The transmural distribution of coronary blood flow during maximal vasodilation.

Experiments were performed to examine the transmural distribution of the coronary blood flow during maximal vasodilation and when intramyocardial pressures were either minimized (cardiac arrest) or maximized (tachycardia). The results reveal a gradient of vascular resistance across the ventricular wall that favors flow to the subendocardium in the presence of maximal vasodilation. Thus a flow gradient favoring the subendocardium was seen when intramyocardial pressures were minimized by cardiac arrest, but when tissue pressures were maximized through tachycardia this gradient of flow was reversed.     

Control of coronary blood flow during exercise

Under normal physiological conditions, coronary blood flow is closely matched with the rate of myocardial oxygen consumption. This matching of flow and metabolism is physiologically important due to the limited oxygen extraction reserve of the heart. Thus, when myocardial oxygen consumption is increased, as during exercise, coronary vasodilation and increased oxygen delivery are critical to preventing myocardial underperfusion and ischemia. Exercise coronary vasodilation is thought to be mediated primarily by the production of local metabolic vasodilators released from cardiomyocytes secondary to an increase in myocardial oxygen consumption. However, despite various investigations into this mechanism, the mediator(s) of metabolic coronary vasodilation remain unknown. As will be seen in this review, the adenosine, K(+)(ATP) channel and nitric oxide hypotheses have been found to be inadequate, either alone or in combination as multiple redundant compensatory mechanisms. Prostaglandins and potassium are also not important in steady-state coronary flow regulation. Other factors such as ATP and endothelium-derived hyperpolarizing factors have been proposed as potential local metabolic factors, but have not been examined during exercise coronary vasodilation. In contrast, norepinephrine released from sympathetic nerve endings mediates a feed-forward betaadrenoceptor coronary vasodilation that accounts for approximately 25% of coronary vasodilation observed during exercise. There is also a feed-forward alpha-adrenoceptor-mediated vasoconstriction that helps maintain blood flow to the vulnerable subendocardium when heart rate, myocardial contractility, and oxygen consumption are elevated during exercise. Control of coronary blood flow during pathophysiological conditions such as hypertension, diabetes mellitus, and heart failure is also addressed.     

Effects of systole-specific pericardial pressure increases on coronary flow

It has been postulated that intrathoracic pressure increases may impair cardiac function by decreasing coronary flow. To determine whether altered coronary flow causes or results from change in cardiac function, we used 14 anesthetized dogs in propranolol-induced heart failure following atrioventricular node ablation. After thoracoabdominal binding, the animals were paced and ventilated at the same frequency, and inspiration was synchronized with cardiac systole, resulting in systole-specific pericardial pressure increases (SSPPI). At SSPPI magnitudes of 15 and 30 mmHg, left atrial transmural pressure decreased and cardiac output increased, whereas decreases in left ventricular end-systolic transmural pressure and myocardial O2 consumption were directly related. Concurrent decreases in coronary sinus flow (CSF) and coronary arteriovenous O2 gradient with SSPPI 15 mmHg indicate autoregulation. However, the arteriovenous O2 gradient remained unaltered with SSPPI 30 mmHg, despite further decrease in CSF. Because the absolute diastolic aortic pressure decreased, a limit may exist for increasing SSPPI above which CSF may be directly affected.     

Effects of exercise training on coronary transport capacity

Coronary transport capacity was estimated in eight sedentary control and eight exercise-trained anesthetized dogs by determining the differences between base line and the highest coronary blood flow and permeability-surface area product (PS) obtained during maximal adenosine vasodilation with coronary perfusion pressure constant. The anterior descending branch of the left coronary artery was cannulated and pump-perfused under constant-pressure conditions (approximately equal to 100 Torr) while aortic, central venous, and coronary perfusion pressures, heart rate, electrocardiogram, and coronary flow were monitored. Myocardial extraction and PS of 51Cr-labeled ethylenediaminetetraacetic acid were determined with the single-injection indicator-diffusion method. The efficacy of the 16 +/- 1 wk exercise training program was shown by significant increases in the succinate dehydrogenase activities of the gastrocnemius, gluteus medialis, and long head of triceps brachii muscles. There were no differences between control and trained dogs for either resting coronary blood flow or PS. During maximal vasodilation with adenosine, the trained dogs had significantly lower perfusion pressures with constant flow and, with constant-pressure vasodilation, greater coronary blood flow and PS. It is concluded that exercise training in dogs induces an increased coronary transport capacity that includes increases in coronary blood flow capacity (26% of control) and capillary diffusion capacity (82% of control).     

Regional myocardial O2 consumption and coronary blood flow responses to acetylcholine in rabbit heart

The effect of acetylcholine on regional coronary blood flow and myocardial O2 consumption was determined in order to compare its direct vasodilatory effects with the metabolic vasoconstriction it induces. Experiments were conducted in seven untreated control anaesthetized open chest rabbits and seven rabbits which were infused with acetylcholine (1 microgram/kg/min). Myocardial blood flow was determined before and during acetylcholine infusion using radioactive microspheres. Regional arterial and venous O2 saturation was analyzed microspectrophotometrically. Acetylcholine reduced heart rate by 30% and significantly depressed the arterial systolic and diastolic blood pressure. The mean O2 consumption was significantly reduced with acetylcholine from 9.6 +/- 2.0 to 6.1 +/- 3.6 ml O2/min/100 g. Coronary blood flow decreased uniformly across the left ventricular wall by about 50% and resistance to flow increased by 42% despite potential direct cholinergic vasodilation. O2 extraction was not affected by acetylcholine infusion. It is concluded that the acetylcholine infusion directly decreased myocardial O2 consumption, which in turn lowered the coronary blood flow and increased the resistance. The decreased flow was related to a reduced metabolic demand rather than a direct result of lowered blood pressure. Unaffected myocardial O2 extraction also suggested that blood flow and metabolism were matched. This indicates that direct cholinergic vasodilation of the coronary vasculature does not allow a greater reduction in metabolism than flow in the anaesthetized open chest rabbit heart during acetylcholine infusion.     

Function of mature coronary collateral vessels and cardiac performance in the exercising dog

Formation of extensive collateral vessels after chronic constriction of a coronary artery in dogs can provide for similar increases in blood flow to native and collateralized regions of myocardium during exertion. Previous investigations have not compared myocardial blood flow and cardiac functional responses during exercise in constricted and nonconstricted (sham) animals. Thus we evaluated left ventricular performance and myocardial blood flow at rest and during mild, moderate, and severe exertion in sham-operated dogs and in dogs 2-3 mo after placement of an Ameroid occluder around the proximal left circumflex artery. Changes in double product, maximal left ventricular dP/dt, and pressure-work index were similar in both groups for each level of exertion. Despite similar increases in estimated myocardial O2 demand and similar diastolic perfusion pressures, average transmural myocardial blood flow increased less in the constrictor animals, particularly during severe exercise (2.74 +/- 0.22 vs. 1.45 +/- 0.29 ml X min-1 X g-1). The smaller increases in blood flow occurred equally in native and collateralized regions as well as in the papillary muscles and boundary areas between the native and collateralized regions. The differences in flow in the native and collateralized regions were uniform across the wall of the myocardium. We also observed smaller increases in stroke volume and cardiac output in the constrictor group, disparities which increased with increasing exertion (stroke volume, severe exercise = 0.92 +/- 0.13 vs. 0.53 +/- 0.09 ml/kg). We postulate that myocardial active hyperemia is limited either because the coronary vessels remaining after chronic circumflex occlusion cannot dilate sufficiently or that there is inappropriate active vasoconstriction during severe exertion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial tissue pressure and blood flow during coronary sinus pressure modulation in anesthetized dogs.

To determine whether coronary sinus outflow pressure (Pcs) or intramyocardial tissue pressure (IMP) is the effective back pressure in the different layers of the left ventricular (LV) myocardium, we increased Pcs in 14 open-chest dogs under maximal coronary artery vasodilation. Circumflex arterial (flowmeter), LV total, and subendocardial and subepicardial (15-microns radioactive spheres) pressure-flow relationships (PFR) and IMP (needle-tip pressure transducers) were recorded during graded constriction of the artery at two diastolic Pcs levels (7 +/- 3 vs. 23 +/- 4 mmHg). At high Pcs, LV, aortic and diastolic circumflex arterial pressure, heart rate, myocardial oxygen consumption, and lactate extraction were unchanged; IMP in the subendocardium did not change (130/19 mmHg), whereas IMP in the subepicardium increased by 17 mmHg during systole and 10 mmHg during diastole (P < or = 0.001), independently of circumflex arterial pressure. Increasing Pcs did not change the slope of the PFR; however, coronary pressure at zero flow increased in the subepicardium (P < or = 0.008), whereas in the subendocardium it remained unchanged at 24 +/- 3 mmHg. Thus Pcs can regulate IMP independently of circumflex arterial pressure and consequently influence myocardial perfusion, especially in the subepicardial tissue layer of the LV.     

Subendocardial and subepicardial pressure-flow relations in the rat heart in diastolic and systolic arrest

Ischemic heart disease is more apparent in the subendocardial than in subepicardial layers. We investigated coronary pressure-flow relations in layers of the isolated rat left ventricle, using 15 microm microspheres during diastolic and systolic arrest in the vasodilated coronary circulation. A special cannula allowed for selective determination of left main stem pressure-flow relations. Arterio-venous shunt flow was derived from microspheres in the venous effluent. We quantitatively investigated the pressure-flow relations in diastolic arrest (n=8), systolic arrest at normal contractility (n=8) and low contractility (n=6). In all three groups normal and large ventricular volume was studied. In diastolic arrest, at a perfusion pressure of 90 mmHg, subendocardial flow is larger than subepicardial flow, i.e., the endo/epi ratio is approximately 1.2. In systolic arrest the endo/epi ratio is approximately 0.3, and subendocardial flow and subepicardial flow are approximately 12% and approximately 55% of their values during diastolic arrest. The endo/epi ratio in diastolic arrest decreases with increasing perfusion pressure, while in systole the ratio increases. The slope of the pressure-flow relations, i.e., inverse of resistance, changes by a factor of approximately 5.3 in the subendocardium and by a factor approximately 2.2 in the subepicardium from diastole to systole. Lowering contractility affects subendocardial flow more than subepicardial flow, but both contractility and ventricular volume changes have only a limited effect on both subendocardial and subepicardial flow. The resistance (inverse of slope) of the total left main stem pressure-flow relation changes by a factor of approximately 3.4 from diastolic to systolic arrest. The zero-flow pressure increases from diastole to systole. Thus, coronary perfusion flow in diastolic arrest is larger than systolic arrest, with the largest difference in the subendocardium, as a result of layer dependent increases in vascular resistance and intercept pressure. Shunt flow is larger in diastolic than in systolic arrest, and increases with perfusion pressure. We conclude that changes in contractility and ventricular volume have a smaller effect on pressure-flow relations than diastolic-systolic differences. A synthesis of models accounting for the effect of cardiac contraction on perfusion is suggested.     

The effects of propranolol, phentolamine, and atropine on canine coronary vascular gradients

The objective of this study was to measure pressure gradients in the coronary circulation following the administration of three receptor-blocking drugs, propranolol, phentolamine, and atropine when administered singly and in sequence. As well, we examined the responses of these gradients to eight interventions: left stellate ganglion or left vagosympathetic trunk stimulation, administration of isoproterenol, acetylcholine, noradrenaline, adenosine, phenylephrine, or adrenaline. Using a multiple linear regression model we examined the actions and interactions of the receptor-blocking agents on hemodynamic variables and vascular gradients. Propranolol reduced heart rate as expected and blocked the responses to isoproterenol administration. As well, it abolished the epicardial coronary artery diastolic gradient. The gradient was restored when propranolol was the second receptor blocker administered but was abolished when it was the third. Phentolamine induced vasodilation with a decrease in coronary small vessel gradients. This effect persisted without regard to the sequence of administration. When it was the second or third agent it decreased the microcirculation and small vein gradients, an action it did not manifest when given singly. Atropine singly did not alter pressures or gradients; but as the second agent it altered the transmural, outflow tract, epicardial diastolic, and microcirculation and small vein diastolic gradients; and as the third agent the changes were in the transmural, epicardial systolic and diastolic, and small artery systolic and diastolic gradients. The pattern of responses was not predictable and that indicates that unique changes occur in the responses of the coronary circulation when multiple receptor-blocking agents are employed. Adrenergic control tends to dominate in the coronary arterial circulation, and muscarinic control in the coronary microcirculation and veins with considerable overlap.     

Exercise training increases coronary transport reserve in miniature swine

Female yucatan miniature swine were trained on a treadmill (ET) or were cage confined (C) for 16-22 wk. The ET pigs had increased exercise tolerance, heart weight-to-body weight ratio, and skeletal muscle oxidative capacity. After anesthesia the left anterior descending coronary artery was cannulated and pump perfused with blood while aortic, central venous, and coronary perfusion pressures, electrocardiogram, heart rate, and coronary blood flow were monitored. Capillary permeability-surface area product (PS) for EDTA was determined with the single-injection indicator-diffusion method by use of an organ model based on the Sangren-Sheppard equations for capillary transport. Coronary blood flow (CBF) and PS were compared before and during maximal adenosine vasodilation with coronary perfusion pressures at 120 mmHg. Results indicate that there were no differences in base-line CBF or PS between C and ET groups. alpha-Receptor blockade with phentolamine and/or prazosin, before adenosine vasodilation, produced increases in PS in C pigs but had little effect in ET pigs. During maximal vasodilation with adenosine, ET pigs had greater CBF (447 +/- 24 vs. 366 +/- 27 ml.min-1.100 g-1) and greater PS (83 +/- 9 vs. 55 +/- 7 ml.min-1.100 g-1) than the C group. It is concluded that ET induces an increased coronary transport capacity in miniature swine that includes a 22% increase in blood flow capacity and a 51% increase in capillary exchange capacity.     

Mechanism of action of arachidonic acid in the isolated perfused rat heart

The purpose of this study was to elucidate the mechanism of action of arachidonic acid in the isolated rat heart perfused with Krebs solution at a constant flow. Administration of arachidonic acid, 3.3-33 nmol, into the heart caused a small transient increase followed by a pronounced decrease in coronary perfusion pressure and increased myocardial tension, heart rate, and the output of prostaglandins (6-keto-PGF1 alpha, PGE2, and PGF2 alpha). Administration of structurally similar fatty acids, dihomo-gamma-linolenic acid, and 8,14,17-eicosatrienoic acid, produced vasoconstriction and decreased myocardial tension without affecting heart rate or the output of prostaglandins. Infusion of PGI2, PGF2 alpha, or PGE2 produced coronary vasodilation and increased myocardial tension, whereas PGF2 alpha increased heart rate, an effect which was not prevented by propranolol. Indomethacin blocked the effect of arachidonic acid on myocardial tension and heart rate, but only reduced the duration of coronary vasodilation. The initial component of arachidonic acid induced coronary vasodilation which was unaffected by indomethacin and also remained unaltered during the infusion of three structurally dissimilar lipoxygenase inhibitors, eicosatetraynoic acid, nordihydroguaiaretic acid, and 1-phenyl-3-pyrazolidone. Indomethacin did not alter the effects of the exogenously administered prostaglandins on perfusion pressure or myocardial tension; however, it blocked the effect of PGF2 alpha on heart rate. The effect of arachidonic acid or PGF2 alpha to increase heart rate was not blocked by thromboxane synthetase inhibitors, imidazole, or OKY-1581. We conclude that the cardiac effects of arachidonic acid are mediated primarily through its conversion to cyclooxygenase products.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acidaemia reduces cardiac output and left ventricular contractility in conscious lambs

We studied the effects of HCI-induced metabolic acidaemia on cardiac output, contractile function, myocardial blood flow, and myocardial oxygen consumption in nine unanaesthetized newborn lambs. Through a left thoracotomy, catheters were placed in the aorta, left atrium and coronary sinus. A pressure transducer was placed in the left ventricle. Three to four days after surgery, we measured cardiac output, dP/dt, left ventricular end diastolic and aortic mean blood pressures, heart rate, aortic and coronary sinus blood oxygen contents, and left ventricular myocardial blood flow during a control period, during metabolic acidaemia, and after the aortic pH was restored to normal. We calculated systemic vascular resistance, myocardial oxygen consumption and left ventricular work. Acidaemia was associated with reduction in cardiac output, maximal dP/dt, and aortic mean blood pressure. Left ventricular end diastolic pressure and systemic vascular resistance increased, and heart rate did not change significantly. The reduction in myocardial blood flow and oxygen consumption was accompanied by fall in cardiac work. Cardiac output returned to control levels after the pH had been normalized but maximal dP/dt was incompletely restored. Myocardial blood flow and oxygen consumption increased beyond control levels. This study demonstrates that HCI-induced metabolic acidaemia in conscious newborn lambs is associated with a reduction in cardiac output which could have been mediated by the reduction in contractile function and/or the increase in systemic vascular resistance. The decreases in myocardial blood flow and oxygen consumption appear to reflect diminished cardiac work. The restoration of a normal cardiac output after normalization of the pH appears to have resulted from the increases in heart rate and left ventricular filling pressures in conjunction with an incomplete restoration of contractile function.     

Normal patterning of the coronary capillary plexus is dependent on the correct transmural gradient of FGF expression in the myocardium

The formation of the coronary vessel system is vital for heart development, an essential step of which is the establishment of a capillary plexus that displays a density gradient across the myocardial wall, being higher on the epicardial than the endocardial side. This gradient in capillary plexus formation develops concurrently with transmural gradients of myocardium-derived growth factors, including FGFs. To test the role of the FGF expression gradient in patterning the nascent capillary plexus, an ectopic FGF-over-expressing site was created in the ventricular myocardial wall in the quail embryo via retroviral infection from E2-2.5, thus abolishing the transmural gradient of FGFs. In FGF virus-infected regions of the ventricular myocardium, the capillary density across the transmural axis shifted away from that in control hearts at E7. This FGF-induced change in vessel patterning was more profound at E12, with the middle zone becoming the most vascularized. An up-regulation of FGFR-1 and VEGFR-2 in epicardial and subepicardial cells adjacent to FGF virus-infected myocardium was also detected, indicating a paracrine effect on induction of vascular signaling components in coronary precursors. These results suggest that correct transmural patterning of coronary vessels requires the correct transmural expression of FGF and, therefore, FGF may act as a template for coronary vessel patterning.     

Positive hemodynamic interaction between amrinone and diltiazem in anesthetized dogs

The direct negative inotropic actions of calcium channel blockers limit the use of these otherwise effective systemic and coronary vasodilators in patients with heart failure. We studied the effects of amrinone pretreatment on the dose--hemodynamic response curve of diltiazem in order to test the hypothesis that amrinone might potentiate diltiazem's positive effects in anesthetized dogs. The control group (no pretreatment, n = 6) had a typical dose-related response to diltiazem (50, 100, and 150 micrograms/kg): coronary and systemic vasodilation, increased stroke volume, and no change in myocardial work and power. Amrinone pretreatment of the study group (n = 7) altered the hemodynamic response, thus maximal systemic vasodilation and stroke volume increase at a lower diltiazem dose, a 15 to 35% increase in myocardial work and power, and more profound coronary vasodilation. We propose that amrinone, by inhibiting phosphodiesterase, potentiates diltiazem vasodilation and reflexly secreted catecholamines' actions on the heart. This positive interaction may permit effective use of lower doses of diltiazem, thus circumventing its dose-limiting direct negative effects while still profitting from beneficial peripheral, reflex, and coronary actions.     

Blood supply to the heart and coronary vasodilation reserves in experimental myocardial hypertrophy

The effects of pressure overload left ventricular hypertrophy (LVH) on heart performance and coronary circulation were investigated in dog experiments. The data obtained clearly demonstrate that left ventricular systolic and end-diastolic pressures were increased in LVH dogs. The heart rate and cardiac output were unchanged. However, there was a tendency toward lowering in the maximal rate of myocardial contractility and relaxation (+dP/dtmax and--dP/dtmax). It has been shown that in LVH dogs, the coronary blood flow was higher and coronary artery resistance was lower than in control ones. The peak reactive hyperemic flow was higher in LVH dogs but the coronary artery resistance calculated at the height of reactive hyperemia was similar both in control and LVH dogs, evidence of a reduction in the total coronary vasodilator reserves in the latter ones. The diastolic pressure-time index-tension time index (DPTI/TTI) ratio in LVH dogs decreased so that the value was sufficiently low to predict a reduction in endocardial perfusion even in experimental increased coronary perfusion pressure.     

Effect of sildenafil on coronary active and reactive hyperemia

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6. 7 +/- 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise (P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 +/- 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow x arterial O(2) content) was unchanged. Furthermore, sildenafil did not alter coronary venous PO(2), indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.     

Effects of coronary sinus pressure elevation on coronary blood flow distribution in dogs with normal preload

Coronary sinus pressure (Pcs) elevation shifts the diastolic coronary pressure-flow relation (PFR) of the entire left ventricular myocardium to a higher pressure intercept. This finding suggests that Pcs is one determinant of zero-flow pressure (Pzf) and challenges the existence of a vascular waterfall mechanism in the coronary circulation. To determine whether coronary sinus or tissue pressure is the effective coronary back pressure in different layers of the left ventricular myocardium, the effect of increasing Pcs was studied while left ventricular preload was low. PFRs were determined experimentally by graded constriction of the circumflex coronary artery while measuring flow using a flowmeter. Transmural myocardial blood flow distribution was studied (15-micron radioactive spheres) at steady state, during maximal coronary artery vasodilatation at three points on the linear portion of the circumflex PFR both at low and high diastolic Pcs (7 +/- 3 vs. 22 +/- 5 mmHg; p less than 0.0001) (1 mmHg = 133.322 Pa). In the uninstrumented anterior wall the blood flow measurements were obtained in triplicate at the two Pcs levels. From low to high Pcs, mean aortic (98 +/- 23 mmHg) and left atrial (5 +/- 3 mmHg) pressure, percent diastolic time (49 +/- 7%), percent left ventricular wall thickening (32 +/- 4%), and percent myocardial lactate extraction (15 +/- 12%) were not significantly changed. Increasing Pcs did not alter the slope of the PFR; however, the Pzf increased in the subepicardial layer (p less than 0.0001), whereas in the subendocardial layer Pzf did not change significantly. Similar slopes and Pzf were observed for the PFR of both total myocardial mass and subepicardial region at low and high Pcs. Subendocardial:subepicardial blood flow ratios increased for each set of measurements when Pcs was elevated (p less than 0.0001), owing to a reduction of subepicardial blood flow; however, subendocardial blood flow remained unchanged, while starting in the subepicardium toward midmyocardium blood flow decreased at high Pcs. This pattern was similar for the uninstrumented anterior wall as well as in the posterior wall. Thus as Pcs increases it becomes the effective coronary back pressure with decreasing magnitude from the subepicardium toward the subendocardium of the left ventricle. Assuming that elevating Pcs results in transmural elevation in coronary venous pressure, these findings support the hypothesis of a differential intramyocardial waterfall mechanism with greater subendo- than subepi-cardial tissue pressure.     

Progressive epicardial coronary blood flow reduction fails to produce ST-segment depression at normal heart rates

ST-segment depression is commonly seen in patients with acute coronary syndromes. Most authors have attributed it to transient reductions in coronary blood flow due to nonocclusive thrombus formation on a disrupted atherosclerotic plaque and dynamic focal vasospasm at the site of coronary artery stenosis. However, ST-segment depression was never reproduced in classic animal models of coronary stenosis without the presence of tachycardia. We hypothesized that ST-segment depression occurring during acute coronary syndromes is not entirely explained by changes in epicardial coronary artery resistance and thus evaluated the effect of a slow, progressive epicardial coronary artery occlusion on the ECG and regional myocardial blood flow in anesthetized pigs. Slow, progressive occlusion over 72 min (SD 27) of the left anterior descending coronary artery in 20 anesthetized pigs led to a 90% decrease in coronary blood flow and the development of ST-segment elevation associated with homogeneous and transmural myocardial blood flow reductions, confirmed by microspheres and myocardial contrast echocardiography. ST-segment depression was not observed in any ECG lead before the development of ST-segment elevation. At normal heart rates, progressive epicardial stenosis of a coronary artery results in myocardial ischemia associated with homogeneous, transmural reduction in regional myocardial blood flow and ST-segment elevation, without preceding ST-segment depression. Thus, in coronary syndromes with ST-segment depression and predominant subendocardial ischemia, factors other than mere increases in epicardial coronary resistance must be invoked to explain the heterogeneous parietal distribution of flow and associated ECG changes.     

Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study.

OBJECTIVE--To examine the hypothesis that a J curve relation between blood pressure and death from coronary heart disease is confined to high risk subjects with myocardial infarction. DESIGN--Cohort longitudinal epidemiological study with biennial examinations since 1950. SETTING--Framingham, Massachusetts, USA. SUBJECTS--5209 subjects in the Framingham study cohort followed up by a person examination approach. MAIN OUTCOME MEASURES--Coronary heart disease deaths and non-cardiovascular disease deaths in men and women with or without myocardial infarction relative to blood pressure. RESULTS--Among subjects without myocardial infarction non-cardiovascular disease deaths were twice to three times as common as coronary heart disease deaths. Furthermore, there was no significant relation between non-cardiovascular disease death and diastolic or systolic blood pressure. Also coronary heart disease deaths were linearly related to diastolic and systolic blood pressures. Among high risk patients (that is, people with myocardial infarction but free of congestive heart failure) death from coronary heart disease was more common than non-cardiovascular disease death. There was a significant U shaped relation between coronary heart disease death and diastolic blood pressure. Although there was an apparent U shaped relation between coronary heart disease death and systolic blood pressure, it did not attain statistical significance when controlling for age and change in systolic blood pressure from the pre-myocardial infarction level. None of the above conclusions changed when adjustments were made for risk factors such as serum cholesterol concentration, antihypertensive treatment, and left ventricular function. The U shaped relation between diastolic blood pressure and high risk subjects existed for both those given antihypertensive treatment and those not. CONCLUSIONS--These data suggest that an age and sex independent U curve relation exists for diastolic blood pressure and coronary heart disease deaths in patients with myocardial infarction but not for low risk subjects without myocardial infarction. The relation seems to be independent of left ventricular function and antihypertensive treatment.     

Biophysical Model of the Spatial Heterogeneity of Myocardial Flow

The blood flow in the myocardium has significant spatial heterogeneity. The objective of this study was to develop a biophysical model based on detailed anatomical data to determine the heterogeneity of regional myocardial flow during diastole. The model predictions were compared with experimental measurements in a diastolic porcine heart in the absence of vessel tone using nonradioactive fluorescent microsphere measurements. The results from the model and experimental measurements showed good agreement. The relative flow dispersion in the arrested, vasodilated heart was found to be 44% and 48% numerically and experimentally, respectively. Furthermore, the flow dispersion was found to have fractal characteristics with fractal dimensions (D) of 1.25 and 1.27 predicted by the model and validated by the experiments, respectively. This validated three-dimensional model of normal diastolic heart will play an important role in elucidating the spatial heterogeneity of coronary blood flow, and serve as a foundation for understanding the interplay between cardiac mechanics and coronary hemodynamics.