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J Thorac Cardiovasc Surg 1995;110:952-962
© 1995 Mosby, Inc.
SURGERY FOR ACQUIRED HEART DISEASE |
Louisville, Ky.
Supported in part by a grant from the Jewish Hospital Heart and Lung Institute.
Received for publication Dec. 19, 1994. Accepted for publication March 6, 1995. Address for reprints: Paul Spence, MD, Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Louisville, Louisville, KY 40292.
Abstract
Despite the superior long-term patency of arterial grafts, surgeons are often reluctant to use arterial grafts on coronary vessels that supply large areas of myocardium because postoperative shock may occur. We hypothesized that supramaximal flow through small arterial conduits would decrease distal intraluminal pressure, thereby reducing afterload on the smooth muscle and rendering the arterial graft vulnerable to spasm. Fourteen internal thoracic and eight gastroepiploic arteries were harvested from adult pigs (220 to 250 pounds). Arteries were mounted on a computer-controlled perfusion system with inflow pressure at 80 mm Hg and outflow resistance adjusted to simulate normal (in situ) or supramaximal (coronary artery bypass graft) flow demands. Artery pressures and flow rates were measured at baseline and after norepinephrine was added to the system. Internal thoracic arteries had no hemodynamic response to norepinephrine at normal flow. Under supramaximal flow demands, large internal thoracic arteries (2.5 to 3.0 mm) had no hemodynamic response to norepinephrine. However, for small internal thoracic arteries (2.1 to 2.9 mm), norepinephrine reduced distal internal thoracic arterial pressure (63.2±2.2 to 27.0±1.9 mm Hg) and flow rate (99.4±5.0 to 45.4±2.7 ml/min, median effective dose = 9.12 x 10 -9 mol/L). Under normal flow demands, the flow rate in gastroepiploic arteries (1.0 to 2.0 mm diameter) decreased (14.1±0.5 to 4.8±0.8 ml/min, p<0.05) only at high concentrations of norepinephrine (median effective dose = 1.26 x 10 -6 mol/L). Supramaximal flow demandsreduced distal gastroepiploic arterial pressure (77.5±0.5 to 49.5±3.8 mm Hg, p <0.05), which resulted in a greater decrease in flow rate (80.0±3.7 to 6.8±1.6 ml/min, p <0.05) at lower concentrations of norepinephrine, (median effective dose = 3.24 x 10 -8 mol/L, p <0.05). In four studies in internal thoracic arteries and eight in gastroepiploic arteries, arteries were cut in half, reattached, and reperfused. The proximal half of the internal thoracic artery did not respond to norepinephrine, but the distal half had a 53%±7% decrease in flow. Both gastroepiploic artery halves reacted and flow rate decreased by 88%±2% (proximal half) and 89%±3% (distal half). In conclusion, small arterial conduits develop large transconduit pressure gradients under supramaximal flow demands. Under these conditions, arteries are very sensitive to vasoconstrictors and flow may cease with higher drug concentrations. Myocardial failure after arterial bypass grafting to coronary vessels supplying large amounts of myocardium may result from an increased sensitivity to vasoconstriction leading to graft spasm and myocardial ischemia. (J THORAC CARDIOVASC SURG 1995;110:952-62)
Since the unequivocal demonstration in the internal thoracic artery (ITA) of improved graft patency, patient survival, and fewer late postoperative cardiac complications, the ITA has become the conduit of choice for coronary artery bypass grafting. 
1-3 Almost all ITA grafts are patent at 10 years, whereas two thirds of saphenous vein grafts are occluded or diseased at 10 years. 3-5 It is not surprising that numerous attempts have been made to expand the use of arterial grafts. Some surgeons perform bilateral ITA grafting, and others use gastroepiploic artery (GEA), inferior epigastric artery, or radial artery grafts. 6
Although the arterial grafts are disease resistant, 7 initially the ITA graft delivers less flow to the coronary arteries in comparison with that delivered by saphenous vein grafts, 8 and this lower flow can be further reduced by spastic reactions of the ITA. 9 Insufficient graft flow can result in early and late myocardial ischemia. 8,10 ITA grafts may be particularly vulnerable if the initial native flow requirement is high. Such conditions may exist when the ITA is grafted to a coronary bed with a large distal runoff, as may occur with sequential grafting, 11 or when the ITA graft serves a perfusion bed with a physiologically increased resting flow requirement, as may occur with ventricular hypertrophy. 12-14 One particularly lethal situation appears to result from the replacement of a diseased, but patent vein graft to the left anterior descending coronary artery with an ITA alone. 15
This study examined why an artery that normally does not exhibit spasm becomes vulnerable to spasm when used as a bypass graft. We hypothesized that supramaximal flow demands would decrease the distal pressure within the conduit (afterload) and thus increase the sensitivity to constrictors. To eliminate neural and humoral effects, we used an in vitro perfused artery preparation. In both porcine ITAs and GEAs, the response to norepinephrine was measured under normal and supramaximal flow rates.
METHODS
The pigs and porcine tissue used in this study were handled in the laboratory according to the guidelines set by the American Physiological Society. The University of Louisville Animal Care and Use committee approved this protocol.
Experimental preparation.
At the slaughterhouse, porcine stomachs or sternums, or both, were harvested from adult pigs (200 to 250 pounds), placed in cold physiologic salt solution (approximately 5° C), and transported to our laboratory within 10 minutes. At the laboratory the ITA (n = 14) or GEA (n = 8) artery segments (10 to 12 cm long) were excised from the specimens with an electrocautery knife and with the arterial branches occluded with the use of small hemoclips. The arteries were then cannulated with a trimmed 14-gauge Angiocath catheter (Deseret Medical, Sandy, Utah) and attached to a perfusion system. 16-18
The perfusion system (Fig. 1) consisted of a flow pump (Masterflex model 7013, Cole-Palmer International, Chicago, Ill.), a reservoir, an arterial bath, and two distal resistances. The reservoir (100 ml) and arterial bath contained a physiologic salt solution composed of (in millimoles per liter): NaCl 130.0, KCl 4.7, CaCl2 1.6, KH2PO4 1.2, MgSO4 0.7, NaSO4 2.4, NaHCO3 14.9, dextrose 5.5, and ethylenediaminetetraacetic acid (10-7 mol/L), pH 7.4. All solutions were maintained at 37° C and were equilibrated with 95% O2 and 5% CO2.
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Experimental protocol.
The ITA and GEA were perfused at 80 mm Hg and high distal resistance. This gave a flow rate of about 15 to 20 ml/min. This design simulated normal perfusion pressure and flow rates for 1.5 to 2 mm diameter arteries 19 ; that is, the normal flow demands for arteries of this diameter. Norepinephrine was then incrementally added to the perfusate to obtain molar concentrations ranging from 10-9 , 3.3 x10-9 , 10-8 . . . to 10-5 . Each norepinephrine concentration was maintained for at least 3 minutes or until a steady-state response was obtained. Hemodynamic variables were recorded continuously, digitized (every second), and stored in the Apple II+ microcomputer.
The perfusate was then replaced with fresh physiologic salt solution and the artery was allowed to stabilize for 2 hours. The distal resistance was set to allow a maximal flow rate of 100 to 120 ml/min. This design simulated maximal coronary flow demands: flow conditions in the graft that are often present after bypass operations. The norepinephrine dose-response relation was determined as previously described herein. In half the experiments, this order was reversed: that is, low distal resistance and supramaximal flow were used on first exposure to norepinephrine and high distal resistance and normal flow on second exposure to norepinephrine.
If the artery had no measurable flow decrease in response to norepinephrine, the artery was fixed as described later. For arteries in which norepinephrine reduced flow, the arteries were then cut in half. Both the proximal and distal segments were reattached to the perfusion systems and pressures and flow rates were measured separately in each segment. The perfusate was replaced with fresh physiologic salt solution and the arterial segments were allowed to stabilize for 2 hours at 80 mm Hg. With the perfusion pressure at 80 mm Hg and a low distal resistance, the norepinephrine dose-response relation was determined for each segment.
The perfusate was replaced with fresh physiologic salt solution and the arteries flushed and flow rates returned to baseline levels. All arteries, including those without a measurable flow response to norepinephrine, were then fixed by perfusion with a 10% formalin solution at 80 mm Hg. At 1 cm increments along its length, the artery was cut into 2 mm rings. A slide of arterial rings was then obtained with a 35 mm camera (K1000, Pentax, Garden City, N.Y.) equipped with a macro lens. The lens provided optical magnification with high resolution. To enhance contrast, a black sheet was placed under the optically clear bath. Thus the artery appeared white against a black background. For calibration purposes, a metric ruler was placed by the artery. Slides were obtained on Kodak film (Ektachrome 100, Kodak, Rochester, N.Y.).
Data analysis.
The artery resistance was calculated as (proximal pressure minus distal pressure) divided by flow. The mean and standard errors were calculated for the initial and final values for flow rate, pressure, and distal resistance. For each norepinephrine dose response, the half maximal effective concentration (ED50) was determined by a log-logit transformation of the dose-response relationship for each experiment by solving for the 50% dose level. The pressures, flow rates, and resistance values were compared with a Student's t test with a Bonferroni correction for multiple comparison where appropriate.
Dimensional analysis was conducted by projecting the image of the artery. For each arterial ring we measured two perpendicular diameters. Three to four rings were analyzed for the proximal, middle, and distal areas of the artery. These diameters were then averaged. For these average values, the means and standard errors were calculated for the proximal, middle, and distal segments. Findings in the diameter segments were compared by Student's t test with a Bonferroni correction for multiple comparison.
RESULTS
Hemodynamics.
All GEAs responded to norepinephrine. Fig. 2, A, plots proximal pressure, distal pressure, and flow versus time from one GEA experiment. In this example, the GEA was perfused at 80 mm Hg with a high distal resistance, that is, normal flow demands. The initial drop in distal pressure was only 4 mm Hg with a flow rate of 15 ml/min. At the arrows, norepinephrine was added incrementally to the perfusate. The distal pressure and flow began to decrease at a norepinephrine concentration of 3.3 x 10 -7 mol/L. Distal pressure and flow decreased further as the norepinephrine concentration increased to a final distal pressure of 33 mm Hg and flow rate of 6 ml/min (ED50= 8.0 x 10-7 ).
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At normal flow demands, the ITAs were hemodynamically nonresponsive to norepinephrine; that is, distal pressure and flow were unaltered even at the highest norepinephrine concentration. On the basis of the hemodynamic response to norepinephrine at supramaximal flow demands, the ITAs were divided into two groups: hemodynamically nonresponsive (N = 9) and responsive (N = 5). Fig. 3, A, presents the typical pressure and flow versus time from a hemodynamically nonresponsive ITA. Supramaximal flow demands resulted in an initial drop in distal pressure and an initial flow rate of 102 ml/min. Norepinephrine was added incrementally to the perfusate, and the artery was visually observed to constrict. However, the artery was still hemodynamically nonresponsive to norepinephrine: distal pressure and flow were unaltered even at the highest norepinephrine concentration (10-5 mol/L).
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Table I summarizes the results. The hemodynamically nonresponsive ITAs had no hemodynamic responses to norepinephrine at both normal and supramaximal flow demands. At normal flow demands, norepinephrine had no effect on distal pressure, flow rate, or arterial resistance: the initial and final values were almost identical. Supramaximal flow demands caused an initial drop in the distal pressure, but even at the highest norepinephrine concentration distal pressure, flow, and arterial resistance were unaltered. For the hemodynamically responsive ITA, distal pressure, flow rate, and arterial resistances were unaltered by norepinephrine under normal flow conditions. Supramaximal flow demands (low distal resistance) decreased the initial distal pressure and increased the sensitivity to norepinephrine. In response to norepinephrine, distal pressure and flow decreased and arterial resistance increased significantly. In the GEA, norepinephrine caused a dose-dependent decrease in distal pressure and flow and an increase in arterial resistance under normal flow conditions. Lowering the distal resistance increased by more than 39-fold the sensitivity to norepinephrine for the GEA (ED50 from 5.90 ± 0.09 [1.26 x 10-6 mol/L] to 7.49 ± 0.36-logM [3.23 x 10-8 mol/L]).
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Table II summarizes the dimensional analysis. As previously stated, the ITAs were divided into two groups on the basis of the hemodynamic response to norepinephrine. The hemodynamically nonresponsive ITAs had a slight taper with a 22.8% difference between the proximal and distal diameter. The responsive ITAs had a proximal diameter size similar to that of the hemodynamically nonresponsive ITAs. However, the distal diameter was significantly smaller. Further, there was no overlap in the range in the distal diameter data: the largest distal diameter (1.5 mm) in the responsive ITA group was smaller than the smallest distal diameter (2.05 mm) in the hemodynamically nonresponsive group. The hemodynamically responsive ITAs were also more tapered with a difference of 64% difference between the proximal and distal ends. The GEAs were significantly smaller than the hemodynamically nonresponsive ITAs at every location. The GEAs were also smaller than the proximal and middle diameters of the responsive ITAs, but there were no significant differences between the distal diameters. These porcine GEAs were relatively nontapered with only an 11% difference between the proximal and distal ends.
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Table III summarizes the comparison of proximal and distal arterial segments. For the tapered ITA, the proximal segment was significantly larger than the distal segment. The response to norepinephrine was also very different. In the proximal segment, final values for distal pressure, flow rate, and arterial resistance were unaltered even at the highest concentration of norepinephrine. However, for the distal segment, distal pressure and flow rate decreased. For the GEA, the responses to norepinephrine were similar in the proximal and distal segments. In both segments, norepinephrine caused a dose-dependent decrease in distal pressure and flow rate and an increase in arterial resistance.
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We examined potential mechanisms for insufficient graft flow and susceptibility to vasoconstriction in ITA and GEA arteries. Porcine GEAs and small and large ITAs were examined in an in vitro perfusion system. The key findings were (1) with normal flow demands, norepinephrine-induced vasoconstriction caused a slight decrease in flow rate in the GEA, and this flow rate decrease only occurred at high norepinephrine concentrations, (2) increasing flow demands increased the sensitivity to norepinephrine and led to large decreases in flow rate in both the small ITA and GEA, (3) norepinephrine-induced decreases in flow rate did not occur in the larger ITAs, (4) in the relatively nontapered GEA, both the proximal and distal segment were vulnerable to norepinephrine-induced flow decreases, and (5) in the tapered ITA, the proximal segments were less sensitive to norepinephrine.
Mechanism.
The diameter of a vessel is determined by the balance between distending pressure and vasomotor forces. We believe that the interaction of intraluminal pressure changes and vasoconstriction can explain the results of this study. Although often overlooked, intraluminal arterial pressure is a major determinant of vessel size and is the afterload against which vasoconstrictors work. 20 The pressure-induced vessel dimension changes equal in magnitude the vasoconstriction-induced dimensional changes. Germane to the present study, the effects of vasoactive agents are directly related to intraluminal pressure; that is, high arterial pressures (afterload) inhibit vasoconstriction. In one study that used a uniform vasoconstriction stimulus, 20 the arterial diameter decreased by 30% at an intraluminal pressure of 20 mm Hg, whereas no effective vessel shortening occurred at an intraluminal pressure higher than 140 mm Hg.
In normal large-conduit arteries, localized vasoconstriction does not alter intraluminal pressure. Thus arterial pressure is ignored when vasoreactivity is considered. However, in stenotic arteries by the conversion of potential to kinetic energy and in long bypass arterial grafts by accumulative viscous energy losses, intraluminal pressure can change substantially. In previous studies on stenotic arteries, we observed a close relationship between intraluminal pressure changes, flow rate, and dimensions. 16,18 Exaggerated shortening occurred when the stenotic arterial distending pressure decreased. In another study, changing stenotic pressure altered the hemodynamic response to norepinephrine. 21 Interventions that raised stenotic pressure increased the threshold concentration of norepinephrine required to reduce flow, whereas interventions that lowered stenotic pressure decreased the threshold concentration of norepinephrine. These pressure-induced alterations in the hemodynamic responses did not occur in normal arteries. 21
We believe that this same interaction of reduced distal intraluminal pressure and vasoconstriction can explain how a normal artery becomes susceptible to spasm when used as an artery graft (Fig. 6). With normal flow demands, only a small pressure drop occurs along the artery. However, after bypass, a small-diameter artery experiences much higher flow rates than normal. These supramaximal flow rates cause large pressure drops along the vessel (see Figs. 2 and 3 and 
Table I). Under these conditions, vasoconstrictors can further decrease the luminal area, leading to further decreases in intraluminal pressure; that is, there is a positive feedback mechanism. Thus, in an arterial graft, as the artery begins to constrict the intraluminal pressure opposing constriction (afterload) decreases dramatically. The combination of constriction and pressure decreases results in exaggerated diameter reductions and can cause vasospasm with a paradoxic decrease in flow.
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Implications.
These supramaximal flow demands increase the sensitivity of the arterial grafts to norepinephrine, with resulting effective ED50values within the range of perioperative circulating norepinephrine levels. In normal persons, mean circulating norepinephrine levels are about 1.67 x10-9 mol/L andincrease to 5.6 x10-9 mol/L withactivity. 22 Anesthesia and coronary artery bypass grafting raise norepinephrine levels from 200 to 700 pg/ml (1.2 x10-9 to 4.1 x10-9 mol/L) and these levelsremain elevated for up to 24 hours after operation. 23 In instances of deep hypothermia with circulatory arrest, the norepinephrine levels are even higher with a mean peak concentration of 4543 pg/ml (2.7 x10-8 mol/L) reached during rewarming.Thus, with supramaximal flow demands, the effective ED50 values are within the range of circulating norepinephrine levels that occur during the perioperative period and can render the arterial grafts susceptible to spasm.
The results of the present study also provide a theoretic basis for many practical procedures used by surgeons to prevent insufficiency. This study indicates that the long length and small diameter of an arterial graft can restrict flow through the vessel and might cause insufficiency. In many patients postoperative myocardial perfusion may not be exclusively dependent on ITA graft flow for many reasons, such as good collateral circulation and the absence of critical coronary stenosis. In such cases early ITA vasospasm is unlikely to be a clinical problem. However, spasm may be a severe problem in situations that demand supramaximal flow rates. The higher flow rates can decrease pressure within the arterial graft, leaving the graft vulnerable to vasoconstriction and spasm and leading to a paradoxic decrease in flow rate. This situation can be anticipated with ventricular hypertrophy, when a vein graft is replaced at reoperation, or possibly when multiple arterial grafts are used.
On a practical basis there are several approaches for the surgeon to prevent graft insufficiency. Preparation of the arterial conduit is most important. The conduit should be handled carefully and consideration should be given to dilation by mechanical and pharmacologic means. This should decrease the sensitivity to endogenous and exogenous vasoconstrictors. The conduit can be cut to the shortest length possible, removing the tapered part of the vessel, and thus eliminating a segment of vessel that may be more prone to spasm. 24 This study particularly demonstrates how the distal ITA segment (tapered) is responsible for the spasm observed. However, this option will not be available for nontapered arterial grafts. In our study, the proximal and distal segments of the relatively nontapered porcine GEA had similar responses.
When high flow demands are anticipated, supplementary grafting with a saphenous vein may be advisable. The vein can be applied to the same coronary vessel or to one that is adjacent to the coronary vessel (such as a diagonal). The vein graft provides additional flow to support the myocardium and reduces the flow rate in the arterial graft. The reduced flow rate should reduce the pressure loss along the arterial graft and decrease the risk of spasm in the arterial graft. Clearly this strategy places the arterial graft in direct competition with the vein. Many fear the development of the string sign under these circumstances. However, the immediate survival of the patient is often at stake and so this is only a secondary consideration. It is interesting, however, that recent clinical experience suggests that ITA narrowing may be a reversible phenomenon and that when high flow demand occurs the arterial grafts may revert to a more normal size. 25-28
Acknowledgments
We would like to express our thanks to Fischer's Packing Company of Louisville, Kentucky, for their support in the conduct of this experiment.
References
This article has been cited by other articles:
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  Z. S. Meharwal and N. Trehan Routine Use of the Radial Artery for Coronary Artery Revascularization Asian Cardiovasc Thorac Ann, March 1, 2002; 10(1): 20 - 24. [Abstract] [Full Text] [PDF]
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 S. V. Moran, R. Baeza, E. Guarda, R. Zalaquett, M. J. Irarrazaval, E. Marchant, and C. Deck Predictors of radial artery patency for coronary bypass operations Ann. Thorac. Surg., November 1, 2001; 72(5): 1552 - 1556. [Abstract] [Full Text] [PDF]
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E. E. Weinschelbaum, A. Macchia, V. M. Caramutti, H. A. Machain, H. A. Raffaelli, M. R. Favaloro, R. R. Favaloro, E. A. Dulbecco, J. A. Abud, M. D. Laurentiis, et al. Myocardial revascularization with radial and mammary arteries: initial and mid-term results Ann. Thorac. Surg., October 1, 2000; 70(4): 1378 - 1383. [Abstract] [Full Text] [PDF]
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 E. E. Weinschelbaum, E. D. Gabe, A. Macchia, R. Smimmo, and L. D. Suarez TOTAL MYOCARDIAL REVASCULARIZATION WITH ARTERIAL CONDUITS: RADIAL ARTERY COMBINED WITH INTERNAL THORACIC ARTERIES J. Thorac. Cardiovasc. Surg., December 1, 1997; 114(6): 911 - 916. [Abstract] [Full Text]
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