Christian A. Plass

Active endothelin is an important vasoconstrictor in acute coronary thrombi.

Acute coronary syndrome is characterized by compromised blood flow at the epicardial and microvascular levels. We have previously shown that thrombectomy in ST-elevation myocardial infarction (STEMI) accelerates ST-segment resolution, possibly by preventing distal embolization. We hypothesized that thrombus constituents contribute to microcirculatory dysfunction. Therefore, we analyzed the molecular and cellular composition of acute coronary thrombi, and correlated vasoconstrictive mediators with the magnitude of ST-segment resolution within one hour of percutaneous coronary intervention (PCI). Fresh coronary thrombi were retrieved in 35 consecutive STEMI patients who were treated with the X-Sizer thrombectomy catheter, and thrombus cell counts and vasoconstrictor concentrations were assessed. Twelve-lead ECG recordings were analyzed prior to and one hour after PCI. Concentration of endothelin (ET) was 20.0 (7.9-52.2) fmol/ml in thrombus compared with 0.1 (0.1-0.3) fmol/ml in corresponding peripheral plasma (p < 0.0001), representing a selective 280 (70.0-510.0)-fold enrichment, exceeding enrichment of noradrenaline, angiotensin II and serotonin. Human coronary thrombus homogenates exerted vasoconstriction of porcine coronary artery rings that was inhibited by the dual ET receptor blocker tezosentan. Extracted ET (r = 0.523 p = 0.026) and number of leukocytes (r = 0.555 p = 0.017) were correlated with the magnitude of ST-segment resolution. In conclusion, the amount of active ET and white blood cells aspirated from STEMI target vessels correlated with improvement of territorial microcirculatory function as illustrated by enhanced ST-segment resolution.

Light-Induced Vasodilation of Coronary Arteries and Its Possible Clinical Implication

BACKGROUND Low-level laser therapy and light-emitting diodes (LED) are increasingly used in phototherapy. Their therapeutic effects are at least partly mediated by light-induced vasodilation. The aim of this study was to determine the effect of different light sources on coronary arteries. METHODS Porcine left coronary arteries were cut into 4-mm rings that were irradiated either by a semiconductor nonthermal gallium-arsenide diode laser or a noncoherent athermic red light source both with the same energy density up to 16 J/cm(2). After precontraction with 9, 11-dideoxy-11α, 9α-epoxymethano-prostaglandin F(2)α, respective relaxation responses were evaluated. The role of endothelium as well as intracellular pathways was investigated. RESULTS Maximum vasodilation after exposure to laser was observed at 10 J/cm(2) (56.8% ± 1.2%) and decreased to 43.9% ± 2.8% at 16 J/cm(2) (p < 0.003). After adjusting exposure time to achieve equivalent energy densities in the LED group, vessel segments revealed photorelaxation of 52.9% ± 6.5% and 47.5% ± 0.6%, respectively. Vasodilations achieved by either light source were comparable at 10 J/cm(2) (p < 0.574) and 16 J/cm(2) (p < 0.322). Furthermore, vasodilation could be inhibited by administration of 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (nitric oxide scavenger) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (guanocyclase inhibitor) but not with L-nitro-arginine methyl ester or deendothelialization. CONCLUSIONS Vessels exposed to either light source showed a remarkable as well as comparable photorelaxation at definite energy densities. This effect is mediated by an intracellular nitric oxide-dependent mechanism. As LED sources are of small size, simple, and inexpensive build-up, they may be used during routine coronary artery bypass surgery to ease suturing of anastomosis by target vessel vasodilation.

Decellularized, xenogeneic small-diameter arteries: Transition from a muscular to an elastic phenotype in vivo

Reports regarding the biocompatibility of xenogeneic, decellularized bioprosthetic implants differ between bioinertness and complete graft degradation. We investigated heparin-crosslinked and nonheparinized, xenogeneic vascular substitutes in a rat model. Porcine arteries (15 x 1.5 mm) were decellularized by multistep detergent and enzymatic techniques, which were followed by heparin-crosslinking in 50% of the implants. Prostheses were implanted into the abdominal aorta of 76 rats for 1 day and up to 6 months. Retrieved specimens were evaluated by histology, immunohistochemistry, laser scanning, and scanning electron microscopy. Graft patency did not differ between groups (97.3%). Heparinized grafts showed a statistically significant lower rate of aneurysm formation (p = 0.04 %). Implants revealed infiltration with granulocytes and macrophages up to 3 months. Recellularization with endothelial cells and myofibroblasts was detectable within 1 month. After 6 months elastin biosynthesis and complete graft remodeling toward an elastic vessel was evident. These results indicate that temporary inflammation does not interfere with long-term vascular remodeling.

Time Course of Endothelium-Dependent and -Independent Coronary Vasomotor Response to Coronary Balloons and Stents : Comparison of Plain and Drug-Eluting Balloons and Stents

OBJECTIVES This study sought to determine the time dependency of the endothelium-dependent and -independent vascular responses after percutaneous coronary intervention (PCI) with drug-eluting (DEB) or plain balloons, bare-metal (BMS), and drug-eluting (DES) stents, or controls. BACKGROUND Long-term endothelial dysfunction after DES implantation is associated with delayed healing and late thrombosis. METHODS Domestic pigs underwent PCI using DEB or plain balloon, BMS, or DES. The dilated and stented segments, and the proximal reference segments of stents and control arteries were explanted at 5-h, 24-h, 1-week, and 1-month follow-up (FUP). Endothelin-induced vasoconstriction and endothelium-dependent and -independent vasodilation of the arterial segments were determined in vitro and were related to histological results. RESULTS DES- and BMS-treated arteries showed proneness to vasoconstriction 5 h post-PCI. The endothelium-dependent vasodilation was profoundly (p < 0.05) impaired early after PCI (9.8 ± 3.7%, 13.4 ± 9.2%, 5.7 ± 5.3%, and 7.6 ± 4.7% using plain balloon, DEB, BMS, and DES, respectively), as compared with controls (49.6 ± 9.5%), with slow recovery. In contrast to DES, the endothelium-related vasodilation of vessels treated with plain balloon, DEB, and BMS was increased at 1 month, suggesting enhanced endogenous nitric oxide production of the neointima. The endothelium-independent (vascular smooth muscle-related) vasodilation decreased significantly at 1 day, with slow normalization during FUP. All PCI-treated vessels exhibited imbalance between vasoconstriction-vasodilation, which was more pronounced in DES- and BMS-treated vessels. No correlation between histological parameters and vasomotor function was found, indicating complex interactions between the healing neoendothelium and smooth muscle post-PCI. CONCLUSIONS Coronary arteries treated with plain balloon, DEB, BMS, and DES showed time-dependent loss of endothelial-dependent and -independent vasomotor function, with imbalanced contraction/dilation capacity.

Secretome of apoptotic peripheral blood cells (APOSEC) attenuates microvascular obstruction in a porcine closed chest reperfused acute myocardial infarction model: role of platelet aggregation and vasodilation.

Although epicardial blood flow can be restored by an early intervention in most cases, a lack of adequate reperfusion at the microvascular level is often a limiting prognostic factor of acute myocardial infarction (AMI). Our group has recently found that paracrine factors secreted from apoptotic peripheral blood mononuclear cells (APOSEC) attenuate the extent of myocardial injury. The aim of this study was to determine the influence of APOSEC on microvascular obstruction (MVO) in a porcine AMI model. A single dose of APOSEC was intravenously injected in a closed chest reperfused infarction model. MVO was determined by magnetic resonance imaging and cardiac catheterization. Role of platelet function and vasodilation were monitored by means of ELISA, flow cytometry, aggregometry, western blot and myographic experiments in vitro and in vivo. Treatment of AMI with APOSEC resulted in a significant reduction of MVO. Platelet activation markers were reduced in plasma samples obtained during AMI, suggesting an anti-aggregatory capacity of APOSEC. This finding was confirmed by in vitro tests showing that activation and aggregation of both porcine and human platelets were significantly impaired by co-incubation with APOSEC, paralleled by vasodilator-stimulated phosphoprotein (VASP)-mediated inhibition of platelets. In addition, APOSEC evidenced a significant vasodilatory capacity on coronary arteries via p-eNOS and iNOS activation. Our data give first evidence that APOSEC reduces the extent of MVO during AMI, and suggest that modulation of platelet activation and vasodilation in the initial phase after myocardial infarction contributes to the improved long-term outcome in APOSEC treated animals.

Low-level-laser irradiation induces photorelaxation in coronary arteries and overcomes vasospasm of internal thoracic arteries†‡

As low‐level laser irradiation (LLLI) seems to induce vasodilation besides many other known biological effects, LLLI has been increasingly used in therapy of medical conditions with various irradiation parameters. The aim of this study was to investigate the effect of LLLI on photorelaxation of human coronary and internal thoracic arteries (ITA).

Drug-Eluting Introducer Sheath Prevents Local Peripheral Complications : Pre-Clinical Evaluation of Nitric Oxide–Coated Sheath

OBJECTIVES This study evaluated the protective effect of nitric oxide-coating of introducer sheath on the local complications in juvenile porcine femoral arteries with similar size to human radial arteries. BACKGROUND Insertion of an introducer sheath induces vasospasm and transient or permanent vessel occlusion of radial arteries. METHODS Nitric oxide-coated or control introducer sheaths with or without spasmolytic cocktail (control + C-sheath) were inserted into porcine femoral arteries, followed by percutaneous coronary intervention (PCI). The diameter of the femoral artery at the puncture site, distally and proximally, was measured by quantitative angiography. Histopathological and histomorphometric parameters of the femoral arteries were analyzed 1 h or 1 week after PCI. RESULTS Insertion of femoral sheath led to mild or severe spasms, with significantly higher vessel diameter at the access site (2.69 ± 0.81 mm vs. 1.77 ± 0.77 mm and 1.85 ± 0.66 mm, p < 0.001), and proximal and distal to it, during PCI in the nitric oxide-sheath group versus the control-sheath and control + C-sheath groups, respectively. Immediately following PCI, significantly less luminal thrombosis (12% vs. 33% and 31% of all analyzed segments, p < 0.001) was observed in the nitric oxide-sheath arteries. At 1 week, lower intimal inflammation score (0.43 ± 11 vs. 1.03 ± 0.35 and 1.04 ± 0.32, p < 0.05), less luminal thrombosis (8% vs. 21% and 30% p < 0.05), and smaller intimal hyperplasia (0.31 ± 0.31 mm(2) vs. 0.47 ± 1.00 mm(2) and 0.86 ± 0.82 mm(2), p < 0.05) were observed in NO-sheath arteries at the injury site. CONCLUSIONS Nitric oxide coating on the introducer sheath prevents local complications during PCI and results in less vascular thrombosis and inflammation at the access site, contributing to patency of the access vessel with similar size to the radial artery.

Comparison of short- and long-term results of drug-eluting vs. bare metal stenting in the porcine internal carotid artery.

Purpose To evaluate the development of neointimal hyperplasia after implantation of drug-eluting stents (paclitaxel) compared to bare metal stents in porcine internal carotid arteries (ICAs). Methods While drug-eluting stents have effectively reduced neointimal proliferation in porcine external carotid arteries, the porcine internal carotid artery (ICA) is more sensitive to shear stress and altered flow conditions. Thus, a study was conducted to evaluate bare vs. drug-eluting stents in porcine ICAs. Under general anesthesia, 18 domestic pigs were implanted with paclitaxel-eluting (n=18) and bare (n=18) stents in the left and right ICAs, respectively. After 1 and 3 months, control carotid angiography was performed, followed by histopathological and histomorphometric analyses of the stented ICA. Results Histopathological results (fibrin deposition, necrosis, inflammation) were similar in the groups at 1 and 3 months. Moreover, the injury score and rate of endothelialization did not differ between the groups. Histomorphometric analysis after 1 month revealed significantly (p<0.05) less neointimal hyperplasia after implantation of paclitaxel-eluting stents. The antiproliferative effect of paclitaxel-eluting stents were maintained during the 3-month follow-up: the neointimal area was 0.7±0.5 vs. 1.2±0.6 mm2 (p<0.01), the area stenosis was 23.5%±13.9% vs. 37.8%±14.4% (p<0.01), the maximal neointimal thickness was 0.2±0.1 vs. 0.2±0.9 mm (p<0.05) in paclitaxel-eluting vs. bare stents, respectively. Implantation of paclitaxel-eluting and bare stents did not lead to edge restenosis or vessel remodeling in porcine ICAs at 1 or 3 months. Conclusion Compared to bare metal stents, drug-eluting stents implanted in the porcine ICA produced significantly less neointimal hyperplasia.

Inhomogeneous vasomotor effects of moderate selective and non-selective endothelin-receptor blockade in stable coronary artery disease

Objective: To explore the morphological and functional effect of selective and non-selective endothelin (ET)-receptor blockade in coronary artery disease (CAD). Design: Prospective randomised controlled trial. Setting: University hospital. Patients: 26 patients with stable CAD. Interventions: Intracoronary infusion (30 minutes) of the ET-A receptor blocker BQ-123 (40 nmol/min, group A, n = 13) alone or with the ET-B receptor blocker BQ-788 (10 nmol/min, group AB, n = 13) as well. Main outcome measures: Fractional flow reserve (FFR), coronary flow reserve (CFR) and intramyocardial resistance (IMR) by PressureWire, mean arterial blood pressure (MAP), minimal lumen diameter (MLD) and average angiographic lumen diameter (mean LD) of the target vessel before and after intracoronary infusion of ET antagonists. Concentrations of C-terminal pro-endothelin-1 (CT-proET1) in arterial blood were determined before and after infusion. Results: Mean MLD, mean LD, FFR, CFR, IMR and MAP remained unaffected by ET-receptor blockade in both groups; their changes were comparable. Concentrations of CT-proET-1 increased by 6.2 (SD 5.9) pmol/l (95% CI 1.2 to 11.1 pmol/l; p = 0.022) in group A and by 4.1 (SD 4.3) pmol/l (95% CI 1.1 to 7.2 pmol/l; p = 0.014) in group AB. Conclusions: We found a broad variety of individual haemodynamic responses to ET-receptor antagonists with an overall neutral effect after an infusion period of 30 minutes despite an overall effective blockade of ET-receptors. Prolonged infusion time may be needed to cause a more distinct vasomotor response. Trial registration number: NCT00427232.

Target vessel reopening by guidewire insertion in ST-elevation myocardial infarction is a predictor of final TIMI flow and survival

ST-elevation myocardial infarction (STEMI) results from acute thrombotic obstruction of a coronary artery. Percutaneous coronary intervention (PCI) is the treatment of choice to restore blood flow. The incidence of guidewire-induced reopening of the infarct-related coronary artery (IRA) and its association with post-procedural TIMI flow and long-term mortality were assessed. Angiograms of consecutive STEMI patients admitted to the catheter laboratory of the Medical University of Vienna between January 2003 and December 2005 were analysed. TIMI flow was graded prior to and after guidewire insertion into the distality of the IRA, and at the end of the procedure. Initial TIMI 0 flow was present in 476 (47.0%) of 1,012 cases. Target vessel reopening after guidewire insertion defined as any flow >TIMI 0 flow occurred in 150 patients (37.2%), and was associated with improved survival after a median of 914 (609-1,238) days (p=0.017). Reflow after guidewire insertion was an independent predictor of post-procedural TIMI flow (odds ratio=3.10, 95% confidence interval [CI]=1.64 - 5.86], p<0.001) and mortality (hazard ratio=0.51, CI=0.28 - 0.94], p=0.029). Target vessel reopening by guidewire insertion is a new predictor of prognosis. Target vessel flow after guidewire insertion should be assessed in a standardised fashion during PCI.