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J Am Coll Cardiol, 2006; 47:981-986, doi:10.1016/j.jacc.2005.10.053 (Published online 8 February 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH

Intense Vasoconstriction in Response to Aspirate From Stented Saphenous Vein Aortocoronary Bypass Grafts

Kirsten Leineweber, PhD*, Dirk Böse, MD{dagger}, Magdalene Vogelsang, MSc*, Michael Haude, MD, FACC{dagger}, Raimund Erbel, MD, FACC{dagger} and Gerd Heusch, MD, FACC*,*

* Institute of Pathophysiology
{dagger} Department of Cardiology, University of Essen School of Medicine, Essen, Germany

Manuscript received March 29, 2005; revised manuscript received September 29, 2005, accepted October 10, 2005.

* Reprint requests and correspondence: Prof. Dr.med Dr.h.c. Gerd Heusch, Institute of Pathophysiology, University of Essen Medical School, Hufelandstrasse 55, 45147 Essen, Germany (Email: gerd.heusch{at}uni-essen.de).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: We sought to identify soluble vasoconstrictor substances that are released during stent implantation into saphenous vein aortocoronary bypass grafts.

BACKGROUND: Atherosclerotic saphenous vein aortocoronary bypass grafts are particularly vulnerable to plaque rupture. Protection devices prevent particulate debris from being embolized. Additional soluble vasoconstrictor substances possibly also contribute to impaired microvascular perfusion.

METHODS: Peripheral venous blood (VB) and aspirate (AS) were obtained from 14 patients with a significant stenosis in a saphenous vein graft during stent implantation under protection with a distal balloon occlusion device. In five additional patients, arterial blood (AB) was also taken distal to the stented lesion before intervention. Vasomotor substances in VB, AB, and AS plasma were identified in a bioassay of rat mesenteric arteries with intact (+E) and denuded endothelium (–E). Vasoconstriction was normalized to that induced by potassium chloride depolarization (100%).

RESULTS: Venous blood, AB, and AS plasma induced maximum vasoconstriction within six minutes. The AS plasma induced a vasoconstriction of 138 ± 13% (–E) and 87 ± 14% (+E); VB, of 70 ± 14% (–E) and 23 ± 4% (+E); and AB plasma obtained before intervention, of 49 ± 9% (–E) and 36 ± 8% (+E). The vasoconstrictor potency of AS plasma in endothelium-denuded vessels was related to the severity of anginal symptoms, angiographic stenosis severity, plaque volume, and plaque burden as determined by intravascular ultrasound. The AS plasma-induced vasoconstriction was largely attenuated by combined serotonin/5-hydroxytryptamine (5-HT)2A/2C- and 5-HT1A/1B-receptor blockade and eliminated by additional thromboxane A2 thromboxane-prostanoid (TP)-receptor blockade.

CONCLUSIONS: Stent implantation releases, apart from and in addition to particulate debris, soluble vasoconstrictor substances that possibly contribute to impaired microvascular perfusion.

Saphenous vein aortocoronary bypass grafts are not only prone to developing graft vasculopathy, but are also particularly vulnerable to plaque rupture and microembolization during stent implantation (1). Apart from particulate debris leading to distal microvascular obstruction, infarctlets, and peri-infarctlet inflammation, plaque rupture also results in the release of vasomotor, thrombogenic, and pro-inflammatory soluble substances (2–4). Such substances possibly contribute to impaired microvascular perfusion (the "slow" or "no reflow" phenomenon) (2,3,5). Whereas thrombolytic and antiplatelet agents are inadequate to prevent such adverse events during stent implantation into saphenous vein grafts, a more effective protection is achieved by devices that trap or aspirate large pieces of plaque debris and thrombotic material (6–10). We have now developed a bioassay that measures the aspirate-induced force of contraction in rat mesenteric arteries with intact and denuded endothelium to identify vasoconstrictor substances in the soluble fraction of the aspirate.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   Nineteen symptomatic patients (18 men, 1 woman) with a significant stenosis in a saphenous vein aortocoronary bypass graft were studied. Target grafts, concomitant diseases, and current medications are presented in Table 1. Full informed consent was obtained from all patients before participating in the study. The investigation conforms to the principles outlined in the Declaration of Helsinki. Patients with total occlusion, stenoses in native coronary vessels, ostial lesions, and acute myocardial infarction were excluded from this study.


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  		Table 1. Patient Characteristics
 
Quantitative coronary angiography.   All patients were on aspirin (100 mg/day) and received 10,000 IU heparin intravenously. Coronary angiography was performed via the femoral approach after intracoronary injection of 0.2 mg nitroglycerin before and after the intervention. Quantification of stenosis severity was performed with the use of off-line caliper measurements (QCA-MEDIS, Leiden, the Netherlands) as described elsewhere (11).

Intravascular ultrasound (IVUS) imaging.   All IVUS analyses were performed before stent implantation with a commercially available mechanical sector scanner (Boston Scientific, Natick, Massachusetts) as described elsewhere (12). An entire segment analysis was performed off-line using a computerized analysis system with automated contour detection and editing (QCA-MEDIS). Quantitative analyses were performed according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measurement, and Reporting of IVUS (13). The analyzed data were averaged over the stented segment. A three-dimensional reconstruction with volume measurements of the treated segment was also performed.

Interventional procedure.   Implantation of balloon-expandable stents via the femoral approach was performed using maximum balloon pressures of ≥14 atm and a balloon-to-vessel ratio of 1:1.1. To prevent microembolization, a distal balloon occlusion device (TriAktiv, Kensey Nash, Exton, Pennsylvania) was mounted on a guide wire and inflated at 2 atm with carbon dioxide (CO2) during stent implantation. Aspiration of plaque debris was performed via the guiding catheter after a special flushing catheter was advanced proximal to the inflated wire balloon. During slow withdrawal of the flushing catheter, the stented area was washed with saline (approximately 55 ml). After the extraction process, the balloon was deflated and a post-interventional angiography was performed. Serum troponin I was measured before and 6 h after the intervention.

Blood samples.   Venous blood (VB) (5 ml potassium-EDTA S-Monovette, Sarstedt, Germany) was obtained via a vena femoralis before intervention, and 20 ml aspirate (AS) was obtained during the intervention, diluted with approximately 55 ml saline, and filtered through a 40-µm mesh filter. In each instance, visible particulate debris was retained on the filter.

In five additional patients, arterial blood (AB) was also taken distal to the stented lesion via the flushing catheter (10 ml into potassium-EDTA S-Monovette) before intervention and compared with AS after stent implantation.

The VB, AB, and filtered AS were immediately centrifuged (600 g for 10 min at 4°C), and the plasma was removed, quickly frozen in liquid nitrogen, and stored at –20°C until further use.

Vasomotor bioassay.   Human coronary arteries and rat mesenteric arteries are characterized by a comparable receptor arrangement for thromboxane A2, norepinephrine, and serotonin (14–17). Hence, we used rat mesenteric arteries for this bioassay to characterize soluble vasoconstrictor substances in human plasma. All animal experiments were performed according to the German laws for animal welfare and were approved by the local committee for animal studies.

Male Lewis rats (200 to 300 g body weight) were killed by rapidly removing the heart after anesthesia with enflurane. The mesentery was immediately removed and transferred into carbogenated (5% CO2/95% O2) Krebs-Henseleit buffer (mmol/l: 119 NaCl, 4.7 KCl, 2.5 CaCl2x2 H2O, 1.17 MgSO4x7 H2O, 25 NaHCO3, 1.18 KH2PO4, 0.027 EDTA, 5.5 glucose). Arteries (250 to 350 µm diameter, 2 mm length) were carefully dissected, and the endothelium was mechanically removed by passing a cat whisker through the lumen to mimic and verify the dual effect of endothelium-mediated vasodilators in vessels with intact (+E) and denuded endothelium (–E) that were mounted in the same Mulvany myograph bath chamber (Danish Myo Technology, Aarhus, Denmark).

Arteries were equilibrated for 20 min in 10 ml aerated (5% CO2/95% O2) Krebs-Henseleit buffer warmed to 37°C before an intravascular pressure of 100 mm Hg = 13.3 kPa was applied. The vessels were equilibrated for a further 30 min with frequent buffer changes before challenge with KCl (120 mmol/l) to estimate maximum vasoconstriction. Arteries were washed and re-challenged with norepinephrine (10 µmol/l) and carbachol (100 µmol/l) to verify the lack of endothelial cells.

To characterize the endothelium-dependent actions of thromboxane A2 (by using the metabolically stable analogue U-46619), norepinephrine, and serotonin, we first performed cumulative concentration-response curves (1 nmol/l to 10 µmol/l) in the presence of 5 µmol/l cocaine (monoamine transporter inhibitor that blocks the uptake of, for example, serotonin and norepinephrine) and 1 µmol/l propranolol (unselective ß1- and ß2-adrenoceptor blocker). In comparison to arteries with intact endothelium agonist concentration that induces 50% of maximum response [EC50], nmol/l; for U-46619: 64 ± 1, for norepinephrine: 150 ± 8, for serotonin: 790 ± 9, n = 8 each) concentration response curves were shifted for all three agonists significantly (each p < 0.05) to the left in arteries with denuded endothelium (EC50, nmol/l; for U-46619: 41 ± 1, for norepinephrine: 58 ± 1, for serotonin: 270 ± 12, n = 8 each), without a difference in the order of potency: U-46619 > norepinephrine > serotonin, an order described also for human coronary arteries (14,15).

Thereafter, arteries were washed, and VB or AB and AS plasma, diluted to a final dilution of 1:10 (v/v) each with Krebs-Henseleit buffer, containing 5 µmol/l cocaine, 1 µmol/l propranolol, and 10 µmol/l phentolamine ({alpha}1- and {alpha}2-adrenoceptor blocker), were added separately. Arteries were washed and re-challenged with norepinephrine (10 µmol/l) and carbachol (100 µmol/l) to verify the viability of the vessels. VB plasma served as a control to exclude possible unspecific, irreversible, and receptor-independent vasoconstrictor effects of human plasma on rat arteries per se, and to match for individual platelet count, coagulation factors, and medical treatment. Arterial blood plasma served as a control to confirm that the vasoconstrictor substances were released from the treated plaque by stent implantation.

For each individual patient, two myograph bath chambers were prepared to analyze the vasoconstrictor substances in VB or AB and AS plasma in parallel.

To investigate to what extent serotonin and/or thromboxane A2 might contribute to the vasoconstrictor potential of AS plasma, vessels were equilibrated for 30 min before AS plasma addition, either with a combination of 1 µmol/l ketanserin (5-hydroxytryptamine [5-HT]2A/2C-receptor blocker with {alpha}1-adrenoceptor blocker effects) and 0.1 µmol/l pindolol (ß-adrenoceptor blocker with 5-HT1A/1B-receptor blocker effects) or with a combination of ketanserin, pindolol, and 10 µmol/l ICI 185,282 (thromboxane A2 thromboxane-prostanoid (TP)-receptor blocker) in the presence of 5 µmol/l cocaine, 1 µmol/l propranolol, and 10 µmol/l phentolamine. Finally, arteries were washed and re-challenged with norepinephrine (10 µmol/l) and carbachol (100 µmol/l) to again verify their viability.

Statistics.   Data are mean values ± SEM. Statistical differences were assessed with repeated-measures analysis of variance with Bonferroni post-hoc tests for multiple comparisons. Concentration-response curves were fitted and analyzed by computer-supported iterative non-linear regression analysis (sigmoidal concentration-response curve: y = bottom + (top – bottom)/(1 + 10(logEC50 – x)) where x = the logarithm of agonist concentration and y = response) using the Prism program (Graph-Pad Software, San Diego, California) to calculate EC50-values (= agonist concentration that induces 50% of maximum response). All correlations and statistical calculations were performed with the Prism program, and a p value < 0.05 was considered to be significant.

Drugs.   Chemicals used were as follows. [-]-Norepinephrine bitartrate salt, carbachol, phentolamine, and propranolol were purchased from Sigma, Deisenhofen, Germany; ICI 185,282 (5-(z)-7(4-O-hydroxyphenyl-Z-trifluoromethyl-1,3-dioxan-cis-5-yl)-heptenoic acid), ketanserin tartrate, and pindolol were purchased from BioTrends Tocris, Cologne, Germany; U-46619 (9,11-dideoxy-9a,11a-methanoepoxy-prostaglandin F2{alpha}) was purchased from Calbiochem, Darmstadt, Germany. All other chemicals were of the purest grade commercially available.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Patient characteristics.   The patients' mean age was 69 ± 2 years, Canadian Cardiovascular Society (CCS) functional class was 2.4 ± 0.2 (range, I to IV), systolic blood pressure was 135 ± 4 mm Hg, diastolic blood pressure was 80 ± 3 mm Hg, heart rate was 64 ± 2 beats per minute, total cholesterol was 170 ± 7 mg/dl, high-density lipoprotein cholesterol was 50 ± 3 mg/dl, low-density lipoprotein cholesterol was 91 ± 5 mg/dl, and the triglyceride level was 133 ± 13 mg/dl. The graft age was 13 ± 1 years (range, 3 to 19 years). The percent diameter stenosis of the saphenous vein graft was 66 ± 2%. Serum troponin I levels 6 h after the intervention (0.13 ± 0.04 ng/ml) were within the normal range and not significantly different from pre-interventional levels (0.07 ± 0.04 ng/ml).

Angiographic and IVUS data.   Baseline and post-interventional angiographic data and IVUS data are shown in Table 2.


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  		Table 2. Baseline and Post-Interventional Angiographic Characteristics and IVUS Data
 
Vasomotor bioassay.   Rat mesenteric arteries immediately constricted after exposure to VB, AB, and AS plasma; an almost stable maximum in constriction (normalized to KClEmax, 100%) was reached within 6 min. For VB as well as AS plasma (n = 14), the extent of vasoconstriction was endothelium-dependent (±E) with an order of potency: AS–E >> AS+E ≥ VB–E >> VB+E, with maximum mean values of 138 ± 13% (AS–E), 87 ± 14% (AS+E), 70 ± 14 (VB–E), and 23 ± 4% (VB+E) (Fig. 1). The AB plasma (n = 5), taken distal to the lesion before intervention, induced a vasoconstriction of 49 ± 9% (–E) and 36 ± 8% (+E). After stent implantation, the corresponding AS plasma (n = 5) induced a vasoconstriction of 137 ± 11% (–E) and 92 ± 11% (+E), respectively (Fig. 2), indicating that the vasoconstrictor substances in the aspirate were released from the plaque by stent implantation.


Figure 1
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  		Figure 1 Vasoconstrictor action of venous blood (VB, open circles/closed circles) and aspirate plasma (AS, open squares/closed squares) on rat mesenteric arteries with intact (open symbols = +E) and denuded endothelium (filled symbols = –E). Values are mean ± SEM of 14 patients. *p < 0.05 vs. AS–E; #p < 0.05 vs. VB+E, p < 0.05 with Bonferroni correction for six comparisons.

 

Figure 2
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  		Figure 2 Vasoconstrictor action of arterial blood (AB, open triangles/closed triangles) taken distal to the lesion and aspirate plasma (AS, open squares/closed squares) on rat mesenteric arteries with intact (open symbols = +E) and denuded endothelium (filled symbols = –E). Values are mean ± SEM of five patients. *p < 0.05 vs. AS–E; #p < 0.05 vs. AS+E with Bonferroni correction for six comparisons.

 
Additionally, we addressed potential intra-individual differences by repeating the aspirate-induced vasoconstriction in arteries with denuded endothelium; aspirate of four patients induced in the first set a maximum of 111 ± 19% and in the second set a maximum of 105 ± 9% vasoconstrictor response, indicating good reproducibility of the bioassay.

In arteries with denuded endothelium, the AS plasma-induced maximum of vasoconstriction was significantly correlated with the severity of anginal symptoms (CCS I to IV), diameter stenosis, plaque volume, and plaque burden (Table 3).


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  		Table 3. Correlations Between AS Plasma-Induced Maximum in Vasoconstriction (% KClEmax) and CCS Functional Class, Angiographic Diameter Stenosis, and IVUS Plaque Volume and Plaque Burden of the 19 Patients
 
The amount of particulate debris retained on the filter was 4.4 ± 1 mg/dry weight and did not correlate with the individual responses to the aspirate.

In the presence of serotonin-receptor blockade, the vasoconstrictor effect of AS-plasma was reduced by about 80% in arteries without endothelium (28 ± 4%) and by about 75% in arteries with endothelium (21 ± 4%) (Fig. 3). In the presence of combined serotonin and thromboxane A2 TP-receptor blockade, the vasoconstrictor effect of AS plasma on arteries without endothelium (14 ± 1%) and with endothelium (12 ± 2%) was abolished (Fig. 3).


Figure 3
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  		Figure 3 Vasoconstrictor action of aspirate plasma in the absence (open squares/closed squares AS+/–E) and in the presence of 1 µmol/l ketanserin (5-HT2A/2C-receptor blocker) and 0.1 µmol/l pindolol (ß-adrenoceptor and 5-HT1A/1B-receptor blocker) (open diamonds/closed diamonds AS+/–E with 5-HT-R blockade) or in the presence of 1 µmol/l ketanserin, 0.1 µmol/l pindolol, and 10 µmol/l ICI 185,282 (thromboxane A2 TP-receptor blocker) (open inverted triangles/closed inverted triangles AS+/–E with 5-HT and TP-R blockade) on rat mesenteric arteries with intact (open symbols = +E) and denuded endothelium (filled symbols = –E). Values are mean ± SEM of 14 patients. *p < 0.05 vs. AS–E; #p < 0.05 vs. AS+E with Bonferroni correction for 15 comparisons.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
We have identified serotonin and thromboxane A2 in potently vasoconstricting amounts to be released during stenting of saphenous vein aortocoronary bypass grafts, apart from and in addition to particulate debris. This finding confirms and extends the observation of Wilson et al. (2) who reported, apart from any distal emboli, a transient and humorally mediated profound impairment in microvascular blood flow after coronary angioplasty.

The coronary vascular tone depends on the functional integrity of the endothelium. Numerous studies have shown that atherosclerosis is associated with endothelial dysfunction characterized by impaired coronary blood flow in response to the endothelium-dependent vasodilators acetylcholine or serotonin (18–21). One of the humoral mediators released during angioplasty and stent implantation is serotonin, and its amount correlates with the degree of impaired microvascular perfusion (3). However, patients treated before angioplasty with ketanserin, a 5-HT2A/2C-receptor blocker with {alpha}1-adrenoceptor blocker effects, still had substantial (over 30%) vasoconstriction, implying the involvement of additional mechanisms (3). In human coronary arteries, the serotonin-induced vasoconstriction is not only mediated by 5-HT2A receptors but also by 5-HT1B receptors, as reflected by the side effects of the anti-migraine agent sumatriptan, a 5-HT1B/1D-receptor agonist, including coronary vasoconstriction, ischemia, and myocardial infarction (14,22–24).

In our bioassay, which measures the "soluble" aspirate-induced force of contraction in rat mesenteric arteries with intact and denuded endothelium, aspirate plasma reached or even exceeded the maximum of KCl-induced vasoconstriction. In arteries with intact endothelium, the aspirate plasma-induced maximum of vasoconstriction was attenuated, most likely reflecting the vasodilator and endothelium-dependent effect of serotonin (Fig. 1).

However, platelet activation and disruption release not only serotonin, but also thromboxane A2 (25). Thromboxane A2 and serotonin may act synergistically to induce coronary vasoconstriction, and in isolated human saphenous veins thromboxane A2 also amplifies noradrenergic constrictions and contractions to KCl, which are mediated by voltage-dependent calcium channels (15,26). On the other hand, all patients were treated with aspirin (100 mg/day), that is, a dose expected to maintain complete inhibition of platelet thromboxane A2 production (27). However, thromboxane A2 is also synthesized in non-adherent and adherent human monocytes/macrophages and vascular cells via cyclooxygenase (COX)-2. Although platelets are persistently inactivated by aspirin (plasma half-life, 15 to 20 min), those nucleated cells can rapidly (2 to 4 h) recover from the aspirin-dependent irreversible inhibition of COX-2 activity through de novo synthesis of COX-2 in response to inflammatory and mitogenic stimuli, especially in symptomatic atherosclerotic plaques (28–31). However, we cannot exclude an insufficient suppression of platelet thromboxane A2 production in some of our patients (32). Accordingly, thromboxane A2 can still play an important role in coronary vasoconstriction, moreover, because only nanomolar concentrations of thromboxane A2 are necessary to amplify the vasoconstrictor effect of serotonin in coronary arteries (15). In our bioassay, the presence of thromboxane A2 in AS plasma is indicated by the degree (about 20%) of vasoconstriction left in the presence of serotonin-receptor blockade, whereas in the presence of serotonin-receptor and thromboxane A2 TP-receptor blockade, the AS plasma-induced vasoconstriction was abolished.

In conclusion, these results indicate that during stenting of saphenous vein aortocoronary bypass grafts, soluble vasoconstrictor substances are released that, apart from and in addition to particulate debris, are possibly responsible for distal microvascular obstruction. Apparently, the severity of graft vasculopathy also determines the amount of vasoconstrictor release. Our data would therefore favor aspiration over filter protection devices. In the future, the particulate fraction of aspirate will also have to be studied and appropriate measures to attenuate the profound vasoconstriction will have to be defined.

Study limitations.   It was not feasible to investigate the individual vascular response to each aspirate on isolated vessels obtained from the same patient. Therefore we used standardized rat mesenteric arteries, which possess a similar receptor arrangement for thromboxane A2, norepinephrine, and serotonin as coronary arteries and saphenous veins (14–17). We simulated endothelial dysfunction, which is regularly found in coronary artery disease (18–21), by mechanical removal of the endothelium. Clearly, mechanical denudation of the endothelium in a rat mesenteric artery is not the same as endothelial dysfunction in a human coronary vessel, but both show a lack of vasodilation or a reversal to vasoconstriction in response to acetylcholine (18,20). Accordingly, in our bioassay we only used mesenteric arteries as arteries +E and –E with a carbachol-induced relaxation of 82 ± 5% and 24 ± 4%, respectively.

Our qualitative analysis by using specific serotonin and thromboxane A2 blockers indicates that these mediators were released in potently vasoconstricting amounts during stent implantation, although we did not measure their amount quantitatively. Nevertheless, we cannot exclude that other vasoconstrictor substances such as angiotensin II, endothelin, oxidized low-density lipoprotein, or lipoprotein(a) also contributed to the observed vasoconstriction.

The AS plasma-induced vasoconstriction was intense, whereas vasoconstriction induced by VB plasma was negligible. Because VB and AS plasma were investigated in parallel, it seems unlikely that the different medication given to each patient before the procedure could have resulted in inter-individual differences in VB and AS plasma-induced maximum of vasoconstriction, although we cannot completely exclude it.


   Footnotes
 
This work was supported by a grant (HE 1320/14-1) from the German Research Foundation.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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