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Ann Thorac Surg 2002;73:1341-1345
© 2002 The Society of Thoracic Surgeons

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Review

Remodeling of arterial conduits in coronary grafting

^a Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

* Address reprint requests to Dr Barner, Division of Cardiothoracic Surgery, Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, Suite 3108 Queeny Tower, St. Louis, MO 63110 USA
e-mail: barnerh{at}msnotes.wustl.edu

	Abstract

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
In the initial decade of coronary surgery, serial angiography of internal thoracic artery grafts revealed increased caliber in some, decreased caliber in others, and "string sign" in a few, which was occasionally documented to be reversible. Although we speculated on possible causes of these changes, it was not until discovery of the endothelial role in modulating arterial diameter to maintain shear stress in a narrow range that we began to gain insight into the mechanisms responsible for remodeling of the arterial wall. This review provides a glimpse of the physiology and biology of arterial remodeling and summarizes observations on the various arterial conduits when subjected to flow alterations.

	Introduction

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Arteries remodel in response to chronic changes in blood flow. Remodeling is an active process of integrated activity involving endothelium, smooth muscle cells, fibroblasts, and extracellular matrix that includes sensing of the vascular milieu and intracellular and intercellular signaling to achieve alterations in vessel structure.

Increased arterial pressure will increase the ratio of the width of the arterial wall to the lumen by an increase in muscle mass of the media or by decreasing the lumen without medial hypertrophy. Chronic alterations in flow will alter lumen diameter to achieve "normalization" of shear stress leading to unchanged or decreased wall thickness associated with dilation and increased wall thickness when the lumen is reduced by diminished flow.

Although the concept of vascular remodeling is not new, a review article failed to consider the arterial conduit in its commentary [1], perhaps because that report focused on mechanisms of disease, whereas the concept as it applies to the arterial conduit is a physiologic happening that bears on its performance. For more than 30 years we have witnessed the internal thoracic artery (ITA) as a coronary artery graft become larger, remain unchanged, or diminish in caliber. This brief review is intended to provide surgeons with a better understanding of the physiology and biology of arterial conduits used as coronary grafts.

	Blood flow and the endothelium

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Flowing blood creates two principal vectors in a vessel. One is perpendicular to the wall and is determined by the blood pressure. The other is parallel to the wall and creates a frictional force, shear stress, at the endothelial surface. The entire vessel wall is subjected to cyclic stretch because of the pulsatile nature of the blood pressure. Mean wall shear stress is in the range of 20 to 40 dyne/cm², but varies from negative values to 50 dyne/cm² in disturbed flow regions of large arteries during the cardiac cycle [2]. Flow velocity, and therefore shear stress, varies with the cardiac cycle and is also influenced by curvatures in the vessel wall, bifurcations, and branches, although the coronary arterial bypass conduit is relatively uniform in caliber and free of these perturbations except for curves. Instantaneous shear stress is difficult to measure in vivo, but transients in excess of 100 dyne/cm² during increased cardiac output have been recorded [3]. Surface shear is influenced by the shape of the endothelial cell and its topography. Endothelial cells align in the direction of flow, but cell orientation is lost with flow disturbances [4, 5]. Shear stress is greater over the nuclear bulge [6] and also varies over the cell surface owing to waviness (< 6 µm) [7].

	Endothelial cell response to stress

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Stress acting on the luminal surface of an endothelial cell causes internal stresses that are transmitted by the cytoskeleton to sites of cell attachment (focal adhesions) to the subendothelial matrix [8] and neighboring cells [9], as well as to the nucleus [10]. The alignment of endothelial cells in the direction of flow is driven mainly by reorganization of the cytoskeleton [4]. These changes are associated with an increased resistance of the cell surface to deformation, which represents stability provided by the cytoskeleton and not by stiffening of the cell membrane itself [7].

	Mechanotransduction of the flow signal

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
To respond to shear stress, the endothelium must sense and then transduce the stimulus [11]. Although the mechanism of activation is unclear, potassium channels are activated by flow [12]. The mechanism could involve shear stress-mediated deformation of cytoskeletal elements [13].

Alternatively, glycoproteins of the glycocalyx, which may be receptors themselves or linked to receptors of the plasma membrane, can be physically displaced by flow [14].

Flow-sensitive endothelial potassium-channel activity has been linked to release of an endogenous nitrovasodilator in arterial rings [15, 16]. The same pathway is involved in the flow-induced transcription of transforming growth factor ß₁ [17]. Thus, a common mechanotransducer may initiate vasodilation in response to increased flow and later vascular remodeling if the flow increase persists.

By hyperpolarizing the endothelial cell, the flow-activated potassium channel maintains the electrochemical gradient for calcium entry. The flow-induced changes in calcium influx may also be modulated by vasoactive agents such as adenosine triphosphate [18] and the activity of protein kinases. This calcium influx is necessary for synthesis and release of nitric oxide (NO).

	Indirect mechanisms of flow stimulation

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Flowing blood influences the potentially high local concentration of solutes at the cell surface, such as adenosine diphosphate released by platelet aggregation or neurotransmitters released by endothelium. These solutes may be influenced by receptor-mediated endocytosis (minutes), or by rapid degradation at the cell surface (adenine nucleotides, bradykinin, and angiotensin) [19]. Endothelial release of adenosine triphosphate, acetylcholine, endothelin, and substance P from flow stimulation in vitro suggests an autocrine mechanism for stimulation of receptors for these agonists present on the same cells [20]. Intracellular calcium responses are highly sensitive to fluid motion at the cell surface. Small increases of flow stimulate large calcium transients with return to baseline in 4 minutes, whereas decreasing flow had an opposite effect [21].

	Shear stress and vasoregulation

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
In 1933, vasomotion in response to altered blood flow was reported [22], and Rodbard [23] suggested that the endothelium may sense shear stress, but Furchgott and Zawadski [24] proved that endothelium was necessary for this to occur. Intraarterial pressure has little effect on endothelial control of vasoactivity, and the contractile response of smooth muscle cells to increasing pressure is smooth muscle-dependent and endothelium-independent [25]. Shear stress is the principal endothelial regulator of arterial diameter and is directly proportional to viscosity. When viscosity was altered by hemoconcentration or hemodilution, or by addition of dextrans, vasodilation developed as a function of increasing viscosity when flow and pressure were constant and physiologic [26].

Endothelial release of NO is the principal mediator of shear stress-induced vasoregulation [27]. Additional flow-mediated vasoregulatory substances are prostacyclin (prostaglandin I₂) and endothelin-1. NO is a short-lived molecule with a half-life in physiologic buffer of a few seconds and is readily scavenged by hemoglobin. Its effect is potentiated by superoxide dismutase, an enzyme that destroys free radicals that sequester NO [28]. The enzyme NO synthase (NOS) converts L-arginine to L-citrulline with release of NO [27]. Endothelial NOS (eNOS) is constitutively expressed at a basal level, and its activity is calcium dependent and calmodulin dependent [27]. Steady laminar flow-induced NO synthesis is dependent on a shear stress magnitude of 2 to 12 dyne/cm² and upregulates the level of eNOS messenger RNA [29]. Step-change increases of laminar shear stress of the same magnitude increase NO synthesis. Additionally, NO production is biphasic after the onset of flow, with an initial rapid rise that is independent of shear stress magnitude (range 6 to 25 dyne/cm²) and a sustained release phase that is shear dependent [30]. NO activates soluble guanylate cyclase, which elevates intracellular cyclic guanosine monophosphate in endothelium, smooth muscle cells, and platelets, where it results in inhibition of shape change and aggregation.

Expression of eNOS involves shear stress-responsive elements within the promotor region of the gene. The consensus sequence for shear stress-responsive elements in the eNOS promoter is GAGACC, a putative transcription factor binding site that is common to the promoter regions of many endothelial genes that are responsive to shear stress, including tissue plasminogen activator, intracellular adhesion molecule-1, transforming growth factor ß₁, and endothelin-1 [31].

	Arterial remodeling

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Flow-mediated vasodilatation occurs in a few seconds, and shear stress usually returns to its previous level (15 to 20 dyne/cm²) [32]. Remodeling of the arterial wall in response to changes in flow (increase or decrease) occurs over weeks to months, involves changes in gene expression, and results in a shear stress similar to the baseline level. Chronic flow increase achieves an enlarged lumen [33], whereas reduced flow induces intimal thickening and a decrease in lumen diameter [34]. Both of these responses involve changes in arterial wall composition and organization [35]. Removal of the endothelium prevents these alterations [36]. It has also been shown that changes of stretch and tensile stress in endothelial and smooth muscle cells may alter synthesis and secretion of collagen, elastin, and connective tissue protease. Increased laminar shear stress induces the expression of transforming growth factor ß₁ and the increased secretion of biologically active transforming growth factor ß₁ [17], which inhibits growth of vascular smooth muscle cells [37]. How the endothelium mediates extracellular matrix synthesis by smooth muscle cells is unclear.

	Experimental remodeling of large arteries

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Increasing flow by means of an arteriovenous fistula of the aorta or carotid or iliac arteries will increase arterial diameter and return shear stress to control in 2 months in rats [38] or 6 to 8 months in larger animals [38–41]. Reducing flow by branch ligation will result in reduced diameter. These responses are endothelium dependent [41]. With increased flow, wall thickness was unchanged in all three models. Vessel wall remodeling in the aorta was associated with a significant increase in elastin (5%) and collagen (3%) content [38]. Interestingly, when the fistula was opened in the rat, the cyclic guanosine monophosphate content in the proximal aorta rose significantly.

	Remodeling of the internal thoracic artery

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Experimental studies of the in situ canine internal thoracic artery (ITA) have demonstrated narrowing when flow was reduced by side branch ligation (luminal area, control, 2.64 ± 0.47 mm² versus treated, 2.21 ± 0.53 mm²; p = 0.009) and dilation (luminal area, control, 3.01 ± 0.73 mm² versus treated, 3.61 ± 0.57 mm²; p = 0.019) when flow was increased by an arteriovenous fistula between the artery and the vein at the level of the sixth rib and followed for 2 months [42]. Thickness of each wall component of the ITA was not different from control for the high-flow group, but medial and total wall thickness were greater than control in the low-flow group. Shear stress had not returned to control at 2 months in either group, but shear stress normalized in iliac arteries of cynomolgus monkeys 6 months after creation of an arteriovenous fistula [40], suggesting that completion of remodeling requires more than 2 months.

Growth of the ITA used as a coronary artery bypass graft in children was not surprising [43]. Seki and coworkers [44] first established a correlation between late ITA diameter and the severity of coronary stenosis. In 12 of 16 left ITA grafts to the left anterior descending coronary artery with a stenosis of less than 50%, there was a string sign (ITA diameter of 1.0 mm or less) or occlusion was present.

Internal thoracic artery grafts to coronary arteries with 80% to 100% stenosis (n = 28), 60% to 79% stenosis (n = 16), and 40% to 59% stenosis (n = 6) were studied 2 weeks to 5 years (median 25 weeks) postoperatively with a late distal ITA diameter in group 1 of 2.27 ± 0.23 mm (p < 0.01 versus group 2), in group 2 of 2.00 ± 0.28 mm (p < 0.01 versus group 3), and in group 3 of 1.07 ± 0.27 mm [45].

Doppler guidewire assessment of no-flow (by angiography) left ITA grafts revealed to-and-fro flow signals with systolic reversal and diastolic antegrade signals in the distal segment of the ITA under baseline conditions [46]. Hyperemia induced by adenosine infusion resulted in disappearance of retrograde flow and preponderance of antegrade flow in the ITA conduit. Distal ITA graft diameter was 1.9 ± 0.2 mm in no-flow grafts and 2.5 ± 0.2 mm in control (functioning) grafts. Proximal left anterior descending artery stenosis in no-flow ITA grafts was 57% ± 5% at the time of study, which would not be expected to reduce resting flow but could be flow restrictive during hyperemia (exercise or pharmacologic vasodilation) [47]. The 13 control patients had proximal left anterior descending coronary occlusion and patent ITA grafts with antegrade systolic and diastolic flow and a flow velocity reserve of 2.6 ± 0.3.

Coronary flow reserve in left ITA grafts to the left anterior descending coronary at 1 month and 1 year postoperatively (measured with a Doppler flow wire and dipyridamole-induced hyperemia) increased from 1.8 ± 0.3 to 2.6 ± 0.3 (p < 0.01) [48]. During this interval, ITA diameter increased from 2.4 ± 0.1 to 2.9 ± 0.2 mm (p < 0.05), and time averaged peak velocity fell from 27 ± 9 to 19 ± 6 cm/s (p < 0.01), with a coronary stenosis of 98% ± 2%.

It is apparent that the ITA adjusts its diameter to the flow requirements placed on it, whether experimentally or clinically.

	Remodeling of the radial artery

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Assessment of the in situ radial artery (RA) used as an arteriovenous fistula (created at least 3 months previously) for hemodialysis in chronic renal failure patients revealed a sixfold increase in blood flow (126 ± 135 mL/min; control, 22 ± 24 mL/min; p < 0.01) a 1.4-fold increase in internal diameter (3.31 ± 1.09 mm; control, 2.40 ± 0.61 mm; p < 0.001), and a constant shear stress (14.4 ± 8.4 dyne/cm²; control, 8.2 ± 10.3 dyne/cm²; not significant) [49]. Structural remodeling did not result in increased wall thickness, as wall cross-sectional area was not increased (2.4 ± 1.0 mm²; control, 2.0 ± 0.7 mm²; not significant). This remodeling is associated with an increase in circumferential wall stress (98 ± 32 kPa; control, 65 ± 17 kPa; p < 0.001) [49]. The 38% increase in diameter with remodeling compares with a 10% short-term increase in the RA diameter with acetylcholine infusion [50].

We have observed anecdotal remodeling of the RA used as a T-graft with narrowing of the proximal segment between the T-anastomosis and the first coronary anastomosis to the obtuse marginal artery (50% stenosis) with dilatation of the distal segment from this anastomosis to the posterior descending artery (proximally occluded) anastomosis in which the obtuse marginal artery supplied flow to the posterior descending artery through the RA. In another patient, the RA T-graft to the obtuse marginal artery was patent at 16 months postoperatively, but an angioplasty of the first obtuse marginal artery (at that time) resulted in closure of the RA when studied 1 year later. We view these changes in RA caliber or closure of the conduit as related to flow requirements in the conduit determined by absent or competitive native coronary flow. We have observed a decrease in RA patency when the coronary stenosis is less than 70% [51].

Radial artery grafts (n = 48) to coronary arteries studied 1 and 5 years postoperatively increased in diameter from 2.08 ± 0.45 mm at 1 year to 2.54 ± 0.53 mm (p < 0.001) at 5 years [52]. At 5 years, five of six RAs to arteries with less than 70% stenosis at operation were occluded (4 cases) or had a string sign (1 case).

	Remodeling of the gastroepiploic artery

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Preoperative and 3-week to 5-week postoperative angiography was performed in 88 patients to determine gastroepiploic artery (GEA) diameter and flow patterns, which were classified on the basis of the postoperative coronary angiogram as GEA dependent (n = 61), balanced (n = 16), and native dependent (n = 11) [53]. The preoperative diameters of the GEA were not significantly different among the flow patterns, but the postoperative diameters were: GEA dependent, preoperative 2.25 ± 0.36 versus 2.32 ± 0.38 mm; balanced, preoperative 2.31 ± 0.38 versus 2.03 ± 0.43 mm; and coronary dependent, preoperative 2.30 ± 0.21 versus 0.83 ± 0.62 mm, with postoperative diameters significantly different among all groups (p < 0.05). The flow pattern was dependent on the severity of stenosis (15 of 16 with 99% stenosis and 31 of 51 with 90% stenosis had a GEA-dependent pattern) and the location of the stenosis: a 75% stenosis between the proximal and distal right coronary artery was not associated with a GEA-dependent pattern, but if the stenosis was located in the posterior descending artery or the atrioventricular artery, there was a GEA-dependent pattern in 7 of 9.

	Comment

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 
Remodeling of coronary bypass arterial conduits has been recognized since the mid-1970s, but only after the report of 1980 [24] and the subsequent explosion of knowledge about the myriad and complex functions of the endothelium have we had some understanding of the unique ability of this organ to influence and guide the behavior of the arterial wall. It has become apparent that conduit (and other) arteries will adjust their caliber and wall structure to suit the flow requirements placed on them. This propitious event normalizes shear stress at the endothelial interface and allows the conduit to deliver an appropriate flow to the subserved vascular bed. These changes are not so favorable in the circumstance of reduced conduit flow, owing to competitive flow from the grafted coronary artery, which may result in downsizing of the conduit with the possibility of no flow or oscillating flow, leading to stasis and thrombosis. We have learned that conduits are not alike in their sensitivity to competitive flow, with the RA (70% to 80% coronary stenosis) [51, 54] and the GEA (75% to 90% coronary stenosis) [53] being more sensitive in this regard than the ITA (60% coronary stenosis) [55]. Understanding these events may lead us to different operative strategies or to a biologic or pharmacologic approach to the problem.

	References

Top Abstract Introduction Blood flow and the... Endothelial cell response to... Mechanotransduction of the flow... Indirect mechanisms of flow... Shear stress and vasoregulation Arterial remodeling Experimental remodeling of large... Remodeling of the internal... Remodeling of the radial... Remodeling of the gastroepiploic... Comment References

 

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