Determinants of collateral development in a canine model with repeated coronary occlusion.

It is now accepted that repetitive 2-min coronary occlusion can develop collateral vessels to the area perfused by the occluded coronary artery. However, which factors influence collateral development has yet to be fully elucidated. The goal of the present study was to identify the determinants of the rate of coronary collateral development in dogs undergoing repeated coronary occlusion. The study was conducted in 19 conscious dogs instrumented for measurements of a subendocardial segment length in the area perfused by the left circumflex coronary artery (LCCA), LCCA flow, and left ventricular pressure. An externally inflatable pneumatic occluder was placed around the LCCA. After the recovery from surgery, 2-min LCCA occlusions were conducted eight times daily. Following 141 +/- 61 (SD) LCCA occlusions (20 +/- 7 days), an LCCA occlusion produced no reduction in segment shortening and negligible reactive hyperemia. The total number of LCCA occlusions needed for adequate collateral development (the rate of collateralization) correlated well with the severity of myocardial ischemia during the first occlusion, which was determined mainly by the extent of postsurgical initial collateral circulation. On the other hand, the response to the ischemic stimulus in the later stage of collateral development was independent of the extent of development of the initial postsurgical collaterals. It is concluded that the overall rate of collateral development is slower in dogs with initially poorer collaterals; however, the response of each dog to the ischemic stimulus in the later stage of collateral development was similar among dogs regardless of the extent of the initial collaterals.

Effects of nitroglycerin and diltiazem on well-developed coronary collateral circulation in conscious dogs.

The purpose of the present study was to compare the effects of nitroglycerin and diltiazem on coronary collateral circulation. Studies were conducted in 8 conscious dogs instrumented for the measurement of left circumflex coronary artery (LCCA) flow, subendocardial segment lengths in areas perfused by the LCCA, and left anterior descending coronary artery (LAD). Brief, repeated LCCA occlusions sufficiently developed collateral vessels for the resting metabolic requirement in the LCCA region. One week following the cessation of repeated LCCA occlusions, two-minute coronary occlusions with and without drug pretreatment were performed on separate days. The ischemic responses to coronary occlusions were not altered by diltiazem (50 micrograms/kg, IV), but nitroglycerin (5 micrograms/kg, IV) attenuated myocardial ischemia definitely. The authors conclude that nitroglycerin produces greater effects than diltiazem in attenuating myocardial ischemia in the collateral dependent zone when effects of each drug on systemic and coronary circulation were minimized by pretreatment with small doses.

Bidirectional function of coronary collateral channels in conscious dogs.

STUDY OBJECTIVE: The aim was to investigate the bidirectional functional adequacy of collateral perfusion in conscious dogs. DESIGN: Left circumflex coronary artery (LCCA) occlusions of 1 or 2 min duration were repeated to stimulate the development of collateral perfusion to the LCCA area, and the left anterior descending coronary artery (LAD) was occluded once daily to evaluate the development of retrograde LCCA-LAD flow. SUBJECTS: 7 male mongrel dogs were used, weight 25-28 kg. MEASUREMENTS AND MAIN RESULTS: Coronary collateral flow from the LCCA to the LAD perfusion area was measured as the abrupt decrease in the LCCA flow (implanted Doppler transducer) upon release of a brief LAD occlusion. Measurements were repeated daily during the development of collaterals induced by repeated, brief occlusions of the LCCA. After 35(SD17) days of such occlusions; there was no sustained reduction in LCCA regional myocardial function during an LCCA occlusion, and reactive hyperaemic repayment following the occlusion was negligible. Before and after collateral development, the LCCA to LAD collateral flow increased from 1.1(0.2) to 8.6(5.1) cm.s-1. LAD systolic segment shortening during the LAD occlusion increased from 2.1(2.0)% (first occlusion) to 19.3(8.6)% (last occlusion). CONCLUSIONS: LAD to LCCA collaterals serve as functionally significant bidirectional perfusion conduits, and monitoring of collateral perfusion development is practical by measuring the step reduction in LCCA flow upon abrupt release of an LAD occlusion.

Coronary collateral regression in conscious dogs.

To study the effect of long-term coronary reperfusion on regression of newly developed collateral vessels, the authors reoccluded the coronary artery for ten minutes following one to fifteen weeks of reperfusion. They repeated one- or two-minute occlusions of the left circumflex coronary artery (LCCA) in 8 conscious dogs. After 401 +/- 202 (SD) minutes of total LCCA occlusion time (35 +/- 19 days), The LCCA occlusion produced no sustained reduction in regional myocardial shortening and negligible reactive hyperemia. Upon reocclusion following a long-term reperfusion, the subendocardial segment shortening in the region at risk deteriorated markedly. At two minutes of occlusion, percent systolic shortening showed minimal values and thereafter gradually returned to the preocclusion resting levels within six to eight minutes of occlusion. In the presence of a resting heart rate similar to that at the time of functional recovery during the LCCA occlusion, long-term reperfusion did not modify the time course of regional functional response to the prolonged coronary occlusion. It is concluded that the newly developed collateral vessels still serve as significant blood-conveying conduits following a considerable period of reperfusion, and it requires approximately six to eight minutes to restore regional myocardial function in the collateral dependent zone following coronary reocclusion.

Effects of dipyridamole on collateral flow and regional myocardial function in conscious dogs with newly developed collaterals.

Studies were conducted on six conscious dogs instrumented for measurement of subendocardial segment lengths in the area perfused by the left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCCA), LCCA flow, and left ventricular pressure. Externally inflatable occluders were placed around the proximal LAD and LCCA. Collateral channels sufficient for the resting metabolic demands in the occluded LCCA perfusion territory were induced by repeated, brief LCCA occlusions. Dogs were then subjected to two consecutive brief periods of LAD occlusion. Dipyridamole (0.25 mg/kg) was injected intravenously 3 min prior to the second LAD occlusion. The collateral blood flow from the LCCA to the occluded LAD area was measured as the stepwise decrease in LCCA flow upon release of the LAD occlusion. During LAD occlusion after dipyridamole treatment collateral blood flow velocity decreased to 3.8 +/- 1.1 cm/s (+/- standard error) compared with a value of 4.9 +/- 0.9 cm/s measured during LAD occlusion without dipyridamole treatment. Percentage systolic segment shortening in the collateral dependent zone significantly deteriorated from 14.3 +/- 5.2 to 9.7 +/- 5.0% (p less than 0.05). Electrocardiograms taken simultaneously from endocardial ultrasonic transducers in the ischemic segment revealed significant increases in ST-segment level from 4.2 +/- 0.6 to 5.4 +/- 0.6 mV. These findings indicate that dipyridamole adversely affects the extent of myocardial ischemia in the collateral-dependent zone.

An automatic syringe for coronary occlusion in long-term collateralization studies.

A portable apparatus for performing repeated, brief coronary artery occlusions automatically in long-term chronic studies involving dogs and larger animals is described. The battery-operated, back-pack-carried device uses a motorized syringe driven by a digital-programmable timing circuit to inflate a coronary artery occluder for durations of 10 s to 3 min at intervals from 14 s to 16 h. A single battery charge produces 450 occlusions. The generated pressure is adjustable to 1,000 mmHg maximum. A separate fail-safe circuit monitors system operation to open a pressure-relief valve if occlusions exceed a preset duration.

Changes in regional myocardial cross-sectional area during brief coronary occlusion and reperfusion in conscious dogs.

The effect of a brief period of coronary occlusion on a regional myocardial cross-sectional area was studied in 6 conscious dogs. Subendocardial segment length and wall thickness were continuously measured with a sonomicrometer in the central ischemic area perfused by the left circumflex coronary artery during a 2-min circumflex occlusion and subsequent reperfusion. Measurements were repeated before and after collateral development induced by 180 +/- 30 (SEM) 2-min circumflex occlusions (20 +/- 3 days). In order to evaluate the changes in regional myocardial volume, end-diastolic regional cross-sectional area was calculated as a product of end-diastolic segment length and wall thickness. Before collateral development, end-diastolic regional cross-sectional area transiently decreased 1.4 +/- 0.6% (NS) at 10 sec following sudden coronary occlusion, thereafter gradually increased to 3.7 +/- 1.0% (P less than 0.05) at the end of a 2-min occlusion. At 10 sec of reperfusion, end-diastolic regional cross-sectional area further increased to 7.0 +/- 1.1% (P less than 0.05) probably due to increased intravascular volume. Increase in end-diastolic regional cross-sectional area was still 2.5 +/- 0.6% (NS) at 3 min after the release of occlusion. After collateral development, the changes in end-diastolic regional cross-sectional area were 0.1 +/- 0.1% (NS), 0.4 +/- 0.3% (NS), 1.0 +/- 0.6% (NS) and 0.2 +/- 0.4% (NS), respectively. Thus, a significant increase in the regional myocardial cross-sectional area occurs during a brief period of coronary occlusion and reperfusion.

Changes in isovolumic segment shortening following acute coronary occlusion: disproportionate effects of anterior versus posterior ischemia.

We evaluated the changes in left ventricular pressure and isovolumic segment shortening in both the ischemic and nonischemic areas following acute coronary occlusion in 12 conscious dogs instrumented for the measurement of subendocardial segment lengths perfused by the left circumflex coronary artery and left anterior descending coronary artery, and left ventricular pressure. An externally inflatable pneumatic occluder was placed around the left circumflex coronary artery. In 6 dogs, another occluder was installed around the proximal left anterior descending coronary artery. Under the resting conditions, the isovolumic segment shortening in the areas supplied by the left anterior descending coronary artery and the left circumflex coronary artery were 2.1 +/- 0.5% (SE) and -0.1 +/- 0.5% (P less than 0.01; versus values in the area of the left anterior descending coronary artery), respectively. During a 1-min occlusion of the left circumflex coronary artery, the isovolumic shortening in the anterior segment increased to 3.8 +/- 0.5% (P less than 0.001; versus values in the basal state), while the posterior segment produced isovolumic elongation (-2.2 +/- 0.5%, P less than 0.001; versus values in the basal state). By contrast, during a 1-min occlusion of the left anterior descending coronary artery, the extent of isovolumic bulge in the anterior segment and the augmentation in the isovolumic shortening in the posterior segment was less prominent compared with the occlusion of the left circumflex coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Opening of coronary collaterals by repeated brief coronary occlusions in conscious dogs.

The collateral blood flow and regional myocardial function during a one-minute coronary occlusion were compared before and after multiple one-minute coronary occlusions. After repeated coronary occlusions, the collateral blood flow velocity increased significantly from 0.7 +/- 0.1 (SE) to 2.0 +/- 0.2 cm/sec (p less than 0.05), and the blood flow debt repayment decreased from 326 +/- 26% to 189 +/- 12% (p less than 0.05). The systolic segment shortening in the collateral dependent zone improved slightly. Thus, the native coronary collateral vessels open in response to a repeated ischemic stimulus.

Regional myocardial volume alterations induced by brief repeated coronary occlusion in conscious dogs.

The purpose of this study was to evaluate whether brief repeated coronary occlusions induce changes in regional myocardial geometry at rest. Five conscious dogs were instrumented for the measurement of subendocardial segment length and transmural wall thickness in the ischemic area, subendocardial segment length in the normally perfused area, coronary flow and left ventricular pressure. After recovery from surgery, 180 (mean) 2 min coronary occlusions were given over a period of 20 days. The heart rate at rest, left ventricular peak systolic and end-diastolic pressures and peak positive first derivative of left ventricular pressure (dP/dt) remained unchanged throughout the experiment. In the normal area, the end-diastolic segment length at rest did not change significantly. By contrast, in the ischemic area, at 14 days after the initiation of repeated coronary occlusion, the end-diastolic regional cross-sectional area (product of segment length and wall thickness) at rest had increased by 9.7% (p less than 0.05); thereafter it decreased to 6.5% (p less than 0.05) above the value at rest before repeated occlusion despite an additional 6 days of coronary occlusions. At 10 days after the interruption of repeated occlusion, this value had regressed to 4.3% (p = NS) above control. These findings suggest the occurrence of regional myocardial hypertrophy confined to the ischemic area in response to the periodic ischemic stimulus.

Effects of glyceryl trinitrate on functionally regressed newly developed collateral vessels in conscious dogs.

The effects of glyceryl trinitrate on collateral blood flow and regional myocardial function during a 2 min coronary occlusion were evaluated in 10 conscious dogs with well developed collateral vessels. Collateral growth was promoted by brief, repeated, reversible coronary occlusions. After partial regression in collateral function a small dose of glyceryl trinitrate (5 micrograms.kg-1) was injected intravenously 1 min before coronary occlusion. After pretreatment with glyceryl trinitrate the collateral blood flow velocity (mean[SD]) increased from 3.0(0.9) to 4.4(1.4) cm.s-1 (p less than 0.05). After 2 min of occlusion the percentage systolic subendocardial segment shortening in the collateral dependent zone increased from 7.8(6.1) to 12.6(6.7)% (p less than 0.05). The blood flow debt repayment after release of the occlusion decreased from 122(41) to 68(34%) (p less than 0.05). Thus in conscious dogs with regressed newly developed collaterals a major component of the beneficial effects of glyceryl trinitrate on collateral circulation is dilatation of collateral vessels, as evidenced by a pronounced increase in collateral blood flow and myocardial function during a transient period of coronary occlusion.

Electrocardiographic evaluation of collateral development in conscious dogs.

In seven conscious dogs, endocardial ST-segment changes within the central ischemic area at 2 min after coronary occlusion were compared with the amount of reactive hyperemia and collateral blood flow. With the use of ultrasonic dimension gauges implanted in the subendocardium perfused by the left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCCA), endocardial electrocardiograms and regional myocardial dimensions were simultaneously measured. Collateral vessels were developed by repeated 2 min LCCA occlusions during three weeks. Blood flow debt repayment following the release of LCCA occlusion was measured using a Doppler flowmeter. The collateral blood flow from LCCA to the area supplied by the occluded LAD was measured as a stepwise reduction in LCCA flow upon the release of LAD occlusion. With the attenuation of myocardial ischemia due to the collateral development, endocardial ST-segment shift revealed earlier restoration compared with subendocardial function. In the presence of mild ischemia, the ST-segment was still elevated. Thus, endocardial ST-segment changes serve as an indirect functional index of collateral development as well as regional myocardial function and blood flow debt repayment.

Effect of myocardial contraction on systolic coronary resistance in conscious dogs.

We studied the effect of cardiac contraction on systolic coronary resistance under the conditions of maximally dilated coronary resistance vessels in six conscious dogs. Subendocardial segment length in areas supplied by the left circumflex coronary artery, left ventricular pressure and left circumflex coronary artery flow were simultaneously measured. At 5 sec after release of the first 2 min of left circumflex coronary artery occlusion, diastolic coronary blood flow revealed its peak value in association with markedly depressed regional contractile function. With collateral development induced by repeated 2 min left circumflex coronary artery occlusions, segmental dysfunction during occlusion and early reperfusion was progressively attenuated. Before and after collateral development, diastolic coronary resistance at 5 sec of reperfusion remained unchanged, but systolic coronary resistance increased by 41% secondary to restoration of regional myocardial shortening. In each animal, normalized regional shortening correlated well with changes in systolic coronary resistance. The fraction of systolic coronary resistance due to active regional myocardial contraction was 52%. These studies demonstrate that when coronary vasomotor tone is abolished, regional myocardial contraction impedes the coronary systolic flow in proportion to the extent of shortening.

Evaluation of coronary collateral development by regional myocardial function and reactive hyperaemia.

The development of collateral vessels was induced by repeated brief left circumflex coronary artery occlusions in 11 conscious dogs. Subendocardial segment shortening in the central ischaemic area and the ischaemic marginal area and transmural wall thickening in the centre of the ischaemic area were measured together with circumflex coronary flow. Changes in regional myocardial function and reactive hyperaemia were determined daily. The rate of recovery of myocardial function after collateralisation was almost identical in both regions. Before myocardial contractility was restored reactive hyperaemia was greatly attenuated. These data strongly suggest that collateral flow is distributed uniformly over the ischaemic bed and that substantial areas of myocardial tissue at risk are salvaged from ischaemia as a result of effective collateral circulation.

Characterization of nonischemic segment shortening during variable extent of myocardial ischemia in conscious dogs.

Studies were performed on seven conscious dogs chronically instrumented for measurement of subendocardial segment length in the central area perfused by the left circumflex coronary artery (LCCA) and left anterior descending coronary artery, LCCA flow, and left ventricular pressure. We occluded the LCCA for 2 min using an externally inflatable pneumatic occluder placed around the proximal LCCA. Two-minute LCCA occlusions were repeated hourly for 8 h, 5 days/week. The first LCCA occlusion decreased the ejection phase shortening in the ischemic area from 22.2% +/- 2.5% (SEM) to 3.1% +/- 0.7% (P less than 0.001). Concomitantly, heart rate increased from a resting rate of 76 +/- 4 to 117 +/- 6 beats/min (P less than 0.001) after 2 min of LCCA occlusion, and ejection phase shortening in the nonischemic area decreased from 25.5% +/- 1.3% to 21.6% +/- 1.1% (P less than 0.001) despite increases in end-diastolic segment length (15.31 +/- 1.46 mm to 15.69 +/- 1.52 mm, P less than 0.01). These changes in non-ischemic segment shortening and heart rate during LCCA occlusion were attenuated progressively with improvement tin the regional myocardial function at jeopardy due to the development of collateral circulation, and a significant (P less than 0.001) correlation between both the reduced nonischemic segment shortening and the increased heart rate with the degree of dysfunction in the ischemic region was obtained by linear regression analysis with Fisher's Z transformation.

Changes in coronary flow following repeated brief coronary occlusion in the conscious dog.

Studies were conducted in 12 conscious, unsedated dogs instrumented for measurements of subendocardial segment length in the area perfused by the left circumflex coronary artery, blood flow velocity of this artery, and left ventricular pressure. An externally inflatable pneumatic occluder was placed to occlude the circumflex coronary artery for selected durations at selected intervals. Resting coronary blood flow velocity was measured before and after collateral development induced by repeated brief coronary occlusion. Under conditions of comparable myocardial oxygen consumption, shown by the similar pressure-rate product, preocclusion resting coronary blood flow velocity of the repeatedly occluded artery decreased by 21.3% (P less than 0.001) in association with collateral growth. These findings strongly suggest that the perfusion territory of the collateralized artery decreases considerably secondary to the periodic ischemic stimulus.

Hemodynamic effects of hemorrhage and subsequent naloxone treatment in conscious rabbits.

The central and peripheral hemodynamic effects of rapid hemorrhage and subsequent opiate receptor blockade were studied in conscious rabbits. With hemorrhage of less than 12 ml/kg, mean arterial blood pressure (BP) was maintained by an increase in total peripheral resistance (TPR). Cardiac output (CO) declined in spite of an increase in heart rate (HR). Blood loss greater than 13 ml/kg resulted in an abrupt decrease in BP that was largely due to a decline in TPR. CO continued to decline gradually as it did early in hemorrhage. HR also decreased at the transition to hypotension. Subsequent opiate receptor blockade with naloxone (3 mg/kg) produced a prompt increase in BP and a decrease in HR. An increase in TPR accounted for the rise in BP. CO did not change significantly after naloxone. Therefore the hypotension associated with hemorrhage results from a decline in peripheral vascular resistance that is reversible by opiate receptor blockade with naloxone. These results are consistent with the involvement of opiate receptors and endogenous opiate peptides centrally and/or peripherally in control of vascular resistance during acute hemorrhagic hypotension.

Myocardial infarction in the baboon: regional function and the collateral circulation.

Occlusion of the anterior descending coronary artery was produced in sedated baboons 7-15 days after implantation of a micromanometer and ultrasonic crystals for measurement of regional left ventricular dimensions in ischemic, marginal, and control segments. One minute after coronary occlusion (CO), ischemic segments exhibited a marked systolic bulge with wall thinning, and percent systolic shortening of marginal segments decreased. Over the ensuing weeks, there was a progressive increase of end-diastolic lengths in marginal and ischemic segments, whereas systolic shortening in these segments did not improve significantly. Control segments did not change. In control baboons, the coronary collateral index was 55 +/-25 (SE) compared to 560 +/- 74 in normal dogs. One month after CO, the collateral index was 543 +/- 144 in baboons compared to 6,685 +/- 716 in dogs, regions of normal tissue were seen in the infarct (14.2 +/- 2% of left ventricular mass). Minimal coronary collateral development in the baboon provides a likely explanation for differences from the dog in regional functional responses and in the character of the infarct.