Edward S. Kirk

Inhibition of coronary blood flow by a vascular waterfall mechanism.

The mechanism whereby systole inhibits coronary blood flow was examined. A branch of the left coronary artery was maximally dilated with an adenosine infusion, and the pressure-flow relationship was obtained for beating and arrested states. The pressure-flow curve for the arrested state was linear from below 20 to beyond 200 mm Hg. The curve for the beating state was shifted toward higher pressures and in the range of pressures above peak ventricular pressure was linear and parallel to that for the arrested state. Below this range the curve for the beating state converged toward that for the arrested state and was convex to the pressure axis. These resultswere compared with a model of the coronary vasculature that consisted of numerous parallel channels, each responding to local intramyocardial pressure by forming vascular waterfalls. When intramyocardial pressure in the model was assigned values from zero at the epicardium to peak ventricular pressure at the endocardium, pressure-flow curves similar to the experimental ones resulted. Thus, we conclude that systole inhibits coronary perfusion by the formation of vascular waterfalls and that the intramyocardial pressures responsible for this inhibition do not significantly exceed peak ventricular pressure.

Performance of the right ventricle under stress: relation to right coronary flow

Right ventricular performance was studied relative to right coronary artery flow in the chloralose-anesthetized, open chest dog. The right coronary artery was cannulated for measurement and control of flow and pressure. Under control conditions, right coronary artery occlusion caused no change in cardiac output, or right and left ventricular pressures, although right ventricular contractile force fell markedly. With right coronary artery flow intact, incremental pulmonary artery obstruction caused a corresponding decline in cardiac output and elevation of right ventricular end-diastolic pressure with eventual total right ventricular failure and systemic shock. With right coronary artery occlusion, identical degrees of pulmonary artery obstruction resulted in more pronounced changes in cardiac output and right ventricular end-diastolic pressure with right ventricular failure occurring at a much lower level of right ventricular stress.However, with right coronary artery flow intact, the right ventricular decompensation induced by pulmonary artery obstruction, could be reversed by raising right coronary artery perfusion to levels above normal, thus increasing right ventricular performance and restoring cardiac output. We conclude that right ventricular failure and resultant systemic hypotension due to severe pulmonary artery obstruction can be reversed simply by right coronary artery hyperperfusion, and that, although a normally contractile right ventricular free wall is not essential to maintain cardiac performance at rest, during right ventricular systolic stress, over-all cardiac performance becomes increasingly dependent on the right ventricle. The data further imply that increased myocardial impingement on right coronary artery flow during systole in right ventricular hypertension may be an important factor leading to right ventricular failure.

Differential response of large and small coronary arteries to nitroglycerin and angiotensin. Autoregulation and tachyphylaxis.

Large proximal and smaller distal coronary arteries respond differently to pharmacologic agents, but the role of autoregulation is not known. We examined this role in dogs by cannulating the main left coronary artery and a distal left anterior descending artery branch. With coronary flow held constant, the distal coronary artery pressure and the gradient from proximal to distal artery were proportional to the small and the large vessel resistance, respectively. At normal perfusion pressure, nitroglycerin injected directly into the coronary artery caused a transient fall in small vessel resistance and a prolonged decrease in large vessel resistance. During ischemia, when small vessels autoregulated and small vessel resistance was minimal, nitroglycerin lowered only large vessel resistance. Angiotensin injected directly into the coronary artery increased small and large vessel resistance; the slower response of large vessel resistance followed a passive dilation caused by increased perfusion pressure. Continuous infusions of nitroglycerin and angiotensin maintained dilation and constriction of large vessels, respectively, but small vessels demonstrated tachyphylaxis. Only adenosine infusion maintained dilation in both large and small vessels. In response to varying perfusion, small vessels autoregulated and large vessels responded passively to changes in perfusion pressure. We concluded that small coronary arteries respond to cardiac metabolism and demonstrate escape from prolonged dilation and constriction. Conversely, large vessels respond continuously to sustained mechanical and pharmacologic stimuli independently of the nutritional state of the myocardium.

The Effects of Nitroglycerin on Coronary Collaterals and Myocardial Contractility

Nitroglycerin (TNG) causes a prolonged dilatation of coronary collaterals. To demonstrate a functional significance of this dilatation we measured the effect of TNG on myocardial contractile force in dogs 2(1/2)-4 wk after the left anterior descending coronary artery (LAD) had been embolized in closed-chest animals. Development of collaterals was documented by angiography. Via a left thoracotomy the main left coronary artery (LCA) and LAD distal to the embolized plug were cannulated. Coronary flow and perfusion pressure were recorded. Contractile force was measured with gauges sutured to epicardial areas supplied by the left circumflex coronary artery (LCf) and occluded LAD. Coronary perfusion pressure in the LCA was gradually decreased until the contractile force recorded by the LAD gauge diminished while the LCf gauge was unaffected. Under these conditions, with coronary perfusion pressure held constant with the aid of a Starling resistance, TNG (18 mug) injected into the LCA increased peripheral LAD pressure by 3-12 mm Hg and contractile force in the LAD region by 36% (range 20-90%), returning it to near-normal levels, while having minimal effect in the LCf area. These changes persisted for 5 min. When LCf and LAD areas were both ischemic, intracoronary TNG had minimal effect on peripheral LAD pressure and contractile force. Thus, TNG causes prolonged dilatation of coronary collaterals and presumed increased collateral flow with subsequent enhancement of myocardial contractile force in ischemic areas. This effect is seen only when ischemia is limited to an area supplied by the collaterals. When the whole heart is ischemic, collaterals are unresponsive to TNG, suggesting that these collaterals dilate fully when the regions from which they originate become ischemic.

Absence of a lateral border zone of intermediate creatine phosphokinase depletion surrounding a central infarct 24 hours after acute coronary occlusion in the dog.

SUMMARY Myocardial creatine phosphokinase (CPK) activity was measured as an indicator of cell viability 24 hours after ligation of the left anterior descending coronary artery (LAD) in normal myocardium, the entire region spplied by the LAD, and individual samples from the border and center of the infarct. Tissue spplied by the LAD and delineated by dye was carefully dissected from normal tissue along the stained border. CPK activity in the ischemic myocardium was calculated by assuming normal CPK activity in normal myocardium interdigitating with ischemic tissue at the border. Normal tissue was marked prior to occlusion with microspheres injected into the left atrium, whereas the distal portion of the LAD was perfused separately with unlableled blood from a reservoir. With this correction, the CPK activity in the ischemic tissue from the lateral border of the infarct was essentially the same as in samples from the center, whereas that in the normal tissue immediately adjacent to the stained border was equal to values in remote normal myocardium. Thus, CPK depletion throughout the entire ischemic myocardium was nearly equal to CPK depletion in the center of the infarct. The uncorrected intermediate CPK levels in the individual samples from the border of the stained region correlated with the amount of normal tissue contaminating these samples. However, differences in CPK depletion across the heart wall resulted in the most depletion in the sbendocardium and the least in the epicardium. Furthermore, coronary collateral blood flow measured 10 minutes after occlusion correlated well with the sbsequent extent of CPK depletion.

Redistribution of collateral blood flow from necrotic to surviving myocardium following coronary occlusion in the dog.

Early changes in collateral blood flow after acute coronary occlusion may be critical for survival of iscbemic myocardium. We used 15-&mgr;m radioactive microspheres to study myocardial blood flow in thoracotomized dogs 10 minutes and 24 hours after occlusion of the left anterior descending coronary artery (LAD). The iscbemic area was delineated by dye injected into the distal artery, and identification of potentially iscbemic samples was confirmed by a newly developed technique in which microspheres were excluded from the normally perfused LAD. Layers were separated into necrotic or normal as defined by gross inspection and confirmed by histological examination and creatine phosphokinase assay. Infarction always involved endocardial layers and extended toward the epicardium. Average myocardial blood flow in 48 necrotic samples from 16 dogs either remained low ( < 0.05 ml/min g-1) or declined, falling from .11 ± 0.02(SE)at 10 minutes to 0.05 ± 0.01 ml/min g-1 at 24 hours (P < 0.001). In contrast, in the 32 normal-appearing samples which were iscbemic at 10 minutes, flow increased from 0.24 ± 0.03 to 0.9 ± 0.04 ml/min g-1 (P < 0.001). Flow in control myocardium wis 1.43 ± 0.12 and 1.04 ± 0.07 ml/min g-1, respectively. Peripheril mean coronary arterial pressure increased from 26 ± 3 to 35 ± 3 mm Hg, largely because of enlargement of collateral vessels; collateral conductance calculated from retrograde flow in 14 dogs increased from 0.023 ± 0.005 after occlusion to 0.051 ± 0.009 ml/min rnm Hg-1 24 hours later (P < 0.001). Thus, coronary collateral blood flow is redistributed from necrotic endocardial layers to surviving epicardial ones. In combination with a developing collateral supply this process may be essential for sparing myocardium after coronary occlusion.

EFFECTS OF AMIODARONE AND L8040, NOVEL ANTIANGINAL AND ANTIARRHYTHIC DRUGS, ON CARDIAC AND CORONARY HAEMODYNAMICS AND ON CARDIAC INTRACELLULAR POTENTIALS

1. The effects on the coronary and systemic haemodynamics of intravenous and intracoronary injections of two benzfuran derivatives, amiodarone and its brominated analogue (L8040), were studied in open‐chest anaesthetized dogs. The effects of L8040 on cardiac intracellular potentials after 6 weeks of 20 mg/kg intraperitoneal injections in rabbits were also investigated.

Coronary steal: Its role in detrimental effect of isoproterenol after acute coronary occlusion in dogs

Using epicardial electrograms others have established that infusion of isoproterenol increases myocardial injury after acute coronary occlusion. To define the contribution of alterations in collateral blood flow to this increased ischemia, isoproterenol was administered to 10 dogs. After pretreatment with practolol in doses that successfully block inotropic but not vascular effects of beta adrenergic stimulants, intracoronary isoproterenol continued to enhance the magnitude of S-T segment elevation in ischemic areas. Thus, vasodilation induced by isoproterenol appears to divert flow from the ischemic area. To test this hypothesis, intracoronary adenosine was given to cause coronary vasodilation without enhancing inotropy. S-T segment elevation at ischemic and adjacent sites was significantly increased. Neither agent had systemic effects, but each increased coronary blood flow while concomitantly decreasing collateral flow as evidenced by a reduction in retrograde coronary flow and peripheral coronary pressure. In addition, adenosine significantly diminished the rate of xenon-133 clearance from the ischemic myocardium. Thus, isoproterenol, in addition to its positive inotropic effect, increases myocardial injury by its vascular action. Collateral blood flow to acutely ischemic myocardium is diminished by the production of a coronary steal. Intravenously administered isoproterenol additionally diminishes collateral flow by decreasing coronary perfusion pressure. It is postulated that any agent that causes either a primary or secondary coronary vasodilation may cause a coronary steal and subsequently enhance myocardial injury.

The histological lateral border of acute canine myocardial infarction. A function of microcirculation.

Studies from this laboratory have shown that the border of a 24-hour canine infarct is histologically sharp and is composed of numerous interdigitating peninsulas of necrotic and normal tissue. To see if this sharp boundary is spatially related to the capillary beds of occluded and non- occluded arteries, the left anterior descending artery (LAD) was ligated in five mongrel dogs. Twenty- four hours later, white silicone rubber (Microfll) was injected into the LAD distal to the ligature; simultaneously and under the same pressure, red Microfil was injected into the left main coronary artery (LMCA). In hematoxylin and eosin sections from the border of the infarct, capillaries supplied by the LAD (white) were either in areas of necrosis, in normal epicardium or, rarely, in normal tissue along the lateral boundary; those supplied by the LMCA (red) were almost always in normal regions. Quantitative evaluation of this relationship revealed that the majority of the vessels in the normal and necrotic tissue were concordant (i.e., that normal tissue was supplied by the LMCA, and necrotic tissue by the LAD). However, a small zone of vascular discordance, averaging approximately 30 /im in width, was present along the infarct boundary, possibly representing a narrow border zone of little conse- quence. Hence, the complex interdigitation of normal and necrotic tissue in the lateral border of an infarct is predominantly a function of the interdigitation of the capillary beds supplied by the occluded and nonoccluded arteries.

Mechanisms of beneficial effects of vasodilators and inotropic stimulation in the experimental failing ischemic heart

Both vasodilator and inotropic agents improve cardiac function in ischemic heart failure. However, since vasodilators may reduce coronary perfusion pressure and inotropic interventions may increase myocardial oxygen consumption (MVO2), both may increase myocardial ischemia. Accordingly, we determined myocardial blood flow and MVO2 in a canine model of failure induced by propranolol and volume load combined with acute coronary ligation. Both nitroprusside and digitalis reduced ventricular diastolic pressure (LVDP) and increased myocardial blood flow in the ischemic subendocardium. Decreased systolic wall tension also caused a significant reduction MVO2. The benefit of nitroprusside in failing hearts was obtained even with the addition of critical obstruction of the main left coronary artery (LCA). The role of preload reduction is emphasized by the contrasting results with nitroprusside in hearts with low LVDP: (1) decreased myocardial blood flow in ischemic subendocardium, and (2) left ventricular decompensation in animals with critical LCA obstruction. Thus, reduction of LVDP, which decreases subendocardial ischemia, is essential for the beneficial effects of vasodilators and inotropic interventions in ischemic heart failure. Decreased MVO2 caused by reduced heart size may also have a salutary role.