Reduction In Coronary Blood Flow Research Articles

Cardiac PET: microcirculation and substrate transport in normal and diseased human myocardium.

The development and validation of quantitative assay techniques for the noninvasive study of human myocardium has opened up new avenues for the study of the normal and diseased human heart's physiology. Measurements of regional myocardial blood flow, which delineates nutrient rather than coronary blood flow, has enabled the exploration of the coronary microcirculatory physiology under normal and abnormal conditions. It permits the study of pharmacologic effects and of cardiovascular disease on the coronary resistance and capillary perfusion. If combined with metabolic assay techniques, the transcapillary exchange of substrates in oxygen can be quantified and changes imposed by physiologic interventions and substrate metabolism being measured. These study approaches further serve to characterize changes in response to reductions in coronary blood flow as well as altered states of potentially reversible contractile function. It is anticipated that further studies with PET will clarify at the microcirculatory level the changes associated with ischemia, post-ischemic stunning and myocardial hibernation. Further, it offers the possibility to measure potentially beneficial effects of therapeutic interventions or, alternatively, to provide a rationale for novel therapeutic approaches.

Involvement of nitric oxide in coronary vascular responses to 5-hydroxytryptamine in the anaesthetized greyhound.

1. The effect of the intracoronary (i.c.) injection of 5-hydroxytryptamine (5-HT; 0.1-1.0 micrograms/kg) was examined before and after inhibition of nitric oxide (NO) synthesis with N-nitro-L-arginine (NOLA; 5 mg/kg i.c.) in nine anaesthetized greyhounds. Before administration of NOLA, 5-HT increased coronary blood flow (CBF) but decreased large coronary artery diameter indicating simultaneous dilatation of resistance vessels and constriction of large arteries. 2. The administration of NOLA significantly decreased large coronary artery diameter and increased systemic arterial pressure. There was no significant effect on coronary vascular resistance or heart rate. In the presence of NOLA, the 5-HT-induced constriction of the large coronary artery was enhanced and the dilatation of the resistance vessels was reduced. In addition there was a secondary reduction in CBF, a response that was not observed before NOLA treatment. 3. The response to NOLA suggests that a basal release of NO is important in the regulation of coronary and systemic vascular tone. Nitric oxide is an important mediator of coronary vasodilator responses to 5-HT, and in addition the release of NO modulates 5HT-induced constriction of large coronary arteries.

Regional Vasodilating Properties of Isoflurane in Stunned Swine Myocardium

Studies about the coronary vasodilating properties of isoflurane indicate that this drug induces coronary vasodilation. No work has examined isoflurane-induced vasodilation in known stunned myocardium. This study was conducted to determine isoflurane's coronary vasodilation potency in stunned myocardium and to compare the results obtained with normal myocardium. We determined the vasodilating properties of isoflurane in regionally perfused swine myocardium. Six domestic swine were anesthetized with pentobarbital and fentanyl. The left anterior descending artery (LAD) was cannulated and perfused with blood drawn from the carotid artery and passed thorough a membrane oxygenator. LAD arterial flow was controlled by a calibrated roller pump with continuous digital readout, and LAD arterial pressure was measured directly. The anterior interventricular vein was cannulated and dimension crystals placed in the LAD-perfused myocardium. Myocardial stunning was induced by reduction of coronary blood flow (CBF) to 30% of control flow for 20 minutes. One hour after reperfusion, the vasodilatory response to 0%, 1%, and 2% isoflurane administered via the membrane oxygenator was determined and compared to maximum vasodilatation produced by regional intracoronary administration of adenosine. Systemic blood pressure and heart rate remained constant throughout the experiment. At 2% isoflurane, systolic shortening and regional myocardial oxygen consumption decreased 53% and 17%, respectively. The same concentration increased CBF by 33% and reduced coronary vascular resistance (CVR) by 25%. One percent isoflurane affected neither CBF nor CVR. Regional coronary administration of adenosine produced much greater changes in CBF (+509) and CVR (-89.5%).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of nitroglycerin on ornipressin (POR 8)-induced systemic and cardiovascular circulatory changes. An animal experimental study

Local infiltration of ornipressin (OR) is widely used to reduce intraoperative bleeding. However, OR can cause severe side effects including hypertension, deterioration of cardiac performance and coronary vasoconstriction. Suggestions for therapy of haemodynamic side effects of OR include the use of nitroglycerin (TNG). This experimental study was designed to investigate the influence of TNG on changes of systemic haemodynamics and coronary perfusion produced by i.v. administration of OR. 16 anesthetized closed-chest mongrel dogs were studied. Anaesthesia was administered using N2O/O2 (FiO2: 0.33) and enflurane (1Vol%ET). Saline-filled catheters were used to measure intravascular pressures. Left ventricular pressure change (dP/dt) was monitored with a cathetertip manometer. Cardiac output (CO) was determined using thermodilution, myocardial blood flow (MBF) using a Pitot catheter. Baseline values were taken (control) followed by a bolus injection of 0.03 U/kg OR i.v. The dogs were randomly assigned to two groups. Group I (Gr.I) (n = 9) received OR only and group II (Gr.II) (n = 7) was treated by infusion of 4 mg/kg.min TNG 7 to 30 min after injection of OR. Haemodynamic and cardiovascular changes were measured for 60 min at fixed time intervals. In both groups (Gr.I; Gr.II) OR produced significant changes in systolic (APS) (+29%; +32%) and diastolic (APD) (+47%; +37%) aortic pressure, cardiac index (CI) (-33%; -33%), peripheral vascular resistance (TPR) (+116%); +104%), stroke volume index (SVI) (-23%; -34%), ejection fraction (EF) (-29%; -29% endsystolic volume (ESV) (+39%; +45%) and left ventricular enddiastolic pressure (LVEDP) (+50%; +66%). Myocardial blood flow (MBF) was reduced by 30% and 29% respectively and coronary vascular resistance (CVR) was increased (+97%; +84%). Coronary venous O2 saturation (SO2cor) decreased to 19% and 20% resulting in high AVDO2cor. As compared to Gr.I the administration of TNG resulted in significant decreases of APS, APD, TPR, ESV and LVEDP close to control values. However, administration of TNG did not effect MBF, CVR, SO2cor and AVDO2cor. Systemic haemodynamic effects of OR include hypertension due to peripheral vasoconstriction and impaired cardiac performance resulting in reduced cardiac output with low EF, high ESV and LVEDP. Concomitantly, OR produces coronary constriction with a distinct fall in MBF. Thus, myocardial oxygen balance is impaired. With TNG peripheral vascular effects of OR can be abolished but there is no effect of TNG on OR-induced reduction of coronary blood flow. Therefore, use of TNG for treatment of cardiovascular complications following the administration of OR must be considered with extreme caution.

Cardiogenic shock induced by cocaine in swine with normal coronary arteries.

The aim was to test the hypothesis that acute intravenous cocaine administration can cause coronary microvascular constriction culminating in myocardial ischaemia and cardiogenic shock. Systemic haemodynamic variables and coronary blood flow were measured in 14 Yorkshire swine at baseline and following intravenous administration of 1, 3, and 10 mg.kg-1 of cocaine. Epicardial coronary artery diameter was measured from coronary arteriograms and coronary flow velocity was recorded with a Doppler flow wire. Cocaine produced a decrease in mean arterial pressure (65%), cardiac output (80%), and stroke volume (80%), and an increase in pulmonary artery diastolic pressure (60%). Although coronary blood flow decreased by 70%, epicardial coronary cross sectional area decreased by only 37-45%. Pretreatment with prazosin did not abolish the decrease in coronary blood flow. After administration of 10 mg.kg-1 of cocaine, five of 14 animals developed myocardial ischaemia and cardiogenic shock, culminating in ventricular fibrillation and death. In anaesthetised Yorkshire swine, cumulative intravenous doses of cocaine caused a significant reduction in coronary blood flow resulting in myocardial ischaemia, which cannot be attributed to epicardial vasoconstriction alone. This suggest that cocaine-induced coronary ischaemia may result from microvascular constriction, which is only partially prevented by alpha 1 blockade. In addition, direct toxic effects of cocaine on the myocardium may also contribute to the development of cardiogenic shock.

Zatebradine, a specific bradycardic agent, enhances the positive inotropic actions of dobutamine in ischemic myocardium

Objectives. This investigation determined whether attenuation of the tachycardia produced by dobutamine administration would improve perfusion and function distal to a severe coronary artery stenosis.Background. Tachycardia adversely affects perfusion and function distal to a coronary artery stenosis. It is not known whether a specific bradycardic agent can improve blood flow and function in an ischemic zone during administration of dobutamine.Methods. The effects of dobutamine (2, 5 and 10 μg/kg body weight per min) alone and in combination with zatebradine (0.5 mg/kg), a specific bradycardic agent, on hemodynamic status, segment shortening (ultrasound length transducers) and myocardial perfusion (microspheres) were studied in anesthetized dogs with severe left circumflex coronary artery stenosis.Results. A 50% reduction in left circumflex coronary artery blood flow (58 ± 4 to 29 ± 2 ml/min [mean value ± SEM]) produced a decrease in systolic shortening in the ischemic zone. Only a dose of dobutamine that did not elevate heart rate (2 μg/kg per min) produced an increase in segment shortening in the ischemic zone. High doses of dobutamine (10 μ/kg per min) caused an increase in heart rate without improvement in function and a reduction in the subendocardial/subepicardial flow ratio (0.74 ± 0.06 to 0.48 ± 0.05). Zatebradine administered in the presence of dobutamine caused a decrease in heart rate, an increase in subendocardial/subepicardial blood flow ratio (0.48 ± 0.05 to 0.78 ± 0.09) and allowed an increase in ischemic zone segment shortening. When normalized for changes in heart rate, ischemic zone subendocardial flow increased by 123 ± 41% (0.39 ± 0.09 to 0.71 ± 0.12 ml/100 g per beat). Atrial pacing abolished the effects of zatebradine.Conclusions. The present data suggest that the perfusion-contraction matching that accompanies a decrease in heart rate results in enhancement of inotropic stimulation of an ischemic zone. The actions of zatebradine are related to an increase in subendocardial blood flow per beat that allows improvement of regional contractile function.

Cardiac adaptation to one hour of mild regional low flow ischaemia in the pig

The aim was to determine the cardiac consequences of a 1 h period of mild regional low flow ischaemia in the pig heart. In eight pentobarbitone sodium anaesthetised pigs (weight range 23-38 kg), the mid left anterior descending coronary artery was constricted by a hydraulic occluder. Transmural coronary blood flow (Doppler flowmetry) was reduced to approximately 70% of control for 1 h. After complete release of the occluder cardiac function was monitored for 2 h. Left ventricular segment lengths were continuously recorded in the region subjected to low flow ischaemia and in a control region supplied by the circumflex artery. After 1 h with a 28(SEM 3)% reduction in coronary blood flow, the systolic shortening index decreased from 100 to 68(7) (p < 0.001). This index transiently normalised upon reperfusion. Thereafter it declined, reaching a nadir of 72(5) at 1.25 h of reperfusion, and subsequently improved to 82(6) at 2 h of reperfusion. Normalisation of local myocardial function appears during the first minutes of reperfusion after 1 h of mild low flow ischaemia and is followed by a period of stunning.

Sodium Nitroprusside, an Endothelium-Derived Relaxing Factor Congener, Increases Platelet Cyclic GMP Levels and Inhibits Epinephrine-Exacerbated In Vivo Platelet Thrombus Formation in Stenosed Canine Coronary Arteries

Sodium nitroprusside (SNP), a nitrosovasodilator, increases platelet cyclic GMP levels and inhibits platelet activity in vitro. The antiplatelet properties of SNP are not well established in vivo, however, and consequently are not appreciated by clinicians. In our established model of mechanically stenosed canine coronary arteries (MSCA) with intimal damage, periodic acute platelet thrombus formation (APTF) occurs, followed by embolization distally, which then causes cyclic flow reductions (CFRs) in coronary blood flow. Aspirin (ASA) abolished platelet-mediated CFRs in our model, but they recur when epinephrine (EPI) is infused (0.2 microgram/kg/min). SNP was given continuously intravenously (i.v.) to 17 dogs with MSCA; CFRs were abolished in all dogs by SNP at 4.4 +/- 2.7 micrograms/kg/min (mean +/- SD). Mean arterial blood pressure (MAP) decreased by 19 +/- 9 mm Hg (p < 0.001) from control, while heart rate (HR) increased 35 +/- 20 beats/min (p < 0.001). Platelet cyclic GMP levels were 2.9 +/- 1.1 pmol/10(8) platelets before SNP infusion, and increased to 4.3 +/- 1.6 pmol/10(8) platelets (p < 0.05) when CFRs were abolished. CFRs were not renewed during the continued SNP infusion when EPI was infused at 0.2 microgram/kg/min for 20 min in 11 dogs, but CFRs returned within 5-25 min after the SNP infusion was terminated. The return of CFRs occurred together with a decrease in platelet cyclic GMP levels to 3.3 +/- 1.4 pmol/10(8) platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term and long-term role of platelet activating factor as a mediator of in vivo platelet aggregation.

Platelet activating factor (PAF) is a phospholipid released upon stimulation by a variety of cells and has been implicated in several pathophysiological events such as asthma and inflammatory diseases. However, although the ability to aggregate platelets in vitro was the first biological activity ascribed to PAF, its role in contributing to the in vivo formation of arterial thrombi has not been thoroughly clarified. Intravascular platelet aggregation was initiated in two different animal models of arterial stenosis and endothelial injury. An external constrictor was positioned around rabbit carotid arteries and canine coronary arteries. After placement of the constrictor, a typical pattern of flow developed in the stenotic vessels. This pattern of flow, characterized by progressive reductions of carotid or coronary blood flow followed by spontaneous or induced restorations of flow (cyclic flow variations, CFVs), is related to recurrent platelet aggregation at the site of the stenosis followed by dislodgment of the thrombus. After observing CFVs for 30 minutes, BN52021 (up to 1.2 mg/kg), a potent and selective PAF antagonist, was given intravenously to rabbits (n = 12) and dogs (n = 10). BN52021 completely inhibited CFVs in 10 of 12 rabbits, whereas it was relatively ineffective in abolishing CFVs in dogs (only 2 of 10 animals inhibited). This different effect of BN52021 was not explained by too small a dose of the drug to achieve a complete blockade of PAF receptors in dogs, since ex vivo platelet aggregation was completely inhibited in both rabbits and dogs in response to exogenous PAF at concentrations up to 10(-5) mol/L. In a second group of 10 dogs, the hypothesis that PAF may become an important mediator of CFVs in dogs only several hours after endothelial injury was tested. After 30 minutes of baseline CFVs, these animals received a bolus of BN52021 up to 1.2 mg/kg. After this treatment, CFVs were completely abolished in 2 of 10 animals. The remaining 8 dogs were followed for an additional 8-hour period, at the end of which a second bolus of BN52021 was given. At this time, BN52021 was effective, as CFVs were abolished in 6 of 8 animals. These effects of BN52021 at 8 hours were not the consequence of a cumulative dose of the compound, since ex vivo platelet aggregation in response to PAF returned to baseline values immediately before administering the second dose. To identify possible sources of PAF other than aggregating platelets at the site of arterial stenosis, dogs in a third group were killed after 30 minutes (n = 7) and after 8 hours (n = 8) of CFVs. Histological sections of the stenotic coronary artery showed a marked leukocyte infiltration in these arterial segments after 8 hours of CFVs, whereas sections from dogs killed after 30 minutes showed only moderate or no infiltration. These data demonstrate that PAF plays an important role as a mediator of platelet aggregation in vivo in rabbits and dogs. In the canine model, PAF appears to become more important after leukocyte infiltration of the arterial wall, as it may contribute to initiating enough platelet activation to lead to cyclic flow variations at sites of arterial stenosis and endothelial injury. Data from the present study suggest that PAF antagonists may be used as antiplatelet agents.

The role of heart rate in myocardial ischemia and infarction: Implications of myocardial perfusion-contraction matching

The pathophysiology of myocardial ischemia traditionally has been attributed to disturbances of oxygen demand, as observed in classic effort-induced angina pectoris, or to a primary disruption of coronary blood supply, as in unstable angina or acute myocardial infarction. Laboratory research eliciting various types of perfusion-contraction matching has challenged such a historical distinction between supply and demand-induced determinants of myocardial ischemia. A growing number of clinical studies analyzing the role of heart rate in the course of coronary heart disease suggest the possibility that a common perfusion-contraction scheme may underlie these diverse clinical manifestations. During experimental myocardial ischemia, produced by a low coronary blood flow, regional perfusion-contraction matching exists in which the energy demands and regional contraction are reduced to match the diminished myocardial substrate supply. Heart rate is a major factor influencing transmural blood flow distribution and regional function, because when coronary vasodilation is maximal there is an inverse relation between the level of heart rate and subendocardial perfusion. Thus, in experimental regional ischemia, increasing heart rate reduces subendocardial flow and contraction, whereas slowing of heart rate causes improvement of contraction associated with increased subendocardial blood flow, accompanied by a decrease in outer wall blood flow. Also, “interventricular steal” of blood from the left ventricle by the right ventricle during ischemia can be reversed by slowing the heart rate in the presence of regional ischemia. Improvement of contraction by heart rate slowing is more than would be expected on the basis of the increase in subendocardial perfusion alone, reflecting a combination of decreased oxygen demand and increased oxygen supply, and separate curves relating blood flow per minute to contractile function are observed at different heart rates. However, when perfusion is normalized for heart rate by expressing subendocardial blood flow in units per beat, a single relation is observed at different heart rates. This observation supports the concept of a close coupling between subendocardial blood flow per beat and regional performance, or perfusion-contraction matching, during various levels of ischemia. Based on these principles, it can be predicted that exercise-induced regional ischemia in the presence of coronary stenosis will be attenuated by several mechanisms when heart rate is slowed using either a β-blocking agent, or a specific bradycardic drug. In this setting, an exercise-induced decrease in subendocardial flow is offset after such therapy by a substantial increase in subendocardial perfusion (augmentation of subendocardial blood per beat) associated with decreased subepicardial blood flow and improved regional contraction in the ischemic zone. In various clinical settings, it seems likely that increases in heart rate in patients with coronary disease are associated not only with increases of myocardial oxygen demand, but also with decreases in subendocardial blood flow, as evidenced by the close correlation between diastolic perfusion time and anginal threshold during exercise. β-Blockade and calcium antagonists that slow heart rate reduce the number of episodes of transient ischemia in patients with stable angina pectoris, in whom silent ischemic episodes observed with ambulatory ECG monitoring are often associated with an increase in heart rate. In normal human subjects, tachycardia produces a progressive increase of coronary blood flow and flow-mediated dilation of the epicardial coronary arteries. However, in patients with an atherosclerotic lesion, reduction in coronary blood flow occurs together with a progressive loss of luminal area during exercise which is prevented by β-blockade, supporting the perfusion-contraction matching concept. In the setting of acute myocardial infarction, heart rate is an independent predictor of mortality, and the level of heart rate elevation at hospital admission or during the hospital stay is significantly correlated with early as well as 1-year mortality. A beneficial effect on mortality incidence from acute myocardial infarction of β-blockers has been reported in a number of larger trials, and this benefit is significantly related to the reduction in the heart rate produced by these agents. These laboratory and clinical findings emphasize the key role of heart rate in perfusion-contraction matching and in a number of the clinical manifestations of coronary heart disease.

In Vivo Deleterious Effects of a Right Shift of the HbO2 Curve during Hypoxemia

We investigated the influence of a right shift of the oxyhemoglobin dissociation curve on tissue oxygenation in two groups of anesthetized rabbits subjected to short periods of graded hypoxia: Group 1 (n = 5) with elevated P50 due to increased RBC 2,3-diphosphoglycerate and adenosine triphosphate and Group 2 (n = 5) with normal P50 . Hemoglobin fell progressively in all animals due to blood letting for necessary measurements. During 16% inspired O2 (FIO2), both groups remained stable. During 13% FIO2, arterial pO2 was the same in both groups, but only in Group I did it fall below the crossover point (C.O.P.), which was raised by the high P50 . Arterial pH and arterial-venous O2 content difference remained within the normal range in both groups throughout the experiment. During 13% FIO2, animals with high P50 showed a fall in cardiac output and oxygen consumption while animals with normal P50 remained stable. We postulate that when systemic O2 content is sufficiently reduced and tissue O2 extraction is maximal, the O2 needs of the myocardium perfused with a pO2 below the C.O.P. cannot be met: under these conditions cardiac output and systemic O2 consumption fall, presumably due to a reduction in coronary blood flow.

Hypoperfusion of the myocardium relative to myocardial metabolism during delayed coronary constriction

The aim was to test the hypothesis that the myocardium becomes hypoperfused, relative to its metabolic demands, during the delayed coronary constriction which is observed following termination of a period of sympathetic stimulation. This was tested by beat by beat analysis of the ratio of coronary blood flow to the product of heart rate and systolic blood pressure (HR x SBP), an index of myocardial metabolism, in acutely instrumented open chest canine preparations, before, during, and after direct electrical stimulation of the left stellate ganglion. Myocardial metabolism increased in response to stellate stimulation, as evidenced by increases in heart rate, aortic blood pressure, and HR x SBP. These were accompanied by increased blood flow and decreased vascular resistance in the left anterior descending coronary artery. Delayed coronary constriction, defined as the period with the lowest coronary blood flow observed after the end of the stimulation, occurred 1 to 3 min after stimulation was terminated and was characterised by recovery of heart rate, blood pressure, HR x SBP, and coronary blood flow toward control levels, while coronary vascular resistance overshot to above control levels. The ratio of coronary blood flow to HR x SBP fell progressively in the poststimulation period to significantly less (mean 0.715, range of +/- 1 SEM 0.638 to 0.800, p < 0.05) than control (1.0, by definition) in experiments performed with partial prestenosis of the left anterior descending coronary artery. In a selected subgroup of observations with a mean reduction in coronary blood flow during delayed coronary constriction comparable to that reported previously, the flow/metabolism ratio was even lower (mean 0.239, range of +/- 1 SEM 0.202 to 0.284). The phenomenon of delayed coronary constriction clearly involves a mismatch between myocardial supply and demand: coronary blood flow becomes inappropriately low for the prevailing level of myocardial metabolism.

Effect of flow reduction on coronary blood flow heterogeneity.

The purpose of this study was to test the hypothesis that under reduced flow conditions, spatial heterogeneity (segment-to-segment variability) of myocardial blood flow would be inversely proportional to the rate of perfusion and that vasoconstriction would alter this relationship in anesthetized open-chest dogs. A carotid-left circumflex coronary artery shunt was created. Coronary blood flow determinations employed the radioactive microsphere technique. Fifty tissue samples were obtained from the affected left ventricle, including subepicardial and subendocardial samples. The coefficient of variation (CV = 100 x SD/mean), an index of spatial heterogeneity, was computed. Flows were obtained under three separate conditions: control, a 50% flow reduction in the circumflex artery, and vasopressin infusion, in which the administered dose reduced circumflex artery flow by 50%. The within-animal CV increased from a control of 18 +/- 9 to 45 +/- 25 with partial occlusion and 46 +/- 18 with vasopressin. No significant differences in CV were found between the two reduced flow conditions. A significant linear relationship between CV and mean coronary flow was found (r = 0.51, P < 0.001) over the entire range of flows studied (CV = -0.34*flow + 50.91) for control, 50% occlusion, and vasopressin treatment. The correlation was significantly improved (r = 0.69) using the equation CV = (1319.06/flow) + 4.44. Thus, the relative heterogeneity of coronary blood flow increased with reductions in coronary blood flow, regardless of the means of flow reduction.

Comparison of single-photon emission computed tomographic (SPECT) myocardial perfusion imaging with thallium-201 and technetium-99m sestamibi in dogs

Objectives. The purpose of the present study was to compare single-photon emission computed tomographic (SPECT) myocardial images of technetium-99m (Tc-99m) sestamibi and thallium-201 (Tl-201) isotopes in the same dog undergoing partial coronary occlusion during pharmacologic vasodilation.Background. To date, no controlled study has been reported comparing SPECT Tc-99m sestamibi with SPECT T1-201 imaging during stress with anatomic and physiologic standards.Methods. Mongrel dogs were anesthetized with chloralose and instrumented to record left anterior descending coronary blood flow and aortic pressure. Partial coronary occlusion with a hydraulic cuff reduced coronary vascular conductance, which is equal to the coronary blood flow normalized to aortic pressure during peak vasodilation with intravenous adenosine. Each dog received 5 mCi of T1-201, then 30 mCi of Tc-99m sestamibi during partial coronary occlusion at peak vasodilation. Tomographic myocardial imaging was performed in a 180 ° anterior arc scan for 33.5 min, first with T1-201, and later, without moving the dog, for 33.5 min with Tc-99m sestamibi. Postmortem staining defined the region underperfused because of its dependence on the artery that was partially occluded.Results. In seven dogs with moderate reduction in coronary blood flow, coronary vascular conductance decreased with partial coronary occlusion (47 ± 12%) during Tl-201 imaging and (47 ± 8%, p = NS) during Tc-99m sestamibi imaging. The underperfused region was 23.9 ± 6.4% of total left ventricular mass. Counts in the defects were 39% higher (0.86 ± 0.08 of normal counts) for Tc-99m sestamibi than for Tl-201 (0.64 ± 0.09 of normal counts, p < 0.001), and the defect on SPECT Tc-99m sestamlbi images occupied only a fraction (0.37 ± 0.30) of the area of the defect on the Tl-201 images of the same dog. Bull's-eye displays constructed from the pathologic slices showed that the Tl-201 defect size was closer to the underperfused region of the left ventricular mass determined pathologically than was the Tc-99m sestamibi defect size. In four additional dogs a severe, near total coronary occlusion was created during Tl-201 and Tc-99m sestamibi administration. In these dogs, similar defect contrast (0.55 ± 0.12 vs. 0.62 ± 0.09, p = NS) and areas (0.18 ± 0.07 vs. 0.18 ± 0.11, p = NS) were observed with Tl-201 and Tc-99m sestamibi, respectively.Conclusions. Tomographic myocardial imaging with Tc-99m sestamibi during moderately severe partial coronary occlusion underestimated the area of the defect relative to Tl-201 or to the pathologic reference standard in dogs. Defect contrast was sharper with tomographic myocardial Tl-201 than with tomographic myocardial Tc-99m sestamibi during moderately severe partial coronary occlusion.

Neuropeptide Y and coronary vasoconstriction: role of thromboxane A2.

We previously reported that coronary constriction following neuropeptide Y (NPY) was alleviated by cyclooxygenase blockade. To determine the role of thromboxane A2 (TxA2), anesthetized dogs received two paired doses of NPY given 2 h apart. Nine control dogs received NPY alone. Nine test dogs received one of three TxA2 receptor antagonists given between the doses of NPY. Also, five dogs received NPY during which prostaglandins were measured. In controls, NPY decreased coronary blood flow and increased aortic pressure; coronary resistance was increased significantly. Heart rate fell, and myocardial oxygen consumption was unchanged. Thromboxane receptor blockers significantly relieved the coronary constrictor effect of NPY. The reduction in coronary blood flow was blunted, while heart rate, first derivative of left ventricular pressure, and myocardial oxygen consumption were unchanged. Alleviation by TxA2 receptor blockade paralleled that reported for cyclooxygenase inhibitors. Also, significant increases in coronary venous TxA2 were seen at the time of maximal increases in coronary resistance, while prostacyclin was unchanged. In summary, TxA2 appears to mediate part of the coronary constrictor effect of NPY.

Role of alpha 2-adrenoceptors in normal and atherosclerotic human coronary circulation.

Experimental studies on the effects of alpha 2-adrenoceptors on regional coronary blood flow in normal and ischemic myocardium are highly controversial. A beneficial effect on regional ischemic myocardium has been demonstrated in different animal preparations with either alpha 2-adrenoceptor blockade or stimulation. Animal studies also demonstrated that postsynaptic alpha 2-adrenoceptors mediate vasoconstriction in coronary and femoral vascular beds. The aims of the study were 1) to investigate the effects of regional alpha 2-adrenoceptor stimulation on regional coronary blood flow in subjects with angiographically normal coronary arteries, 2) to assess the effect of alpha 2-adrenoceptor blockade on coronary circulation in control subjects, and 3) to examine the influence of atherosclerosis on coronary blood flow response to alpha 2-adrenoceptor blockade. The effect of regional administration of BHT 933 (a selective alpha 2-adrenoceptor agonist) was studied in eight subjects with angiographically normal coronary arteries. The coronary blood flow velocity was measured using a subselective intracoronary 3F Doppler catheter and coronary diameter by quantitative coronary angiography. BHT 933 induced a reduction in coronary artery diameter from 2.5 +/- 0.6 mm to 1.8 +/- 0.4 mm (p less than 0.05) as well as in coronary blood flow velocity (from 6.4 +/- 0.9 cm/sec to 4.6 +/- 1.9 cm/sec, p less than 0.01). In some subjects, ST segment abnormalities occurred. In patients with angiographically normal coronary arteries (n = 6), the regional infusion of a selective alpha 2-adrenoceptor blocking agent after beta-blockade did not change coronary diameter or coronary blood flow velocity. In contrast, in patients with significant coronary stenoses (n = 6), regional infusion of an alpha 2-adrenoceptor blocking agent reduced regional coronary artery diameter (from 2.3 +/- 0.5 mm to 2.1 +/- 0.6 mm, p less than 0.01) as well as coronary blood flow velocity (from 5.8 +/- 0.8 cm/sec to 3.7 +/- 0.6 cm/sec, p less than 0.05); in addition, alpha 2-adrenoceptor blockade significantly increased coronary sinus plasma norepinephrine levels (from 300 +/- 144 pg/ml to 429 +/- 207 pg/ml, p less than 0.01). The selective in vivo stimulation of alpha 2-adrenoceptors produces a reduction in coronary blood flow and diameter in humans with angiographically normal coronary arteries. alpha 2-Adrenergic blockade does not change coronary blood flow in subjects with angiographically normal coronary arteries (suggesting no resting alpha 2-adrenergic vasoconstrictor tone), whereas in patients with coronary artery stenosis, regional coronary blood flow decreases after alpha 2-receptor blockade. Finally, our data also suggest that alpha 2-adrenoceptors participate in the modulation of sympathetic neuronal norepinephrine release in the human heart.

Transient coronary stenosis associated with arrhythmia and ischemia 24 hours after reperfusion

We examined the electrophysiologic sequelae of transient reductions in coronary blood flow (CBF) in conscious dogs. Animals were instrumented to measure arterial pressure, heart rate, repetitive extrasystole threshold (RET), and CBF before coronary stenosis, during 90 minutes of a 50% reduction in CBF, and at 1, 24, 48, and 72 hours after reperfusion. RET was decreased at 24 and 48 hours but returned to baseline by 72 hours after reperfusion. Frequent ventricular ectopic activity (VEA), absent during the control period, was noted during stenosis and at 1, 24, and 48 hours after reperfusion. β-Adrenergic blockade (metoprolol) normalized the decreased RET at 24 hours. Addition of α 1-adrenergic blockade (prazosin) abolished VEA. Endocardial blood flow in the posterior papillary muscle of the left ventricle was reduced by 52 ± 9% during stenosis, was similar to baseline levels by 1 hour after reperfusion, and decreased by 39 ± 5% at 24 hours. We conclude that episodes of modest coronary artery stenosis may be followed by electrophysiologic changes indicative of increased vulnerability to malignant ventricular arrhythmias.

Echocardiographic and angiographic evaluation of left ventricular function during percutaneous transluminal aortic valvuloplasty.

Transesophageal echocardiography was used to study the effect of the balloon inflation on left ventricular function in 20 patients with critical aortic stenosis undergoing balloon valvuloplasty. Balloon inflation caused an increase of end-diastolic (15% to 34%) and end-systolic (57% to 72%) left ventricular volume. Left ventricular wall stress increased from 30 +/- 10 x 10(3) dyn/cm2 at diastole and 121 +/- 40 x 10(3) dyn/cm2 at systole to 44 +/- 11 x 10(3) dyn/cm2 and 191 +/- 55 x 10(3) dyn/cm2, respectively, when the balloon was inflated (P less than 0.05). Turbulent regurgitant jet across the mitral valve increased from 15 +/- 2% to 25 +/- 3% during balloon inflation (P less than 0.01). Continued monitoring of left ventricular function after balloon deflation demonstrated prolonged enlargement of left ventricular volumes. Our data show that balloon inflation causes an increase of left ventricular volume and impairment of contraction. Increase of left ventricular wall stress--associated with a reduction of coronary blood flow, due to lower aortic pressure--could result in ischemic myocardial injury.

Intravenous nitroglycerin infusion inhibits cyclic blood flow responses caused by periodic platelet thrombus formation in stenosed canine coronary arteries : Schultz JD, Stamler J, Loscalzo J: Circulation 83:2122–2127, 1991

BACKGROUNDNitroglycerin and other clinically relevant organic nitrate derivatives have been shown to inhibit platelet aggregation in vitro. This antithrombotic effect of nitrates is potentiated by reduced thiol. To determine the potential relevance of this mechanism of action in vivo, we examined the effect of intravenous nitroglycerin infusion on periodic platelet thrombus formation in a canine model of coronary artery stenosis.METHODS AND RESULTSWe used a canine model of coronary artery stenosis associated with cyclic reductions in coronary blood flow that have been shown to depend on periodic platelet thrombus formation. We quantified the frequency of cycles per 40-minute observation period and monitored the effect of a continuous infusion of intravenous nitroglycerin on the cycle frequency. The administration of 10-15 micrograms/kg/min nitroglycerin reduced cyclic platelet thrombus formation significantly and did so without a significant change in coronary artery blood flow. Pretreatment with the redu...

Management of angina pectoris. Modern concepts.

While William Heberden gave us an excellent clinical description of angina pectoris more than 200 years ago, the understanding and management of this disorder have undergone major development since then, and especially so in recent years. The pathological basis for the disease was established shortly after Heberden's account. The concept of the imbalance between supply and demand was postulated in the nineteenth century. Recent progress has been made in mainly three areas: the better definition of prognosis, new insights into pathophysiology, and newer management modalities and aims. Today, the combination of the patient's functional state (exercise test), his heart (ventricular function) and coronary anatomy (angiography) enables us to accurately define the prognosis of the disease. Sophisticated studies have now demonstrated that during an exercise-induced angina attack there is a reduction in coronary blood flow and an increase in coronary resistance. Mechanisms associated with the angina attack involve the sclerotic epicardial arteries and the microcirculation. Further major advances in the medical management of angina pectoris now depend on our ability to improve prognosis and retard the development of the atherosclerotic process.