and ROS scavenging will restore myocardial oxygen balance thereby improving myocardial perfusion. Methods 12 female swine, with DM (streptozotocin 3x50mg/kg iv), CKD (renal embolization), and HC (high fat, high sugar, high salt diet) and 9 female healthy swine on normal pig chow (Normal) were included. The effect of ROS scavenging on the coronary microvascular tone control was studied in vivo, at rest and during graded treadmill exercise before and after infusion of the ROS scavengers (MPG+Tempol). Additionally, vasodilation to bradykinin was studied in the presence of MPG and TEMPOL and after subsequent addition to catalase, in isolated left ventricle small coronary arteries, in vitro using wire-myography. Results 6 months of DM+HC+CKD resulted in hyperglycemia (18.0±1.3 vs 8.4±0.9mmol/L), hypercholesterolemia (13.4±2.1 vs 1.7±0.1mmol/l), renal dysfunction (plasma creatinine: 166±9 vs 119±3µmol/l), and systemic inflammation (TNFα: 63±8 vs 41±4pg/ml, all P<0.05) associated with impaired endothelium-dependent vasodilator response to bradykinin in vitro. Furthermore, myocardial oxidative stress was increased in DM+HC+CKD animals (8-isoprostane 13±1 vs 10±1pg/ml) and total antioxidant capacity was reduced (0.67±0.02 vs 0.72±0.01nmol Trolox eq./mg protein, both P<0.05). Surprisingly, in vivo ROS scavenging resulted in an even further increase in myocardial oxygen extraction in DM+HC+CKD while it had no effect in Normal, indicating the involvement of a vasodilator ROS (most likely H2O2) in the control of coronary microvascular tone. This was supported by increased activity of catalase in the myocardium of DM+HC+CKD animals (44±3 vs 31±4nmol/min/ml, both P<0.05) and the vascular relaxation response to bradykinin when catalase was added on top of the ROS scavenging in vitro. Conclusion In swine exposed for 6 months to multiple comorbidities, impaired myocardial perfusion is mediated by a loss of NO bioavailability due to increased oxidative stress which was partially compensated by increased H2O2-mediated coronary vasodilation.

Coronary vascular responses to short-term cocaine administration in conscious baboons compared with dogs

OBJECTIVESCardiovascular complications of cocaine use represent an important clinical problem, yet the mechanisms by which cocaine predisposes to myocardial ischemia are poorly understood.BACKGROUNDThe effects of cocaine on the coronary circulation have been studied extensively in experimental animal models, but have failed to recapitulate the clinical findings reported in humans who use cocaine.METHODSWe studied 12 conscious, chronically instrumented dogs and 5 conscious, chronically instrumented baboons to determine whether there were important species differences in the response to cocaine.RESULTSComparable doses of intravenous cocaine caused similar increases in left ventricular systolic, diastolic and mean arterial pressure in the two species. However, the peak coronary blood flow response in baboons (+8 ± 3 from 47 ± 6 ml/min) was less compared with dogs (+15 ± 4 from 41 ± 4 ml/min), while the coronary vascular resistance response was greater in baboons (+0.60 ± 0.09 from 1.94 ± 0.09 mm Hg/ml/mm) compared with dogs (+0.35 ± 0.09 from 2.24 ± 0.10 mm Hg/ml/min). Although myocardial oxygen consumption responses were similar between species, there was a significant difference (p < 0.05) in oxygen delivery between baboons (+164 ± 47 from 705 ± 59 ml of oxygen per minute) and dogs (+397 ± 51 from 656 ± 33 ml of oxygen per minute) that was attributable to a significant (p < 0.05) increase in hemoglobin concentration in dogs (+2.1 ± 0.5 g/dl) that was not observed in baboons. Consequently, cocaine caused a significant increase in myocardial oxygen extraction and decreased coronary sinus pH in baboons, but not dogs.CONCLUSIONSCocaine caused greater coronary vasoconstriction and greater requirements for oxygen extraction in baboons compared with dogs.

Regulation of Myocardial Blood Flow by Oxygen Consumption Is Maintained in the Failing Heart During Exercise

The hemodynamic abnormalities and neurohumoral activation that accompany congestive heart failure (CHF) might be expected to impair the increase in coronary blood flow that occurs during exercise. This study was performed to determine the effects of CHF on myocardial oxygen consumption and coronary blood flow during exercise. Coronary blood flow was measured in chronically instrumented dogs at rest, during 2 stages of graded treadmill exercise under control conditions (n=10), and after the development of CHF produced by 3 weeks of rapid ventricular pacing (n=9). In the normal dogs, coronary blood flow increased during exercise in proportion to the increase in the heart rate x the left ventricular systolic blood pressure product (RPP). After the development of CHF, resting myocardial blood flow was 25% lower than normal (P<0.05). Myocardial blood flow increased during the first stage of exercise, but then failed to increase further during the second stage of exercise despite an additional increase in the RPP. Myocardial oxygen consumption during exercise was significantly lower in animals with CHF and paralleled coronary flow. Despite the lower values for coronary blood flow in animals with CHF, there was no evidence for myocardial ischemia. Thus, even during the second level of exercise when coronary flow failed to increase, myocardial lactate consumption continued and coronary venous pH did not fall. In addition, the failure of coronary flow to increase as the exercise level was increased from stage 1 to stage 2 was not associated with a further increase in myocardial oxygen extraction. Thus, cardiac failure was associated with decreased myocardial oxygen consumption and failure of oxygen consumption to increase with an increase in the level of exercise. This abnormality did not appear to result from inadequate oxygen availability, but more likely represented a reduction of myocardial oxygen usage with a secondary decrease in metabolic coronary vasodilation.

Effects of bucindolol in heart failure

Bucindolol hydrochloride is a phenoxypropanolamine with potent nonselective β antagonist and mild vasodilatory properties. In humans with congestive heart failure, it is extremely well tolerated and produces improvements in left ventricular systolic (ejection fraction, systolic elastance, cardiac index, and stroke work) and diastolic (isovolumic relaxation) performance while reducin pulmonary artery pressures and heart rate. These improvements occur without an increase in myocardial oxygen extraction or oxygen consumption. In addition, functional class improves with this agent although exercise tolerance and maximal oxygen consumption (VO 2max) does not change, an effect that is not unexpected with a β-adrenergic antagonist. Bucindolol produces a decrease in plasma renin activity and plasma norepinephrine, effects that may be beneficial for the long-term treatment of congestive heart failure. However, these effects are most marked in patients with idiopathic dilated cardiomyopathy compared with patients with ischemic heart disease. This agent holds great promise for the treatment of heart failure patients.

Role of thromboxane A2 in the cardiovascular response to intracoronary C5a.

Intracoronary administration of complement component C5a induces transient decreases in coronary blood flow and regional left ventricular segment shortening, associated with intramyocardial granulocyte trapping. We evaluated the influence of a cyclooxygenase inhibitor (acetylsalicylic acid, n = 8) or a thromboxane A2/prostaglandin H2 receptor antagonist (SQ29548, n = 6) on these C5a-induced cardiovascular responses. Open-chest anesthetized pigs were instrumented to monitor heart rate, arterial blood pressure, left anterior descending coronary blood flow, regional left ventricular segment shortening, and dP/dt. Oxygen content, lactate concentration, leukocyte count, and thromboxane B2, the stable metabolite of thromboxane A2, were measured in arterial and regional coronary venous blood. Repetitive injections of intracoronary C5a (500 ng) given 60 minutes apart showed no tachyphylaxis of the hemodynamic response. However, tachyphylaxis was seen in coronary blood flow changes when injections were spaced 30 minutes apart. An increase in myocardial oxygen extraction and lactate production was observed after intracoronary C5a. Administration of acetylsalicylic acid (50 mg/kg i.v.) attenuated C5a-induced decreases in coronary blood flow (-8 +/- vs. -3 +/- 1 ml/min) and regional left ventricular segmental shortening (-10 +/- 3% vs. -2 +/- 1%) and blocked the maximal increase in coronary venous thromboxane B2 (2.0 +/- 0.1 vs. 0.2 +/- 0.1 pmol/ml plasma). Furthermore, SQ29548 (30 micrograms/kg/min) reduced C5a-induced changes in coronary blood flow (-13 +/- 2 vs. -4 +/- 2 ml/min) and segmental shortening (-14 +/- 2% vs. -3 +/- 1%). Neither cyclooxygenase inhibition nor thromboxane A2/prostaglandin H2 antagonism blocked the decrease in coronary venous granulocyte count.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of adenosine and prostacyclin in coronary flow regulation in healthy man

Coronary flow regulation in man is incompletely understood. We addressed the hypothesis that endogenous adenosine and prostacyclin (PGI2) affect basal coronary tone and/or the coronary flow response to increased myocardial work. In healthy volunteers coronary sinus flow and cardiac oxygen extraction were measured at rest and during leg exercise (40-50 W), before and after i.v. administration of theophylline (to block adenosine receptors) and oral administration of ibuprofen (to inhibit prostaglandin synthesis). Before drug, the basal coronary flow was 118 +/- 23 ml min-1 and the cardiac extraction of oxygen 122 +/- 3 ml l-1. Leg exercise elevated coronary flow by 89 +/- 16 ml min-1. Theophylline, at a dose blocking the coronary flow response to dipyridamole (an adenosine-dependent mechanism), induced a moderate increase in myocardial oxygen extraction (by 11%, P less than 0.05), but failed to affect either the basal coronary flow (105 +/- 16 ml min-1) or the increase during exercise (88 +/- 25 ml min-1). Ibuprofen inhibited the urinary excretion of PGI2 metabolite by about 90%, but did not affect basal coronary tone or the coronary response to exercise. These data indicate that endogenous adenosine is of limited importance for normal coronary regulation in man, and that PGI2 has no effect.

Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy.

When angina occurs in patients with hypertension, it is usually attributed to coronary artery disease or left ventricular hypertrophy. To determine the contribution of coronary microvascular abnormalities to angina in patients with hypertension, we evaluated hypertensive patients without coronary artery disease or left ventricular hypertrophy by measuring the coronary responses to rapid atrial pacing before and after administration of ergonovine. We compared 12 hypertensive patients who had pacing-induced angina with 13 normotensive subjects without such angina. The two groups had similar coronary flow (in the great cardiac vein) at rest; however, pacing increased coronary flow less in hypertensive patients with angina than in normotensive subjects (48 vs. 83 percent; P = 0.05). In the hypertensive patients with angina, pacing after ergonovine increased coronary flow by only 32 percent (as compared with 48 percent before ergonovine; P less than 0.05) and decreased coronary resistance by 15 percent (as compared with 28 percent before ergonovine; P less than 0.05), indicating the presence of ergonovine-induced vasoconstriction. In normotensive subjects, in contrast, cardiac pacing after ergonovine increased coronary flow by 112 percent (P less than 0.001), and its effect on coronary resistance was not different from that of pacing before ergonovine. The hypertensive patients with angina had a significant increase in myocardial oxygen extraction during pacing after ergonovine and less of an increase in myocardial lactate consumption - a response consistent with the presence of myocardial ischemia. Thus, angina in hypertensive patients without epicardial coronary disease may be caused by myocardial ischemia, which appears to be due to an abnormally elevated resistance of the coronary microvasculature.

Histamine-induced changes in coronary circulation and myocardial oxygen consumption: influences of histamine receptor antagonists.

The effects of histamine and selected H1 and H2 histamine receptor antagonists on cardiac inotropic and chronotropic activity, coronary perfusate flow (CPF), and myocardial oxygen consumption (MVO2) were studied in isolated guinea pig hearts perfused at constant pressure. Data were collected at the end of a 3-min infusion period at steady state. Cardiac performance increased significantly whereas CPF decreased during histamine infusion. MVO2 remained constant owing to a significant increase in myocardial oxygen extraction. Diphenhydramine attenuated the coronary vasoconstriction but potentiated the positive inotropic response. Cimetidine attenuated the inotropic and chronotropic responses but had no effect on coronary vasoconstriction. In combination, the histamine antagonists attenuated the changes in heart rate, contractility, and CPF. The histamine-induced increase in myocardial oxygen extraction was accompanied by a significant increase in MVO2 in the presence of diphenhydramine. The ratio of the change in oxygen extraction to the change in oxygen consumption caused by histamine was significantly increased by diphenhydramine. This compensated for a histamine-induced decrement in the ratio of the change of CPF to the change in oxygen consumption. Cimetidine had no effect on the changes in coronary flow, oxygen consumption, or the above ratios. Thus, histamine causes direct coronary vasoconstriction via an H1 receptor mechanism, cardiac positive inotropy by an H2 receptor mechanism, and cardiac positive chronotropy by combined H1 and H2 mechanisms. In the presence of a histamine-induced decrease in myocardial oxygen supply, increments in oxygen demand are met by increased oxygen extraction.

Coronary artery hemodynamics in conscious dog during cardiac tamponade.

We tested the hypothesis that coronary artery blood flow is sufficient to meet myocardial requirements throughout cardiac tamponade in a conscious euvolemic canine model recovered from surgery. Seven mongrel dogs were chronically instrumented to measure ascending aortic blood flow (electromagnetic flowmeter); intrapericardial, right atrial, and aortic blood pressures; regional myocardial blood flow (radionuclide labelled microspheres); and myocardial consumption of lactate, pyruvate, and oxygen. Data were collected during progressive cardiac tamponade induced by intrapericardial saline infusion to the point of hemodynamic decompensation. Decompensated cardiac tamponade (DCT) was defined as a decline in mean aortic blood pressure to 70% of the level present when the pericardial space was drained of fluid (baseline) and was produced in all animals within 25 minutes. Cardiac tamponade caused a continuous decline in coronary artery blood flow from 1.26 +/- 0.35 (baseline, mean +/- SD) to 0.53 +/- 0.15 ml/min/g (DCT, p less than 0.01), which was associated with a decrease in myocardial oxygen consumption from 1.26 +/- 0.35 (baseline) to 0.74 +/- 0.27 ml/min/g (DCT, p less than 0.05) and a slight increase in myocardial oxygen extraction from 71 +/- 3 (baseline) to 81 +/- 4% (DCT, p less than 0.05). This change in oxygen extraction occurred because of both an increase in arterial and a decrease in coronary venous oxygen content. At all degrees of cardiac tamponade, the lactate-pyruvate ratio did not change significantly from baseline (7.56 +/- 2.31), there was no evidence of lactate production, and the normal endocardial to epicardial blood flow ratio present at baseline (1.41 +/- 0.23) was preserved.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of atrial fibrillation on myocardial blood flow and energetics.

The changes produced by atrial fibrillation on myocardial blood flow and energetics are unclear. Accordingly, the effects of atrial fibrillation on myocardial blood flow and oxygen consumption were studied in 18 anesthetized dogs. With atrial fibrillation cardiac output and mean aortic pressure declined. Although average myocardial blood flow and oxygen consumption did not change, the alterations in these variables correlated strongly (r = 0.95, P less than 0.01). Moreover, myocardial blood flow changes correlated with those of tension time index and peak dp/dt (r = 0.64, P less than 0.05). Distribution of left ventricular regional flow remained uniform irrespective of the directional changes in blood flow. However, average left ventricular inner to outer wall flow ratio declined and myocardial oxygen extraction increased. Thus, with atrial fibrillation, myocardial blood flow does not change in a consistent fashion, although myocardial blood flow still reflects myocardial oxygen demand. Relative hypoperfusion of subendocardium and an increase in myocardial oxygen extraction suggest that with atrial fibrillation the myocardial blood flow response is abnormal.

Alpha-adrenergic-mediated reduction in coronary blood flow secondary to carotid chemoreceptor reflex activation in conscious dogs.

We examined the late coronary vascular response to carotid chemoreceptor reflex activation in normal, conscious dogs instrumented for the measurement of right main and left circumflex coronary artery blood flows, arterial and right ventricular pressures, and arterial and coronary sinus blood gases and O2 contents. With heart rate held constant by electrical stimulation, and with respiration controlled or allowed to vary spontaneously, carotid chemoreceptor reflex activation (induced by intracarotid nicotine) elicited a striking biphasic coronary vascular response characterized by an early dilation (previously described) and a late constriction. For example, with respiration controlled and with the autonomic nervous system intact, carotid chemoreceptor reflex activation resulted in a late increase in arterial pressure (19 +/- 4%; P less than 0.002), absolute reductions in right main (24 +/- 4%; P less than 0.002), and left circumflex (12 +/- 2%; P less than 0.004) coronary blood flows, and increases in right (62 +/- 13%; P less than 0.002) and left (26 +/- 3%; P less than 0.0001) coronary resistances. This carotid chemoreceptor reflex activation-induced late coronary constriction was also associated with a concomitant increase in myocardial oxygen extraction, i.e., arterial oxygen content remained constant, while coronary sinus oxygen content decreased (19 +/- 6%; P less than 0.04). Neither propranolol nor atropine had any significant effect on the magnitude of the right coronary constriction. However, both the absolute reduction in right coronary blood flow and increase in right coronary resistance were abolished by phentolamine. Furthermore, either total cardiac denervation or adrenalectomy significantly attenuated (P less than 0.01) carotid chemoreceptor reflex activation-induced reductions in right coronary blood flow and increase in right coronary resistance. We conclude that, with autonomic nervous system activity intact, carotid chemoreceptor reflex activation can elicit an absolute reflexly mediated reduction in coronary blood flow in the normal, conscious dog, despite an increase in arterial pressure. The mechanism of this vasoconstriction involves alpha-adrenergic receptor stimulation mediated by both cardiac sympathetic nerves and circulating catecholamines.

Adrenergic coronary vasoconstriction in the presence of coronary stenosis in the dog.

Previous studies have demonstrated competition between sympathetic alpha receptor-mediated coronary vasoconstriction and local metabolic vasodilation during sympathetic activation. The present study tested if this competition also occurs in the presence of coronary stenosis. In closed-chest dogs, the left coronary artery was cannulated, and blood flow from the aorta was restricted by a moderate stenosis (70% area reduction). Intracoronary norepinephrine infusion produced coronary vascular alpha receptor and myocardial beta receptor activation. Norepinephrine infusion was repeated following alpha receptor blockade with phenoxybenzamine (0.25 mg/kg, injected into the coronary artery). Myocardial oxygen and lactate extraction, coronary sinus blood oxygen tension, and coronary resistance were compared at equal levels of myocardial oxygen consumption before and after coronary alpha receptor blockade. In the presence of coronary stenosis, intracoronary norepinephrine infusion decreased coronary sinus oxygen content and increased myocardial oxygen extraction. At comparable myocardial oxygen consumptions coronary vascular resistance was greater with alpha receptors intact than after alpha receptor blockade. The increase in myocardial oxygen extraction was prevented by alpha receptor blockade. We conclude that a sympathetic alpha receptor-mediated coronary vasoconstrictor influence operates, even in the presence of coronary stenosis, to limit oxygen delivery to the heart and increase myocardial oxygen extraction up to the point of cardiac failure, but that this vasoconstrictor effect does not result in net myocardial lactate production.

The Effects of Acute Induced Hypoxia on Coronary Circulation. Hypoxia and Cardiac Oxygen Metabolism

Coronary sinus catheterization was performed on men with normal heart and those with coronary sclerosis, and on dogs with normal heart and those with coronary vascular lesions. Effects of hypoxia upon cardiac oxygen metabolism, especially on regulation of the coronary blood flow were studied. Results were as follows : 1) with regard to the rate of increase in coronary blood flow due to hypoxia, there was no statistical significance of differences between the group of normal men and that of coronary sclerosis. In dogs, however, the rate of increase was lower in dogs with coronary vascular lesions than in the normal dogs.2) In men, there was inverse correlation between the rate of decrease in arterial oxygen saturation and the rate of increase in coronary blood flow due to hypoxia.3) As for the rate of decrease in coronary sinus oxygen tension due to hypoxia, there was no statistical significance of differences between the two groups of men. In dogs, the rate of decrease was less in the group of coronary lesions than in the normal. The rate of decrease in arthrio-coronary venous difference due to hypoxia was less in the dogs with coronary lesions than in normal dogs, though in men there was no statistical significance between the two groups.4) In resting state there seemed to be an inverse correlation between the coronary blood flow and the arterio-coronary venous oxygen difference. The correlation became more apparent when hypoxic state was induced. In the coronary groups of both men and dogs, the increase in coronary blood flow was not so much as it should be expected from the decrease in the arterio-coronary venous oxygen difference.5) In men, there was good inverse correlation between coronary sinus oxygen tension and myocardial oxygen extraction coefficient in hypoxic state, as well as in resting state.6) In hypoxic state in men, release of potassium from myocardium was noted in 6 of 9 cases with coronary sclerosis. In 5 of these 6, there was an increase in myocardial oxygen extraction coefficient.On the contrary, myocardial oxygen extraction coefficient was decreased or not changed in those in which there was measurable myocardial uptake of potassium or no arterio-coronary venous potassium difference.

The effect of hexamethonium bromide upon coronary flow, cardiac work and cardiac efficiency in normotensive and renal hypertensive dogs.

Hexamethonium bromide in normotensive and renal hypertensive dogs resulted in significant reductions in arterial blood pressure, cardiac output and cardiac work. The decrease in cardiac output relative to that in blood pressure suggests that the blood pressure reduction was largely due to the decrease in cardiac output. There was a decrease in coronary flow accompanied by an increase in myocardial oxygen extraction of such Degrees that cardiac oxygen consumption remained unchanged. Since myocardial oxygen consumption remained unchanged despite the decrease in cardiac work the calculated cardiac efficiency was decreased.