© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Temporal dependence of coronary collateral development
Departments of Anesthesiology, Pharmacology, and Medicine (Division of Cardiology), Medical College of Wisconsin, Milwaukee, WI 53226, USA
* Corresponding author. Medical College of Wisconsin, MEB – Room 462C, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. Tel. +1 414 456-5735; Fax +1 414 266-8541.
Received 15 October 1996; accepted 9 December 1996
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Abstract |
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Objective: Previous evidence suggests that episodes of myocardial ischemia of sufficient duration and intensity are required to produce coronary collateral development during repetitive coronary occlusion. This investigation tested the hypothesis that coronary collateral development is also temporal-dependent. Methods: Chronically instrumented dogs (n=16) were subjected to brief (2 min) left anterior descending coronary artery (LAD) occlusions, once every hour, 8 h a day, for 3 weeks or once every hour, 24 h a day for 1 week. Collateral perfusion (radioactive microspheres), LAD contractile function (ultrasonic crystals), and post-occlusive flow debt repayment (LAD flow probe) were measured during occlusions 1, 55, 105, and 155. Results: Increases (P<0.05) in subendocardial collateral blood flow to ischemic myocardium, progressive normalization of contractile function during LAD occlusion, and successive reduction in flow debt repayment were observed in dogs receiving occlusions over 3 weeks. In contrast, dogs receiving the same number of coronary occlusions over 1 week demonstrated minimal increases in collateral blood flow, persistent regional contractile dysfunction, and sustained flow debt repayment. Conclusions: The results demonstrate that LAD collateral development in response to repetitive coronary occlusion requires sufficient time for growth adaptation of the collateral circulation to occur.
KEYWORDS Myocardial ischemia; Collateral vessels; Collateral development; Dog, anesthetized
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Development of the coronary collateral circulation is an important adaptive response to chronic myocardial ischemia. Coronary collaterals provide an alternative source of blood flow to myocardium distal to a severe coronary artery stenosis or occlusion. Increases in perfusion via coronary collaterals can attenuate myocardial ischemia, prevent myocardial necrosis, and limit myocardial dysfunction at rest or during periods of increased oxygen demand [1]. The mechanisms which contribute to coronary collateral development are incompletely understood; however, enhancement of the coronary collateral circulation probably involves both expansion of pre-existing collaterals and creation of new blood vessels (angiogenesis).
Myocardial ischemia of a sufficient degree of intensity and duration is required to initiate collateral development [2]. This process has been shown to be a highly regulated, complex sequence of events, requiring enzymatic degradation of extracellular matrix, endothelial cell migration and proliferation towards the ischemic stimulus, and subsequent migration of smooth muscle cells and fibroblasts along the new endothelial sprout [3]. The frequency and duration of repetitive ischemic episodes have been shown to be important factors determining the development of the coronary collateral circulation. This investigation tested the hypothesis that more frequent episodes of intermittent ischemia do not hasten coronary collateral formation because a sufficient period of time must elapse in order for enhancement of the coronary collateral circulation to occur. Experiments were conducted in a conscious, chronically instrumented canine model of intermittent ischemia resulting from brief, repetitive coronary occlusions. This experimental preparation allows precise quantification of the duration and severity of the ischemic stimulus, reproducibly generates collateral formation in dogs, minimizes the risk of myocardial necrosis, and allows for continuous monitoring of collateral development in response to ischemic stimuli.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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2.1 Implantation of instruments
All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wisconsin. Furthermore, all conform to the Guiding Principles in the Care and Use of Animals of the American Physiologic Society and were in accordance with the Guide for the Care and Use of Laboratory Animals [DHEW (DHHS) publication no. (NIH) 85-23, revised 1996].
Implantation of instruments has been described previously in detail [4]. Briefly, under general anesthesia and aseptic conditions, a thoracotomy was performed in the left fifth intercostal space and the lungs gently retracted. Heparin-filled catheters were inserted in the descending thoracic aorta, the right atrium, and the left atrium for measurement of aortic blood pressure, fluid administration, and administration of radioactive microspheres, respectively. A precalibrated Doppler ultrasonic flow transducer was placed around the proximal left anterior descending coronary artery (LAD) for measurement of phasic coronary blood flow velocity. A balloon-cuff vascular occluder was placed distal to the flow transducer for production of brief coronary artery occlusion. A pair of miniature ultrasonic segment-length transducers were inserted in the subendocardium of the LAD perfusion territory for measurement of regional contractile function. A high-fidelity micromanometer was implanted in the left ventricle for measurement of continuous left ventricular pressure and the peak rate of increase of left ventricular pressure (+dP/dtmax). All instruments were tunneled subcutaneously and exteriorized between the scapulae through several small incisions. The chest was closed in layers and the pneumothorax evacuated by a chest tube. Each dog was permitted to recover for 4 days and trained to stand quietly in a sling prior to the initiation of daily hemodynamic monitoring. Dogs were treated with prophylactic antibiotics [cephazolin (40 mg/kg) and gentamicin (5 mg/kg)] and analgesics (fentanyl) as needed in the immediate postoperative period.
2.2 Regional myocardial contractile function
Regional contractile function in the LAD perfusion territory was evaluated by a pair of ultrasonic segment length crystals monitored by ultrasonic amplifiers. End-systolic segment length (ESL) was determined at 10 ms before maximum negative left ventricular dP/dt, and end-diastolic length (EDL) was determined 10 ms before dP/dt first exceeded 140 mmHg·s–1 (immediately prior to the onset of left ventricular isovolumic contraction). Percent segment shortening (%SS) was calculated using the formula: %SS=(EDL–ESL)x100/EDL.
2.3 Regional myocardial perfusion
Carbonized plastic microspheres (15±2 µm in diameter; New England Nuclear, Boston, MA) labeled with 141Ce, 103Ru, 51Cr, or 95Nb were used to measure regional myocardial blood flow. The sphere suspension was ultrasonicated for 15 min and agitated in a vortex mixer for 5 min prior to injection. Approximately 2–3x106 microspheres were injected into the left atrium as a bolus over 10 s and flushed in with 10 ml of sterile saline. A few seconds before the microsphere injection, a timed collection of reference arterial blood was withdrawn from the thoracic aortic catheter at a constant rate of 7 ml/min for 3 min.
At the conclusion of each experiment, two dyes (Patent Blue; India ink) were simultaneously injected into the LAD and left circumflex coronary artery (LCCA) at a pressure of 100 mmHg to identify the occluded and normal zones, respectively. The heart was divided into 6 rings and transmural tissue samples were selected from both normal (myocardium perfused by the LCCA) and ischemic (myocardium distal to the LAD hydraulic occluder) regions of the left ventricle. Myocardial tissue samples were subdivided into subepicardial, midmyocardial, and subendocardial layers of approximately equal thickness. Samples were weighed and placed in scintillation vials, and the activity of each isotope was determined. Similarly, the activity of each isotope in the reference blood flow sample was assessed. Tissue blood flow (Qm; ml/min/g) was calculated from the equation: Qm=Qr xCm/Cr, where Qr= rate of withdrawal (ml/min) of the reference blood flow sample, Cr= activity (counts/min) of the reference blood flow sample, and Cm= activity (counts/min/g) of the myocardial tissue sample. Transmural myocardial blood flow was the average flow of samples in the subepicardium, midmyocardium and subendocardium of each region.
Tissue samples were subdivided according to the method of Marcus et al. [5]to facilitate intergroup comparisons because the pattern of collateral blood flow varied between dogs [4]. The mean±standard deviation of subendocardial blood flow in the normal zone during the first coronary occlusion was calculated for each dog. Central ischemic zone tissue was defined as subendocardial tissue samples with blood flow <25% of the mean normal zone blood flow. Corresponding tissue samples from subepicardium and midmyocardium were classified according to the designation of the subendocardial sample. Tissue sample designations assigned based on data acquired during the first coronary occlusion were used for all subsequent coronary occlusions.
2.4 Experimental protocol
Dogs (n=18; weight range = 22–27 kg) were assigned to receive 155 brief LAD occlusions over 3 weeks or 1 week in a random fashion. Beginning on the fourth postoperative day, systemic and coronary hemodynamics were monitored daily, recorded on a polygraph, and digitized by a computer interfaced with an analog to digital converter. Coronary collateral development was produced by multiple, brief (2 min) occlusions of the LAD using an automated syringe pump attached to the chronically implanted hydraulic occluder. In the first group of experiments (3-week group), brief occlusions were performed once each hour, 8 times per day, 7 days per week for 3 weeks. In the other experimental group (1-week group), 2 min LAD occlusions were performed once each hour, 24 h a day for 7 days. Hemodynamics, reactive hyperemic responses, and regional myocardial contractile function were monitored before, during, and after each occlusion. Radioactive microspheres were administered during the first 2 min LAD occlusion on experimental day 1, and during LAD occlusions 55, 105, and 155.
2.5 Statistical analysis
Statistical analysis of data within and between groups was performed by multiple analysis of variance (MANOVA) with repeated measures followed by Student's t-test with Duncan's adjustment for multiplicity. Changes within and between groups were considered statistically significant when the probability (P) value was less than 0.05. All data are reported as the mean±standard error of the mean (s.e.m.).
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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A total of 18 dogs were chronically instrumented to provide 16 successful experiments. One dog died from ventricular fibrillation during reperfusion following the first coronary artery occlusion. The LAD could not be reperfused after brief occlusion in another dog. These dogs were excluded from the analysis.
3.1 Hemodynamics, contractile function, and myocardial perfusion in dogs receiving LAD occlusions over 3 weeks
Systemic and coronary hemodynamics were recorded immediately before LAD occlusions 1, 55, 105, and 155 (Table 1). Baseline heart rate, ratexpressure product, heart rate during LAD occlusion, and resting diastolic coronary blood flow velocity decreased significantly (P<0.05) over time. There were no changes in mean arterial pressure, left ventricular systolic and end-diastolic pressures, and left ventricular +dP/dtmax in dogs receiving 155 LAD occlusions over 3 weeks. Percent segment shortening in the LAD region was determined under steady-state conditions before brief occlusions throughout each experiment (Fig. 1). Repetitive, brief LAD occlusions produced stunned myocardium on the first experimental day as indicated by decreases in %SS recorded during the second and third reperfusion periods (measured immediately prior to the third and fourth occlusions, respectively). However, 24 h after commencement of intermittent LAD occlusion (prior to occlusion 9; Fig. 1), %SS had recovered to baseline values. Two-minute LAD occlusions caused aneurysmal bulging of ischemic myocardium (Fig. 2, occlusions 1–4). Segment shortening during coronary occlusion was sustained at pre-occlusion baseline values as the number of LAD occlusions increased over a period of 3 weeks (Fig. 2). Time-dependent increases in transmural blood flow to ischemic myocardium were observed in dogs receiving LAD occlusions over 3 weeks (Fig. 3). Blood flow to normal myocardium (LCCA zone) was unchanged. Increases in central ischemic zone subepicardial, midmyocardial, and subendocardial collateral blood flow were observed during occlusion 55 and approached normal zone values after 3 weeks of intermittent ischemia (Fig. 4). Enhanced coronary collateral perfusion to ischemic zone subendocardium was also demonstrated by increases in the ratio of subendocardial to subepicardial blood flow (endo/epi: 0.45±0.15 to 1.42±0.20 during LAD occlusions 1 and 155, respectively; Fig. 5). Enhanced coronary collateral blood flow was accompanied by time-dependent reductions in flow debt repayment (Table 1).
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Significantly (P<0.05) different from occlusion 1. 
Significantly (P<0.05) different from occlusion 55. 
Significantly (P<0.05) different from occlusion 105. ¶Significantly (P<0.05) different from the corresponding value in dogs receiving occlusions over 3 weeks.
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3.2 Hemodynamics, contractile function, and myocardial perfusion in dogs receiving LAD occlusions over 1 week
No changes in baseline heart rate occurred in dogs receiving 155 LAD occlusions over 1 week (Table 2). Mean arterial pressure, left ventricular systolic or end-diastolic pressures, resting diastolic coronary blood flow velocity, +dP/dtmax, or ratexpressure product were also unchanged. Increases in heart rate produced by LAD occlusion remained constant over the time-course of the experiments. Heart rate during LAD occlusion was greater during occlusions 105 and 155 in dogs receiving occlusions over 1 compared to 3 weeks. Myocardial stunning persisted for 1 day after initiation of repetitive coronary artery occlusions in dogs receiving hourly occlusions for 24 h per day as indicated by persistent depression of contractile function (Fig. 1), in contrast to the findings in dogs receiving LAD occlusions over 3 weeks. Systolic aneurysmal bulging of ischemic myocardium was produced with each LAD occlusion on the first experimental day, findings that were similar to those in dogs in the 3-week group (Fig. 2). However, dogs subjected to brief occlusions every hour over 1 week demonstrated persistent regional dyskinesia during 155 LAD occlusions, in marked contrast to progressive improvement of regional contractility observed in dogs receiving the same number of occlusions over 3 weeks. Increases in collateral blood flow to transmural myocardium (Fig. 3), and subepicardium, midmyocardium, and subendocardium in the central ischemic zone (Fig. 4) were less pronounced in dogs receiving 155 LAD occlusions over 1 week compared to those receiving occlusions over 3 weeks. The ratio of subendocardial to subepicardial blood flow also remained unchanged in dogs receiving occlusions over 1 week. A decrease in flow debt repayment was observed after 155 LAD occlusions, however, flow debt repayment was greater in dogs receiving occlusions over 1 week than in those receiving occlusions over 3 weeks (Table 2).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Increases in blood flow to ischemic myocardium via growth adaptation of coronary collateral vessels stimulated by chronic imbalances in myocardial oxygen supply–demand relations have been shown to occur in experimental animals and humans [4, 6–13]. It has been hypothesized that myocardial ischemia may increase coronary collateral blood flow through expansion of pre-existing collateral vessels within the ischemic region and development of new arterial anastomoses [14]. Experimental evidence accumulated in recent years indicates that collateral development occurs in concert with DNA synthesis and mitosis in proliferating endothelial cells, smooth muscle cells, and fibroblasts [15], and may also be modulated by monocytes and other cellular elements [3, 11, 16]. A variety of growth factors, including vascular endothelial growth factor (VEGF) [17], acidic and basic fibroblastic growth factors (aFGF and bFGF, respectively) [18], platelet-derived endothelial cell growth factor (PD-ECGF) [11]and transforming growth factor β1 (TGF-β1) [19]have also been implicated in the regulation of coronary collateral development. Thus, the integrated actions of multiple cellular elements concomitant with growth factor production and release appear to play important roles in growth adaptation of the coronary collateral circulation.
Coronary collateral development in dogs and ponies has been characterized in studies using similar experimental methodology to that reported in the present investigation [4, 8, 20]. Fujita et al. [20]observed decreases in resting heart rate, normalization of regional contractile function, and attenuation of the reactive hyperemic response in dogs after 147 occlusions of the LCCA, findings that were nearly identical to previous observations by our laboratory [4]. Normal segment shortening and regional myocardial perfusion were also observed after 550 brief LAD occlusions in ponies [8], a species with a poorly developed endogenous coronary collateral circulation. In each of these investigations, 2-min coronary artery occlusions were performed every 30–60 min, 8 h each day, 5–7 days each week. In contrast, Mohri et al. [2]demonstrated that repetitive 15 s LCCA occlusions did not cause coronary collateral formation. Thus, ischemic episodes of sufficient frequency and intensity appear to be required to stimulate coronary angiogenesis in vivo. The temporal dependence of coronary collateral development has not been previously determined.
The present results confirm previous experimental findings and demonstrate that coronary collateral formation occurs when 155 brief LAD occlusions were performed in conscious dogs over 3 weeks. Increases in collateral perfusion to ischemic myocardium, normalization of regional contractile function, and reduction in flow debt repayment were observed after 155 LAD occlusions over 3 weeks. In contrast, coronary collateral development was relatively poor in dogs receiving 155 LAD occlusions over 1 week. In fact, collateral blood flow, regional contractile function, and flow debt repayment were similar after 7 days of repetitive coronary artery occlusions in both experimental groups despite a large difference in the number of occlusions performed. These findings suggest that once a critical degree of chronic ischemia is reached to initiate coronary collateral development, sufficient time must elapse to allow enhancement of the collateral circulation to occur. Interestingly, Banai et al. [17]demonstrated that intracoronary administration of VEGF enhanced collateral development in dogs implanted with a LCCA ameroid constrictor. However, increases in collateral flow above that observed in control dogs did not occur until after 2 weeks of VEGF treatment, findings which support the observed temporal dependence of collateral development in the present investigation.
Intermittent episodes of myocardial ischemia produced a mild degree of ischemia-reperfusion injury (‘stunned’ myocardium) on the first experimental day in both groups. Expression of c-fos mRNA [19], a proto-oncogene involved in encoding proteins that regulate transcription [21], has been shown to be enhanced in stunned myocardium. These findings suggest that myocardial ischemia-reperfusion injury initially produced by brief LAD occlusions in the present investigation may be associated with upregulation of growth factor transcription and translation [19]. Although stunned myocardium was present during the initial reperfusion periods in both experimental groups, evidence of sustained contractile dysfunction was not observed after 24 h in dogs receiving only 8 LAD occlusions per day. Thus, although a more intense ischemic stimulus appeared to be present in dogs receiving 24 brief LAD occlusions per day as indicated by persistent contractile dysfunction, ischemia of greater intensity in this experimental group did not accelerate coronary collateral formation.
The present results must be interpreted within the constraints of several potential limitations. Microscopic examination of tissue for evidence of angiogenesis or vasculogenesis was not performed. Coronary collateral development was demonstrated by functional indicators of enhanced collateral flow and by tissue perfusion measurements. The administration of heparin to maintain patency of surgically implanted catheters may have influenced the results. However, the heparin dose required to maintain catheter patency (500 U/day) was substantially less than the intravenous or subcutaneous heparin doses (7000–10 000 U/day) required to enhance coronary collateral development in intermittently ischemic myocardium [22, 23]. Differences in endogenous collateral perfusion between groups probably did not influence subsequent development of the coronary collateral circulation. Classification of each myocardial tissue sample according to degree of native collateral perfusion present before ischemic stimulation eliminated possible differences between experimental groups in endogenous collateral perfusion because myocardial tissue samples with similar levels of collateral perfusion were directly compared [5]. In addition, collateral blood flow before the onset of repetitive LAD occlusion was similar in dogs receiving LAD occlusions over 1 and 3 weeks. Preferential loss of radioactive microspheres from collateral-dependent or infarcted myocardium may have occurred. This process may contribute to underestimation of collateral blood flow [24]. However, no evidence of gross myocardial infarction was observed on postmortem examination in either group, indicating that preferential loss of microspheres from infarcted myocardium did not occur. The presence of a severe LAD stenosis as a result of instrumentation, in the 3-week as compared to the 1-week group, may have accelerated collateral development in the 3-week group. However, instrumentation of the 2 groups was identical, and post-mortem examination revealed the absence of significant coronary artery stenosis in any dog.
In summary, the present results confirm the findings of several previous studies [2, 4, 8]and indicate that brief, repetitive coronary artery occlusions performed over 3 weeks cause enhancement of the coronary collateral circulation in conscious dogs as demonstrated by time-dependent increases in collateral blood flow, normalization of regional contractile function, and successive reduction in flow debt repayment. In contrast, dogs receiving an equal number of coronary artery occlusions of identical duration over a 1-week period demonstrated markedly less collateral blood flow, persistent contractile dysfunction, and maintenance of flow debt repayment consistent with limited collateral development. These findings demonstrate that sufficient time is required for enhancement of the collateral circulation to occur.
Time for primary review 34 days.
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Acknowledgements |
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This work was supported in part by a FAER Young Investigator/Society of Cardiovascular Anesthesiologists Award (JRK), American Heart Association/Wisconsin Affiliate Grant 95-GB-49 (JRK), and US PHS grants HL 54280 (DCW) and GM 08377 (DCW). The authors extend their appreciation to David Schwabe and Douglas Hettrick for technical assistance and Angela M. Barnes for assistance in the preparation of the manuscript.
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