Modulation of coronary flow by left ventricular volume in the presence and absence of vasomotor tone.

This study was undertaken to determine the relationship between left ventricular (LV) volume and coronary flow in the presence and absence of coronary vasomotor tone in arrested dog hearts. We utilized an isolated, blood-perfused, potassium-arrested dog heart preparation with vascular vasomotor tone present (n = 5) or after maximal vasodilation with adenosine (n = 7). LV volume was controlled with a balloon while left and right coronary flows were recorded. Left and right coronary flows were plotted as a function of LV volume, and the degree of interdependency was quantitatively assessed by the slope of the linear regression and the correlation coefficient (r) between coronary flow and LV volume. With vasomotor tone present, both left (slope = 0.01 +/- 0.06 min-1) and right (slope = -0.01 +/- 0.01 min-1) coronary arterial flows were maintained relatively constant over a wide range of LV volumes. After maximal vasodilation, left coronary flow decreased linearly with LV volume loading (slope = -2.51 +/- 0.47 min-1, r2 = 0.96 +/- 0.02), whereas right coronary flow, similar to the response with tone present, did not change relative to control in most cases. We conclude that changes in coronary vasomotor tone may take place with LV volume loading to compensate for the mechanical vascular resistance changes secondary to myocardial stretch.

Left ventricular mechanics in arrested dog heart: effects of ventricular interaction and vascular volumes.

The present study was designed to determine the effects of right heart pressure on the compliance of the left ventricle (LV). The studies were conducted on isolated, blood-perfused, potassium-arrested dog hearts with vasomotor tone either present (n = 5) or absent (n = 8). A balloon was used to control LV volume, whereas right heart (RHP) or coronary sinus (CSP) pressures were controlled via a column placed in the right heart or coronary sinus, respectively. Control of CSP independently of RHP allowed us to assess the relative contribution of coronary venous pressure to changes in LV compliance under conditions of elevated RHP. LV volume and compliance at a LV pressure of 15 mmHg (V15 and C15, respectively) were calculated to quantify the shift and slope changes of the LV pressure-volume (P-V) relationships. V15 and C15 decreased with vasomotor tone present from 52.8 +/- 1.4 ml and 1.7 +/- 0.1 ml/mmHg at control, to 43.3 +/- 2.1 ml and 1.4 +/- 0.1 ml/mmHg (P < 0.05) with RHP = 0 and 20 mmHg, respectively. Similar effects were obtained with vasodilation, but C15 was significantly lower relative to autoregulation but C15 was significantly lower relative to autoregulation (1.0 +/- 0.1 at control RHP, P < 0.05). Elevation of CSP with vasomotor tone resulted in an upward shift in the LV P-V relationship: V15 decreased from 53.4 +/- 2.1 at CSP = 0 mmHg to 50.9 +/- 1.6 ml at CSP = 20 mmHg (P < 0.05). After vasodilation there was no detectable shift in the LV P-V relationship with elevation of CSP.

Reduced collateral perfusion is a direct consequence of elevated right atrial pressure.

In the present study we determined quantitatively the effects of increased right atrial pressure (RAP) on coronary and collateral flows. In an isolated, blood-perfused, maximally vasodilated dog heart preparation in which the left ventricle was vented, we used the retrograde flow method to assess collateral flow. When RAP was elevated from 5 +/- 1 (control) to 13 +/- 1 and 23 +/- 1 mmHg, retrograde flow from the left circumflex coronary artery (which was open to atmospheric pressure) increased 29 +/- 8 and 97 +/- 21% relative to control while left anterior descending flow decreased 5 +/- 1 and 14 +/- 2%, respectively (P < 0.01; n = 7). The increase in retrograde flow could be due to 1) an increase in collateral flow due to increased pressure at the origin of the collaterals or 2) the elevated RAP (venous outflow pressure), which forces the antegrade collateral flow component in the retrograde direction. To distinguish between these possibilities we embolized the circumflex with 30-microns spheres to eliminate the antegrade flow component. After embolization there was no significant change in retrograde flow with elevated RAP, indicating that the second supposition was correct. We conclude that increased RAP 1) results in a reduction of flow to the collateral-dependent myocardium and 2) reduces perfusion of the unoccluded coronary vessel. Furthermore, we found that under conditions of varying venous outflow pressure, retrograde flow may not serve as a reliable index of collateral flow.

Pressure-flow characteristics of intramural and total coronary collateral networks.

The purpose of the present investigation was to determine the pressure-flow (PF) relationship of intramural collaterals and to determine whether their characteristics differ significantly from those of the total collateral network, defined as the epicardial plus intramural collateral network. Because a significant portion of the collateral flow is diverted away from the retrograde flow measurement, we embolized the coronary vessel on which the retrograde flow was measured with spheres of various sizes until the retrograde flow was maximized and retrograde flow diversion blocked. The PF relationship was obtained before and after the epicardial collaterals were cauterized to determine the characteristics of the total and intramural collateral network. PF data for the collateral circulations were obtained by changing the inflow pressure to all coronary vessels simultaneously and by measuring the retrograde flow while maintaining the retrograde outflow pressure at 0 mmHg. The PF characteristics of the total and intramural collateral circulations could be fitted by either a second-degree polynomial or linear equation. In both cases the pressure intercept crossed the origin of the axes. The average contribution of intramural collaterals to total retrograde flow was 58 +/- 5%. We conclude that the PF characteristics of intramural collaterals parallel those of the total collateral circulation.

Coronary and myocardial adaptations to high altitude in dogs.

The objective of this study was to determine whether exposure to high altitude (hypoxic hypoxemia) induces coronary and/or collateral growth. Fourteen mongrel dogs were maintained at a simulated altitude of 18,000 ft for 1 mo and 7 dogs maintained for 3 mo. Within 2 days after their sojourn, the following data were obtained at ambient pressure: pulmonary, right heart chamber, and wedge pressures as well as cardiac output. On an isolated heart preparation, coronary and collateral flows were determined; each vessel was injected with a different color tracer; and the heart was sliced, separated by perfusion territories, and examined for myocardial hypertrophy. We found that pulmonary artery pressures in altitude-adapted animals were higher compared with controls, and coronary flow per gram was increased after 1 mo of exposure but not different from control after 3 mo. Collateral flows were not significantly different from that of control animals, and biventricular hypertrophy occurred with right ventricular dominance. Comparing these results with those that we obtained previously from anemic animals, we favor the hypothesis that oxygen availability rather than blood flow velocity is most likely linked to vascular growth.

Functional anatomical site of intramural collaterals in dogs.

The objectives of the present study were to determine quantitatively whether the retrograde flow measurement reflects the total flow from collateral vessels or overestimates or underestimates collateral flow, and to determine the functional anatomical origin of intramural collaterals in the native dog heart. In an isolated heart preparation, three experimental procedures were used. 1) The left circumflex coronary artery was embolized with microspheres of different sizes; then retrograde flows and the peripheral coronary pressures were measured. 2) Epicardial collaterals were cauterized, and retrograde flows were measured before and after cautery. 3) Epicardial collaterals were cauterized followed by embolization of the circumflex coronary artery with different size spheres. We found that 1) the retrograde flow measurement underestimates the total collateral flow to the circumflex coronary artery by approximately 25%, 2) intramural collateral flow constitutes 58 +/- 3.5% of the retrograde flow measurement, 3) the antegrade component of blood flow that is not measured during a retrograde flow measurement is from the intramural collateral circulation, and 4) the functional site of origin of intramural collaterals is greater than 25 microns but less than 80 microns in diameter. We conclude that, in our preparation, retrograde flow underestimates total collateral flow, and that intramural collateral flow is a major component of retrograde flow in the native dog heart.

Coronary sinus pressure has a direct effect on gradient for coronary perfusion.

In previous work from this laboratory we demonstrated that the coronary pressure-flow relationship exhibits a zero pressure intercept in the absence of the influence of the collateral circulation. In the present study we determined the effect of varying coronary sinus pressures on coronary perfusion. Specifically, we investigated whether coronary flow would cease when the coronary inflow pressure equaled the coronary sinus pressure. The study was performed while inflow perfusion pressure to all coronary vessels was changed simultaneously in order to reduce the influence of the collateral circulation while coronary sinus outflow was measured. Coronary pressure-flow relationships were obtained for coronary sinus pressures of 0, 10, and 20 mmHg. The results demonstrate a strong correlation between perfusion pressure and coronary sinus pressure (r2 = 0.994 +/- 0.001), which passed through the origin. We conclude that coronary sinus pressures between 0 and 20 mmHg have a direct influence on coronary perfusion.

Microvascular occlusions promote coronary collateral growth.

The objective of this study was to examine whether myocardial ischemia without alterations in pressure gradients between large epicardial coronary arteries was a sufficient stimulus to produce coronary collateral growth and development. To accomplish this aim, we partially embolized the circumflex coronary perfusion territory with 25-microns diameter microspheres to produce multiple microvascular occlusions, sufficient to abolish or greatly attenuate coronary vasodilator reserve. The embolization procedure was performed in two groups of dogs during aseptic surgery. After the dogs recovered for 1-3 wk (short-term embolization) or 6-8 wk (long-term embolization), indexes of vascular growth were compared with a group of control animals in which all operative procedures were performed, except embolization. Retrograde blood flow, an index of collateral blood flow and coronary vascular resistance, was determined in an isolated beating empty heart preparation during coronary vasodilation with adenosine. Circumflex retrograde blood flow from the left anterior descending artery was increased from 0.09 ml.min-1.g-1 (sham) to 0.21 and 0.17 ml.min-1.g-1 in the short-term and long-term groups, respectively (P less than 0.05). Collateral blood flow from the septal artery was also increased from 0.03 ml.min-1.g-1 (sham) to 0.08 ml.min-1.g-1 (P less than 0.05) in the short-term group. Collateral contribution from the right coronary artery was not significantly altered in either group of embolization animals. The contributions of epicardial and intramyocardial collaterals to the total retrograde flow were also determined and were found to be different among the three experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Intramural coronary collateral flow in dogs.

The objective of this study was to determine whether intramural collaterals contribute significantly to total retrograde flow (index of collateral flow). The left circumflex, left anterior descending, right, and septal coronary arteries were separately cannulated, and blood flows through these vessels were monitored on an isolated, blood-perfused beating heart preparation. Epicardial collaterals between the borders of the circumflex and right coronary perfusion territories were cauterized, and retrograde flow from the circumflex coronary artery was determined before and after cauterization. This procedure unmasked the intramural collateral flow component to retrograde flow. By occluding and unoccluding the coronary flows from the right, septal, and left anterior descending coronary arteries during these measurements, we were able to determine their contribution to epicardial and intramural collateral flow. We found that, after cauterization, an average of 58 +/- 3.6% of the total retrograde flow remained. The septal and left anterior descending coronary arteries contributed almost equally to this retrograde flow. We concluded that, because the epicardial collaterals were cauterized, the source of retrograde flow was from intramural collaterals and constituted about one-half of the measured retrograde flow in dogs with a native collateral circulation.

Collateral influence on pressure-flow characteristics of coronary circulation.

The purpose of this study was to determine the role of the coronary collateral circulation on the shape of the coronary pressure-flow (P-F) relationship and its effects on the pressure at zero flow (PZF) or pressure intercept. We investigated the P-F characteristics of the coronary circulation under two conditions. 1) To minimize the influence of collaterals, we measured coronary flow by timed collections of coronary sinus outflow in 15 dog hearts, as perfusion pressure to all vessels was varied; 2) to maximize the effect of collaterals, we measured circumflex artery flow in six dog hearts, as perfusion pressure to only the circumflex coronary artery was varied and the pressure in the remaining vessels was maintained constant. We used an isolated heart preparation in which ventricular chamber and venous outflow pressures equalled atmospheric pressure and the vessels were maximally dilated with adenosine. In the first condition, the P-F relationship was curvilinear with a PZF of 0 mmHg; in the second condition, the P-F relationship was curvilinear with a PZF of 16 +/- 2 mmHg, and flow was retrograde at pressures below PZF. We conclude that in both conditions the curvilinearity of the coronary P-F relationship was the result of nonlinear elastic properties of blood vessels, not requiring the "waterfall" concept to be invoked, and that in the second condition the influence of collateral vessels produced the positive pressure intercept.

Regression and recovery of well-developed coronary collateral function in canine hearts after aorta-coronary bypass.

After restoration of antegrade blood flow by coronary artery bypass grafting to a region of myocardium supplied by well-developed collateral vessels, there is regression of collateral supply to that region. There is controversy as to how rapidly this regression occurs, how soon collateral flow might return after an acute occlusion of the bypass graft, and how effective pharmacologic agents such as nitroglycerin might be in accelerating this return. To investigate this problem, 14 canine hearts were collateralized by Ameroid occlusion of the left anterior descending coronary artery. Regression and recovery of well-developed collateral function were studied after opening and closing an aorta-coronary bypass. Before bypass, peripheral coronary pressure was 82 +/- 2 mm Hg, retrograde flow 63 +/- 7 ml/min, collateral flow 21 +/- 2 ml/min, and collateral resistance 0.96 +/- 0.13 mm Hg/ml/min. One hundred minutes of bypass perfusion significantly decreased peripheral coronary pressure by 27%, retrograde flow by 52%, and collateral flow by 42%, and significantly increased collateral resistance by 319%. When the bypass was acutely occluded for 30 minutes, collateral resistance decreased spontaneously by 37%. When intracoronary nitroglycerin was administered for 5 minutes immediately after bypass occlusion, collateral resistance rapidly decreased by 72%, but subsequent collateral regression was not alleviated. Increased flow through regressed collateral vessels during retrograde flow diversion was associated with a decrease in collateral resistance. Results demonstrate rapid but not instantaneous regression and recovery of mature collateral function in response to requirements of collateral-dependent myocardium. Regressed collateral vessels can be dilated by nitroglycerin. Flow-dependent changes in collateral vascular tone appear to be responsible for early regression and recovery of collateral function.

Pressure-flow characteristics of coronary collaterals in dogs.

In this study we utilized two methods to investigate the pressure-flow, P-F, relationship of the coronary collateral vessels in a beating, blood-perfused, isolated heart preparation. In the first method (free-flow method), 12 dog hearts were perfused at pressures ranging from 100 to 0 mmHg, whereas the retrograde flow (index of collateral flow) was measured on the circumflex coronary artery, LCA, against atmospheric pressure, first during autoregulation and then after maximum vasodilation. In the second method (back-pressure method), the back pressure to retrograde flow was varied from 0 to 100 mmHg, whereas the perfusion pressure to the remaining vessels was maintained constant at 100 mmHg. This procedure was performed on four hearts with and without embolization of the LCA by 25-microns spheres. The free-flow method demonstrated a linear P-F relationship with an average correlation coefficient, r, of 0.98. The pressure intercept was 1.7 +/- 1.2 mmHg. The back-pressure method yielded a relationship that was more curvilinear with an average pressure intercept of 13 mmHg without embolization and 38 mmHg with embolization. An analog of the coronary and collateral circulation was used to illustrate that, in the back-pressure method, changes in the coronary resistance at low pressures contributed to the nonlinearity of the collateral P-F characteristics and that the network formed between the collateral and coronary resistances was responsible for the higher pressure intercept value.

Septal collateralization: demonstration of canine intramyocardial collaterals.

The anatomical distribution of intramyocardial collateral arteries that develop from the septal to the other major coronary arteries was studied in dogs following gradual Ameroid occlusion of the circumflex artery. The septal artery was cannulated and injected with Batson's plastic compound resulting in a cast of the coronary circulation. Collateral vessels radiated from the septal vascular bed to both the circumflex and anterior descending arteries. The collaterals developed from the entire base-to-apex extent of the septal artery and were found on both the right and left sides of the septum. Collateral growth appeared to be more concentrated at the apex of the heart. The anatomical details of septal collateral circulation illustrate the importance of intramyocardial collateralization in the dog, which was thought to exhibit primarily epicardial collaterals.

Hypertrophy and coronary and collateral vascularity in dogs with severe chronic anemia.

The purpose of this study was to determine 1) whether a severe hypoxic stimulus could produce an increase in coronary and collateral vascularization and 2) whether minimal coronary resistance, which increases with hypertension-induced hypertrophy, decreases when hypoxia is superimposed on volume load hypertrophy. Data were obtained on 11 dogs rendered anemic to a hematocrit of 11 +/- 0.2 vol% and maintained at this level for 4 wk. Eighteen dogs with a hematocrit of 42 +/- 0.02 vol% were used as controls. After chronic anemia the coronary and collateral flows were quantitated in a beating, vasodilated, isolated heart preparation perfused solely with blood from two normal donor dogs. The following variables were significantly increased in anemia-exposed hearts compared with controls: coronary flow per gram myocardium for the left anterior descending, the circumflex, the right, and the septal arteries; ratio of total coronary flow of each vessel to body weight; and the collateral flows to each coronary vessel. Both the right and left ventricles were hypertrophied. We conclude that severe chronic anemia produces a dissociation between hypertrophy and increased minimal coronary resistance. Severe chronic anemia appears to increase vascularization of both coronary and collateral circulation probably due to tissue hypoxia. In this model coronary collateral vascularity seems to increase in the absence of a pressure difference across collaterals.

Coronary, collateral, and perfusion territory responses to aortic banding.

The objectives of this study were 1) to separate anatomic from functional variables causing the increased minimal coronary resistance seen with hypertrophy; 2) to investigate whether increased intraluminal pressure and tangential wall stress lead to collateral proliferation; 3) to define changes in vascular perfusion territories resulting from hypertrophy. Coronary and collateral resistances of the four coronary arteries were determined in empty, beating hearts from 10 control dogs and 11 dogs with myocardial hypertrophy produced by 4 wk of aortic banding. In hypertrophied hearts the coronary flow per gram at 100 mmHg and the slope of the pressure-flow line were significantly decreased. Coronary flow-to-body weight ratios were not different; thus the decreased flow per gram tissue with hypertrophy was due to increased tissue mass rather than changes in vascular resistance. Collateral flows were similar for both groups, indicating that increased pressure and wall stress did not cause significant collateral growth. Both ventricles hypertrophied and all vascular beds were equally affected, but distribution of the increased mass varied for different vascular beds.

Reduced resistances of septal artery collateral channels after cardiac sympathectomy.

We have shown that chronic cardiac sympathectomy reduces coronary collateral resistances. The present experiments in isolated dog hearts delineated the role of intramyocardial collateral channels from the septal (SEP) to the circumflex (CIRC), left anterior descending (LAD), and right (RT) coronary arteries in this phenomenon. In 11 controls and 8 2-wk sympathectomized hearts, a retrograde flow technique was used to determine collateral resistances between the epicardial arteries (CIRC, LAD, RT). Collateral resistances between the CIRC and LAD and between the LAD and RT were 42-68% less in sympathectomized hearts (P less than 0.05). Collateral resistances from the SEP to each epicardial artery were determined from retrograde flows simultaneously collected on each epicardial artery when the SEP was the only vessel perfused. Collateral resistances from the SEP to the CIRC and LAD were 51-59% less in the sympathectomized hearts (P less than 0.05). Thus, intramyocardial channels from the SEP to the left coronary arteries show reduced resistances after sympathectomy and can provide a substantial portion of the increased collateral flow to these vessels.

Relationship of coronary flow and perfusion territory in dogs.

In this study the relationship between myocardial flow and perfusion territory at maximal vasodilation was examined for the left anterior descending (A), circumflex (C), right (R), and septal (S) coronary arteries. Average flows to A, C, R, and S were 31.2 +/- 1.5 (SE), 41.2 +/- 13.5 +/- 0.6, and 14.1 +/- 0.6% of total coronary flow. Strong correlations were found between weight and volume, weight and coronary flow, and weight and resistance of the perfusion territories of A, C, R, and S. However, coronary flow (milliliter per minute per gram) to the right ventricle was significantly lower than to the left ventricle. Examination of the distribution of perfusion territories from base to apex of the heart showed that the anterior descending territory increases from base to apex, whereas the right decreases from base to apex. Circumflex flow distribution is relatively uniform between these limits, and the septal artery is most pronounced at midlevel and tapers toward the apex and base.

Myocardial infarction in dogs with acute and gradual occlusion of the circumflex or right coronary arteries.

This study was designed to quantitate and describe the incidence and magnitude of myocardial infarction in the canine heart following acute and gradual occlusion of the circumflex or right coronary arteries. In animals with acute occlusion, the circumflex artery was ligated just distal to the bifurcation of the left coronary artery for 4 hr (seven dogs). Gradual occlusion was produced by placing an Ameroid occluder on the circumflex artery for 1 month (nine dogs), 3 months (nine dogs), and 5 months (eight dogs) and on the right coronary artery for 3 months (nine dogs). Ten dogs served as controls. At the end of the experiments the dogs were sacrificed, and identification of myocardial infarction was made with an enzyme-mapping technique in dogs with acute occlusion and with histological methods in dogs with gradual occlusion. The volume of ventricular infarction was determined with the use of an Apple II Computer and graphics tablet. After 3 months, gradual occlusion of the right coronary artery produced a 22% incidence of infarction which was significantly less (P less than .01, chi 2) than the 67% incidence observed with 3 months of gradual circumflex occlusion. The average infarct volume produced by gradual right coronary occlusion was 0.94 + 0.69%. The average volume of left ventricular infarction in animals with circumflex acute occlusion was 15.6% + 6.6 and the incidence of infarction was 100%. With gradual occlusion of the circumflex artery for 1, 3, and 5 months, average left ventricular infarction was 2.02 +/- 1.01%, 3.13 +/- 1.53%, and 2.96 +/- 1.35%, respectively. There were no significant differences in the amount of damage observed among the three groups with gradual occlusion, and the average incidence of infarction for these three groups was 76%. In the 1-, 3- or 5-month animals with circumflex occlusion, no additional areas of necrosis subsequent to the original damage were found, indicating that infarction is a single event in this model of gradual occlusion. These results suggest that infarct size is determined primarily by factors at the time of total occlusion and that gradual occlusion allows sufficient time for collateral growth, thereby limiting the extent of myocardial injury.