Well-developed Coronary Collateral Vessels Research Articles

Identifying and overcoming obstacles in angiogenic gene therapy for myocardial ischemia.

Well-developed coronary collateral vessels in patients with symptomatic coronary artery disease were shown to be associated with reduced future cardiovascular morbidity and mortality. However, the majority of patients with coronary artery disease lack adequate functional coronary collateral circulation. Stimulation of collateral vessel development by angiogenic growth factor therapy (therapeutic angiogenesis) has been tested in many clinical trials in the past, but the potential of this new treatment paradigm has not been realized yet in late stage clinical trials. Mechanistic insights into collateral vessel development and the collective clinical experience in the past decade identified specific obstacles that might have impeded the progress in the field. This review identifies some of the key conceptual, technical, and clinical hurdles and recommends strategies to overcome them in future clinical trials.

Collateral Function in Patients with Coronary Occlusion Evaluated by 201Thallium Scintigraphy

The present study evaluated the impact of the angiographically documented collaterals on regional myocardial perfusion measured by 201thallium scintigraphy in patients with a chronic total occlusion. The study included 60 patients with chronic total occlusion who underwent rest-stress myocardial perfusion scintigraphy and coronary angiography. All patients had angiographic evidence of coronary collaterals. Patients were divided into two groups: group one had well-developed coronary collateral vessels (n=35) and group II had poor coronary collateral development (n=25). Patients with chronic total occlusion had severe and extensive stress-induced myocardial perfusion defects regardless of the grade of angiographic coronary collaterals. The perfusion defects in the group with good collaterals were predominantly reversible, suggesting that coronary collaterals preserved myocardial viability in the regions subtended by a total coronary occlusion. A significant correlation between good collaterals with complete protection and poor collaterals with no protection was noted. Our results demonstrate a protective effect of collaterals on myocardial perfusion during coronary occlusion. The effective angiographic collaterals may prevent resting regional wall motion abnormalities but do not appear to protect against stress-induced perfusion defect.

Collateral recruitment and “warm-up” after first exercise in ischemic heart disease

Background Proposed mechanisms for “warm-up” after angina on first exercise include ischemic preconditioning and collateral recruitment. The aim of this study was to determine whether patients with ischemic heart disease and well-developed coronary collateral vessels have a greater warm-up response than those with no visible collateral vessels. Methods And Results Fifteen patients with a total coronary occlusion and collateral vessels and 18 patients with a single coronary artery stenosis and no angiographically visible collateral vessels were studied. Warm-up was measured as the difference in ST depression on the second compared with the first of 2 sequential treadmill exercise tests separated by 10 minutes of rest. There was a trend for the duration of second exercise to increase more in patients with occlusion than in those with stenosis (+1.3 vs +0.54 minutes, respectively, P =.087). In both groups, ST depression was less on second exercise than on first exercise. The size of this decrease was greater in the occlusion group than in the stenosis group. ST depression at equivalent submaximal exercise decreased by 0.52 vs 0.19 mm, respectively (P =.049). The rate of increase in ST depression during exercise decreased by 1.08 versus 0.55 mm/min, respectively (P =.034). These differences were less after adjustment for ST depression on first exercise (P =.11 and P =.063, respectively). Conclusions The trend for a greater decrease in ST depression on second compared with first exercise in the patients with total coronary occlusion suggests that an increase in collateral flow is a mechanism for warm-up after first exercise in ischemic heart disease. (Am Heart J 2000;140:121-5.)

Effect of platelet activation on coronary collateral blood flow.

The platelet products thromboxane A2 and serotonin have been shown to cause constriction of well-developed coronary collateral vessels. This study was performed to determine whether intravascular platelet activation produced with platelet activating factor (PAF) can cause a decrease in coronary collateral blood flow. Collateral vessel growth was induced by embolization of a hollow stainless steel plug into the left anterior descending coronary artery (LAD) of adult dogs. The animals were returned to the laboratory 3 to 6 weeks later for surgical instrumentation and measurement of collateral blood flow. Collateral flow was assessed by measuring retrograde blood flow from the cannulated collateral-dependent artery. PAF (10 nmol) was injected into the left main coronary artery to allow products of platelet activation to reach collateral vessels arising from the left coronary system. PAF caused a vasoconstrictor response, which became maximal 3 minutes after injection and resulted in a 40.3+/-7.4% decrease in retrograde blood flow (32.1+/-2.1 to 19.6+/-3.2 mL/min; P<0.05). By 15 minutes after the PAF injection, both retrograde blood flow and transcollateral resistance had returned to normal. After pretreatment with the thromboxane A2 receptor antagonist SQ30, 741, the vasoconstrictor response to PAF was abolished and, in contrast to the decrease in retrograde blood flow from PAF alone, a weak vasodilator effect was unmasked. PAF caused a decrease in coronary collateral blood flow. This vasoconstrictor response required the participation of thromboxane A2.

Endothelium-dependent vasodilation in well-developed coronary collateral vessels.

We examined endothelium-dependent vasodilator responses in well-developed coronary collateral vessels. Collateral vessels and size-matched normal epicardial coronary arteries were isolated from canine hearts 6 months after a hollow plug had been introduced into the left anterior descending coronary artery (LAD) to stimulate collateral vessel growth. Vessel segments were isolated and studied in organ chambers. After preconstriction with prostaglandin F2 alpha, (PGF2 alpha) responses to the endothelium-dependent vasodilators, acetylcholine (ACh), substance P, and bradykinin (BK), as well as the endothelium-independent vasodilator nitroglycerin (NTG), were measured. The maximum relaxation to ACh was greater in collateral vessels (129 +/- 3.6% of the preconstricted tension) than in normal vessels (110 +/- 6.2%, p < 0.001), although the EC50 value for ACh was not significantly different between collateral and normal vessels. Collateral vessels demonstrated sensitivity to BK similar to that of normal vessels, but the maximal vasodilation achieved was greater in collaterals (138 +/- 4.6% of preconstricted tension) than in normal vessels (108 +/- 5.0%, p < 0.05). Both substance P and NTG produced dose-related relaxation that was similar in collateral vessels and normal arteries. These findings demonstrate that endothelium-dependent relaxation is intact in well-developed coronary collateral vessels.

Vasomotor responses of newly developed coronary collateral vessels.

Well-developed coronary collateral vessels contain an abundant muscular media and can undergo active vasomotion. However, early after coronary occlusion, coronary collateral vessels are thin walled with little smooth muscle, suggesting that vasomotor capability might be limited. Consequently, this study determined whether newly developed coronary collateral vessels have active vasomotor activity and whether endothelial function in these newly developed vessels is impaired. Retrograde blood flow was measured as an index of coronary collateral blood flow approximately 2 wk after embolic occlusion of the anterior descending coronary artery of dogs. Agonists were administered into the left main coronary artery to reach collaterals originating from the left coronary system. Baseline retrograde blood flow was 25.1 +/- 2.7 ml/min and increased to 36.7 +/- 3.7 ml/min after nitroglycerin (6 micrograms.kg-1.min-1, P < 0.05). Cyclooxygenase blockade with indomethacin (5 mg/kg i.v.) decreased retrograde collateral blood flow to 16.8 +/- 2.3 ml/min (P < 0.05). Subsequent administration of acetylcholine increased retrograde flow to 29.4 +/- 3.7 ml/min (P < 0.05), indicating intact endothelium-mediated vasodilation. Inhibition of nitric oxide synthase with NG-nitro-L-arginine further decreased coronary collateral retrograde flow to 12.0 +/- 2.8 ml/min (P < 0.05) and markedly blunted the response to acetylcholine. These findings demonstrate substantial vasomotor capability even early during coronary collateral development and indicate that both nitric oxide and cyclooxygenase-dependent endothelial mechanisms are intact.

The mechanism of coronary collateral vasoconstriction in response to cyclooxygenase blockade.

The present study was performed to examine the mechanism by which cyclooxygenase blockade produces vasoconstriction in well-developed coronary collateral vessels. Eight dogs were studied 4 to 6 months after occlusion of the left anterior descending coronary artery (LAD) had been performed to stimulate collateral vessel growth. At the time of study, the LAD was cannulated at the site of occlusion for measurement of retrograde blood flow as an index of collateral blood flow. Levels of 6-ketoprostaglandin F1 alpha were 32 +/- 13% higher in blood diverted from the collateral-dependent LAD than in aortic blood (P < .05); the increase in this stable product of prostacyclin metabolism indicated production of prostacyclin across the coronary collateral system. Administration of arachidonic acid into the left main coronary artery to reach collateral vessels entering the LAD resulted in a 21 +/- 6% increase in retrograde flow (P < .01), demonstrating cyclooxygenase activity with production of vasodilator prostaglandins in the collateral system. Ibuprofen (10 mg/kg IV) caused a 55 +/- 7% decrease in retrograde flow (P < .03), suggesting that cyclooxygenase blockade inhibited tonic production of vasodilator prostaglandins in the collateral system. In contrast, neither thromboxane synthase inhibition with dazmegrel nor thromboxane receptor blockade with SQ 30741 caused a significant change in collateral flow, thus failing to support thromboxane-induced collateral constriction. After cyclooxygenase blockade, prostacyclin infused into the left main coronary artery was able to restore retrograde flow to the preibuprofen level.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Calcitonin Gene-Related Peptide on Well-Developed Canine Coronary Collateral Vasculature

This study was performed to examine the effect calcitonin gene-related peptide (CGRP) on blood flow through well-developed coronary collateral vessels. Studies were performed in 9 adult mongrel dogs 4-6 months after embolic occlusion of the left anterior descending coronary artery (LAD) with a hollow intravascular plug to stimulate collateral vessel growth. At the time of study, the LAD was cannulated to determine inter-arterial collateral flow from measurement of retrograde blood flow. Radioactive microspheres were injected during retrograde flow collection to determine continuing tissue flow in the collateral dependent region. CGRP was infused into the left main coronary artery in a dose of 0.2 microgram/kg/min to reach collateral vessels originating from the left coronary system. Retrograde blood flow was 40 +/- 9 ml/min during basal conditions and increased 22 +/- 9% in response to infusion of CGRP (n = 9, p < 0.05). Tissue flow to the collateral-dependent myocardial region did not change in response to CGRP infusion. Isolated rings of epicardial collateral vessels contracted with prostaglandin F2 alpha (PGF2 alpha) underwent relaxation in response to CGRP which was similar in magnitude to that of normal coronary arteries of comparable size. These data demonstrate that CGRP causes vasodilation of well-developed epicardial coronary collateral vessels, resulting in an increase in collateral blood flow.

Effect of aspirin on coronary collateral blood flow.

Although aspirin exerts beneficial antiplatelet activity in patients with coronary artery disease, cyclooxygenase blockade produced by aspirin causes a potentially deleterious effect by interrupting endothelial production of prostacyclin. Collateral vessels that develop in response to coronary occlusion display prominent endothelial cell proliferation and undergo vasoconstriction in response to indomethacin. This study was performed to test the hypothesis that cyclooxygenase blockade with aspirin would cause constriction of coronary collateral vessels and that such vasoconstriction would be reversed with nitroglycerin. Collateral vessel growth was induced by embolic occlusion of the left anterior descending coronary artery in dogs. Four to 6 months later, coronary collateral flow was measured as retrograde flow from the cannulated collateral-dependent artery. Aspirin (1 mg/kg i.v.) caused 70 +/- 8% blockade of the increase in coronary blood flow produced by intra-arterial arachidonic acid and decreased retrograde flow from 37 +/- 7 to 28 +/- 7 ml/min (p < 0.03). Increasing the dose of aspirin to 15 mg/kg i.v. caused 91 +/- 3% blockade of the response to arachidonic acid and further decreased retrograde flow to 21 +/- 4 ml/min (p < 0.01). After aspirin administration, nitroglycerin (150 micrograms/min i.c.) reversed the collateral constriction and increased retrograde flow to 37 +/- 10 ml/min (p < 0.01). These data suggest that products of cyclooxygenase metabolism cause tonic vasodilation of well-developed coronary collateral vessels. Blockade of cyclooxygenase with even low-dose aspirin caused collateral vessel constriction with a decrease in collateral blood flow. However, nitroglycerin was able to fully reverse aspirin-induced collateral vasoconstriction and restore flow to the control level.

Response of canine coronary collateral vessels to ergonovine and alpha-adrenergic stimulation

The ability of moderately well-developed coronary collateral vessels to undergo vasoconstriction in response to alpha-adrenergic stimulation and to ergonovine was studied. Studies were performed in 15 dogs 4-16 wk after embolic occlusion of the left anterior descending coronary artery had been performed to stimulate collateral vessel growth. Interarterial collateral flow was measured as retrograde flow from the cannulated left anterior descending coronary artery, while microvascular collateral flow was measured as continuing tissue flow determined with radioactive microspheres administered during the retrograde flow collection. Studies were performed after beta-adrenergic blockade with propranolol. Neither cardiac sympathetic nerve stimulation nor alpha 1-adrenergic stimulation with phenylephrine caused significant change in retrograde blood flow or myocardial tissue flow. The selective alpha 2-adrenergic agonist, B-HT 933, decreased tissue flow in the collateral-dependent region but did not significantly alter retrograde flow. Although these data indicate that intramural microvascular collateral communications are capable of vasoconstriction in response to alpha 2-adrenergic stimulation, the larger interarterial collaterals are unresponsive to alpha-adrenergic influences. However, under the conditions of the experiment, adrenergic activity did not appear to influence collateral function, since neither alpha 1-adrenergic blockade with prazosin nor alpha 2-adrenergic blockade with rauwolscine altered collateral flow. Ergonovine, 0.2-0.8 microgram.kg-1.min-1, caused a 22 +/- 4% decrease in retrograde flow (P less than 0.01) but did not alter microvascular collateral flow. Thus, of the agents tested, only ergonovine caused vasoconstriction of the large interarterial coronary collateral vessels.

Functional significance of coronary collateral perfusion in preserving myocardial integrity.

Coronary collateral perfusion to the completely obstructed coronary artery was evaluated by coronary cineangiography in 32 patients. In 13 patients, there was neither history of severe chest pain of longer than 30-min duration nor electrocardiographic evidence of a transmural myocardial infarction (Group I). Among patients undergoing intracoronary thrombolytic therapy for the completely occluded infarct-related coronary artery within 6 h after the onset of symptoms of the first acute myocardial infarction, 19 patients had a history of preinfarction angina (Group II). Collateral visualization (collateral index) was found to be significantly greater in Group I (2.5 +/- 0.5, SD) than in Group II (0.9 +/- 1.0) (p less than 0.01). Group I patients had a longer history of angina (25 +/- 25 months) than did Group II patients (17 +/- 18 months) (p = NS). These findings indicate that well-developed coronary collateral vessels preserve myocardial integrity upon acute coronary occlusion and that a long-standing angina indicative of myocardial ischemia may play an important role in developing collateral channels.

Scintigraphic anatomy of coronary artery disease in digital thallium-201 myocardial images.

One hundred and eight patients with single and multiple vessel coronary artery disease confirmed by arteriography were evaluated by exercise thallium-201 (201Tl) myocardial scintigraphy to determine the scintigraphic appearances of specific coronary stenoses. In general proximal stenoses caused more widespread, but not necessarily more severe, myocardial tracer deficit than distal stenoses. In particular, proximal dominant right coronary artery disease was specifically associated with extensive inferior wall tracer deficit in the anterior scintigram, whereas proximal left circumflex disease caused similar tracer depletion best visualised in the left lateral scintigram. A triad of uptake defects was caused by left anterior descending coronary artery disease: viz. apical tracer deficit (anterior view) in 71% lesions, septal tracer deficit (left anterior oblique view) in 83% of lesions, and anterolateral wall tracer deficit (left lateral projection) in 72% of lesions. The last defect has been termed a 'diagonal window' because it was associated with independent disease of the main diagonal branch of the left anterior descending coronary artery or with disease in the main left anterior descending artery situated proximal to this branch. Diagonal window tracer deficit was the most useful scintigraphic sign distinguishing proximal from distal disease in the left anterior descending coronary artery. False negative scintigraphic defects occurred more commonly in patients with triple vessel disease and in association with well-developed coronary collateral vessels. Certain scintigraphic patterns of 201Tl myocardial accumulation appear invaluable in the noninvasive localisation of stenoses within specific coronary arteries and thus may be useful in predicting life-threatening coronary artery disease which should be confirmed by definite coronary arteriography. The digital 201Tl myocardial scintigram also provides an independent functional guide to the interpretation of coronary arteriograms and may be helpful in the planning of aortocoronary bypass graft surgery.