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Aims: Myocardial infarction (MI) is a major global cause of death. Massive cell death leads to inflammation, which is necessary for ensuing wound healing. Extensive inflammation, however, promotes infarct expansion and adverse remodeling. The DNA sensing receptor cyclic GMP-AMP synthase and its downstream signaling effector stimulator of interferon genes (cGAS-STING) is central in innate immune reactions in infections or autoimmunity. Cytosolic double-strand DNA activates the pathway and down-stream inflammatory responses. Recent papers demonstrated that this pathway is also active following MI and that its genetic targeting improves outcome. Thus, we investigated if pharmacologic pathway inhibition is protective after MI in order to test its translational potential., Main Methods: We investigated novel and selective small-molecule STING inhibitors that inhibit STING palmitoylation and multimerization and thereby downstream pathway activation in a preclinical murine MI model. We assessed structural and functional cardiac remodeling, infarct expansion and fibrosis, as well as cardiomyocyte hypertrophy and the expression of inflammatory genes., Key Findings: Pharmacologic STING inhibition did not reduce mortality due to myocardial rupture in non-reperfused MI. Infarct size at day one was comparable. However, three weeks of pharmacologic STING inhibition after reperfused MI decreased infarct expansion and scarring, increased left ventricular systolic function to levels approaching normal values, and reduced myocardial hypertrophy., Significance: Selective small-molecule STING inhibition after myocardial infarction has the potential to improve wound healing responses and pathological remodeling and thereby attenuate the development of ischemic heart failure., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Gonadal hormones are mainly thought to account for sex and gender differences in the incidence, clinical manifestation and therapy of many cardiovascular diseases. However, intrinsic sex differences at the cellular level are mostly overlooked. Here, we assessed sex-specific metabolic and functional differences between male and female human umbilical vein endothelial cells (HUVECs)., Methods: Cellular metabolism was investigated by bioenergetic studies (Seahorse Analyser) and a metabolomic approach. Protein levels were determined by Western blots and proteome analysis. Vascular endothelial growth factor (VEGF)-stimulated cellular migration was assessed by gap closure. HUVECs from dizygotic twin pairs were used for most experiments., Results: No sex differences were observed in untreated cells. However, sexual dimorphisms appeared after stressing the cells by serum starvation and treatment with VEGF. Under both conditions, female cells had higher intracellular ATP and metabolite levels. A significant decline in ATP levels was observed in male cells after serum starvation. After VEGF, the ratio of glycolysis/mitochondrial respiration was higher in female cells and migration was more pronounced., Conclusions: These results point to an increased stress tolerance of female cells. We therefore propose that female cells have an energetic advantage over male cells under conditions of diminished nutrient supply. A more favourable energy balance of female HUVECs after serum starvation and VEGF could potentially explain their stronger migratory capacity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Differences between men and women are being continuously identified in many human diseases. The underlying reasons are not yet fully understood. Beside the influence of endogenous hormones and life style, intrinsic sex-specific dimorphisms at the cellular level may also play a role. HUVECs from twin pairs of opposite sex provide an excellent tool to address the question of sex-specific differences at the molecular level. We compared for the first time protein levels of male and female HUVECs from dizygotic twins using a proteomic approach. To investigate differences under basal and stress conditions, cells were either left untreated or wounded and serum starved for different time points. Approximately 10% of all proteins monitored showed significant sexual dimorphisms in their level under the different conditions tested. The majority of the proteins displayed a higher abundance in female cells. The magnitude of the difference in protein levels between male and female cells was rather small. The most prominent differences throughout all conditions were observed for several X-chromosome encoded proteins with higher levels in female (UBA1, HDHD1) or in male cells (G6PD). Proteins involved in basic cellular processes, such as gene expression and translation (e.g. HMGN1, SRP54) displayed sex-specific levels in particular conditions only. SIGNIFICANCE: This study provides novel insights into sexual dimorphic protein levels in HUVECs from twin pairs of the opposite sex. The findings identify proteins with sex-specific differences in their levels under different cell culture conditions. The study also highlights the presence of X-chromosome encoded proteins escaping X-chromosomal inactivation. The results emphasize the need to consider the cellular sex of male and female HUVECs in in vitro experiments., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We investigated the biotransformation of very small superparamagnetic iron oxide nanoparticles (VSOP) in atherosclerotic LDLR -/- mice. Transmission electron microscopy revealed an uptake of VSOP not only by macrophages but also by endothelial cells in liver, spleen, and atherosclerotic lesions and their accumulation in the lysosomal compartment. Using magnetic particle spectroscopy (MPS), we show that the majority of VSOP's superparamagnetic iron was degraded within 28 days. MPS spectrum shape indicated changes in the magnetic properties of VSOP during the biodegradation process. Experiments with primary murine bone marrow derived macrophages, primary murine liver sinusoidal endothelial cells, and primary human aortic endothelial cells demonstrated that loading with VSOP induced a differential response of cellular iron homeostasis mechanisms with increased levels of ferritin and iron transport proteins in macrophages and increased levels of ferritin in endothelial cells., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Based on our previous data on the presence of very small superparamagnetic iron oxide nanoparticles (VSOP) on brain endothelial structures during experimental autoimmune encephalomyelitis (EAE), we investigated the mechanisms of VSOP binding on inflamed brain endothelial cells in vivo and in vitro. After intravenous application, VSOP were detected in brain endothelial cells of EAE animals at peak disease and prior to clinical onset. In vitro, inflammatory stimuli increased VSOP uptake by brain endothelial bEnd.3 cells, which we confirmed in primary endothelial cells and in bEnd.3 cells cultured under shear stress. Transmission electron microscopy and blocking experiments revealed that during inflammation VSOP were endocytosed by bEnd.3. Modified sulfated glycosaminoglycans (GAG) on inflamed brain endothelial cells were the primary binding site for VSOP, as GAG degradation and inhibition of GAG sulfation reduced VSOP uptake. Thus, VSOP-based MRI is sensitive to visualize early neuroinflammatory processes such as GAG modifications on brain endothelial cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Significant sex differences exist in cardiovascular diseases. Although an impact of gonadal hormones is presumed, it is largely unknown whether sexually dimorphic gene expression also plays a role and whether cells themselves show intrinsic sex differences., Methods: We performed whole genome expression analyses in human umbilical vein endothelial cells (HUVEC) from 20 male and 20 female donors and compared levels of gene transcription between the sexes. To further assess whether there is a sex-specific response to stress, we subjected male and female HUVEC to shear for 24 h and analysed changes in gene expression., Results: Genes indicative for greater immune responsiveness were stronger expressed in female compared to male HUVEC. There was a significant enrichment of 77 immune-related genes in female HUVEC. These increased transcriptional levels in female cells were verified for 20 genes by real-time RT-PCR. 6.7% of all mRNAs were regulated by shear stress. Female HUVEC showed a more pronounced transcriptional response to shear than did their male counterparts. In addition to quantitative differences, a number of genes were regulated in the opposite direction between the two sexes by shear stress. Functionally, female HUVEC showed a higher cell viability after serum starvation and an increased tube formation capacity compared to male cells., Conclusion: These findings underscore the importance for differentiation between male and female cells in cell culture experiments. This may apply not only to endothelial cells but might be generalized to other cell types as well. The observed sexual dimorphisms in gene expression in endothelial cells may contribute to sex differences between males and females in endothelial function., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Until now, no reliable biomarker has become available for short- or long-term outcome prediction in patients undergoing transcatheter aortic valve implantation (TAVI). Our goal was to investigate whether galectin-3 is also suited for risk assessment in TAVI patients. Galectin-3, a novel marker indicative for myocardial fibrosis, has prognostic value in heart failure. We included 101 patients undergoing TAVI in this prospective, single-center, observational study. Baseline galectin-3 levels were correlated to the VARC 30-day safety and one-year efficacy endpoint as well as to total mortality and cardiovascular events at one year. At baseline, mean galectin-3 level for the entire group was 18.1 (± 11.1) ng/ml. Of the 101 patients, 36 had a galectin-3 value above the cut off value of 17.8 ng/ml. These patients had significantly higher systolic pulmonary artery and capillary wedge pressures. The hazard ratio in patients with galectin-3 > 17.8 ng/ml was 3.36 (95% confidence interval, CI: 1.47-7.69; p=0.004) for the VARC 30-day safety endpoint, 5.12 (95% CI: 2.10-12.47; p<0.001) for one-year cardiovascular events, and 4.48 (95% CI: 1.56-12.91; p=0.005) for all-cause mortality. This prediction remained stable even after adjusting for possible confounders including age, sex, glomerular filtration rate, and NT-proBNP. Furthermore, the prediction was even more valuable when combining galectin-3 with NTproBNP. In summary elevated galectin-3 levels are associated with adverse outcome after TAVI. Combining galectin-3 with NT-proBNP provides additive predictive value of risk stratification., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Stimulation of the liver X receptor (LXR) is associated with anti-inflammatory and vascular-protective effects under hyperlipemic conditions. We examined whether LXR stimulation influences TNF-α-induced endothelial dysfunction under normolipemic conditions. Endothelium-dependent vasorelaxation of aortic rings was determined in an organ water bath. Human umbilical vein endothelial cells (HUVEC) were exposed to TNF-α (10 ng/ml) in the presence or absence of 5 μM of the LXR agonist T0901317 or GW3965 and changes in TNF-α-induced endothelial cell apoptosis, inflammation, oxidative stress, and NO metabolism were analyzed. T0901317 improved TNF-α-impaired endothelium-dependent relaxation of aortic rings in response to acetylcholine. T0901317 decreased the TNF-α-induced apoptosis and inflammation as indicated by a decrease in caspase 3/7 activity, VCAM-1 mRNA expression and subsequent mononuclear cell adhesion. Furthermore, T0901317 reduced the expression of the oxidative stress markers: AT1R, NOX4, and p22phox and normalized the TNF-α-induced NOX activity to basal levels. In line with the reduced AT1R expression, T0901317 impaired the Ang II responsiveness. T0901317 influenced NO metabolism as indicated by a decrease in TNF-α-upregulated arginase activity, a reversal of TNF-α-induced downregulation of argininosuccinate synthase mRNA expression and eNOS expression to basal levels and a raise in NO production. Furthermore, T0901317 decreased the TNF-α-induced superoxide and nitrotyrosine production, but did not upregulate the TNF-α-downregulated eNOS dimer/monomer ratio. Silencing of LXRβ, but not of LXRα, abrogated the anti-apoptotic effects of T0901317. We conclude that LXR agonism improves TNF-α-impaired endothelial function via its anti-apoptotic, anti-inflammatory, and anti-oxidative properties and its capacity to restore TNF-α-impaired NO bioavailability independent of its cholesterol-modulating effects., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aims: We recently demonstrated that non-toxic inhibition of the proteasome upregulates antioxidative enzymes and leads to an adaptive transcriptional pattern in endothelial cells. We therefore hypothesized that proteasome inhibition could prevent experimentally-induced endothelial dysfunction. As there are conflicting data about the effects of proteasome inhibition on endothelial function, we investigated whether proteasome inhibition could prevent experimentally-induced endothelial dysfunction., Main Methods: Endothelial dysfunction in isolated rat aortic rings was induced by incubation of rings with TNFalpha for 48 h. To study the effects of the inhibition of the proteasome, selected rings were co-treated with proteasome inhibitors. Vasorelaxation and expression of genes involved in endothelial function were evaluated., Key Findings: Incubation of rat aortic rings with TNFalpha for 48 h led to significant dose-dependent reduction of acetylcholine-induced vasorelaxation. Co-incubation with TNFalpha and the proteasome inhibitor MG132 resulted in dose-dependent improvement of endothelium-dependent vasorelaxation in comparison to rings treated with TNFalpha alone. Levels of eNOS mRNA and protein were reduced despite improved vascular function after treatment with MG132. MG132 markedly suppressed mRNA levels of NADPH oxidase subunits and increased SOD1 expression. Superoxide production was reduced in rings incubated with MG132 in comparison to controls. TNFalpha-induced upregulation of the potent vasoconstrictor endothelin was abolished by MG132., Significance: Proteasome inhibition prevents TNFalpha-induced vascular dysfunction by reduction of superoxide production and suppression of endothelin levels. The balance between vasoconstriction and vasodilatation is shifted in favour of endothelium-dependent vasodilation.

This paper describes a new and straightforward method for determination of the green tea catechins epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate in human plasma. Sample preparation includes addition only of dimethylformamide and trichloroacetic acid. After centrifugation, the supernatant can be injected into the HPLC. If required, the glucuronides and sulphates of the catechins can be enzymatically hydrolysed before extraction. Recovery ranges from 92.9 to 98.2%; limits of detection, from 2.4 to 5.0 ng/mL; and relative standard deviations, from 3.1 to 8.6%. Twelve samples can be processed within 45 min, and are then ready to be injected into the HPLC. The method was successfully applied to human plasma. This method is suitable for studies on absorption, bioavailability, and kinetics of green tea catechins in plasma. Since manual work and time consumption are minimal, the procedure is especially useful for large numbers of samples.

Hyperplasia and hypertrophy of fat cells can be found in obesity, and increased adiposity is associated with endothelial dysfunction as an early event of atherosclerosis. However, it is unclear whether human adipocytes directly influence endothelial function. To study the crosstalk between fat and endothelial cells, human umbilical venous endothelial cells (HUVECs), and human coronary artery endothelial cells (HCAECs) were cultured in infranatants (Adipo) of primary differentiated human adipocytes. Interestingly, incubation of HUVECs and HCAECs with Adipo significantly increased monocyte adhesion 7.3 and 2.2-fold, respectively. VCAM-1, ICAM-1, and E-selectin in HUVECs were upregulated 3.9, 3.0, and 9.5-fold, respectively, under these conditions. Furthermore, Adipo significantly stimulated NFkappaB activity 1.9-fold. The NFkappaB inhibitor MG-132 and heat inactivation significantly reversed Adipo-stimulated monocyte adhesion. TNFalpha-neutralizing antibodies partly reversed Adipo-induced monocyte adhesion. In contrast, thiazolidinedione-pretreatment of human adipocytes did not alter the effects of Adipo. Adipo did not show cytotoxic effects. Taken together, we demonstrate that endothelial dysfunction is induced by adipocyte-secreted factors via NFkappaB partly dependent on TNFalpha.

Atherosclerosis is a chronic inflammatory disease accompanied by the expression of endothelial adhesion molecules. Phloretin is a plant-derived phytochemical that is mainly present in apples. Because phloretin is reported to promote antioxidative activities, we investigated the effects of phloretin on cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) in human umbilical vein endothelial cells (HUVECs). Phloretin prevented TNF-alpha-stimulated upregulation of VCAM-1, ICAM-1, and E-selectin expression in a concentration-dependent manner. To the same extent as for TNF-alpha, phloretin also inhibited IL-1beta-induced upregulation in expression of all 3 adhesion molecules. Inhibition of cytokine-induced adhesion molecule expression for VCAM-1, ICAM-1, and E-selectin was detected already at the level of mRNA. Preincubation with phloretin dose-dependently attenuated TNF-alpha-stimulated adhesion of monocytic THP-1 cells to HUVECs and human aortic endothelial cells. Phloretin did not affect TNF-alpha-stimulated activation of nuclear factor kappaB (NF-kappaB) but inhibited activation of interferon regulatory factor 1, a transcription factor involved in the regulation of endothelial cell adhesion molecule expression. In human platelets, phloretin diminished adenosine diphosphate (ADP) and thrombin receptor-activating peptide-stimulated expression of the activated form of the GPIIb/IIIa complex and reduced platelet aggregation stimulated by ADP. Thus phloretin may have beneficial effects in the onset and progression of cardiovascular diseases.

Attachment of leukocytes to the vascular endothelium and the subsequent migration of cells into the vessel wall are early events in atherogenesis. This process requires the expression of endothelial adhesion molecules. Since tea catechins are reputed to promote antiatherogenic activities, we investigated the effects of various tea catechins-i.e., epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG)-on cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) in HUVECs by ELISA. EGCG and to a lesser extent ECG prevented the induction of VCAM-1 expression in a concentration-dependent manner after stimulation with TNF-alpha, whereas EC and EGC were without effect. EGCG also inhibited the IL-1beta-induced induction of VCAM-1 expression. Inhibition of cytokine-induced VCAM-1 expression was manifested already on the transcriptional level. Furthermore, EGCG reduced the TNF-alpha-induced adhesion of THP-1 cells to HUVECs. EGCG did not influence TNF-alpha-stimulated NF-kappaB activation.

The effects of proteasome inhibition (PI) on heat-shock protein (HSP) expression in cardiomyocytes were investigated. Neonatal rat cardiomyocytes were incubated with MG132 (0.1-10 microM) for 1 h. Induction of various HSPs was determined by real-time PCR and Western blotting. PI induced a 2- to 3-fold increase in HSP27, HSP60, and HSP90, and a 18-fold increase in HSP70 mRNA expression, whereas HSP40 levels were unaffected. Western blotting revealed increased protein expression for HSP70 after PI. Similar results were obtained with MG262. HSP induction correlated with enhanced survival of neonatal cardiomyocytes after sublethal heat stress in XTT testing. In papillary muscles, pretreatment with MG132 (10 microM, 90 min) was associated with enhanced recovery of the contractile parameters after a 40-min hypoxia. In these proof-of-principle experiments, we show that PI induces differential heat-shock response in cardiomyocytes, accompanied by enhanced cell survival and functional recovery after various forms of stress., (©2002 Elsevier Science (USA).)

Although three common MTHFR polymorphisms (C677T, A1298C, T1317C) have been reported, only polymorphism C677T has been investigated intensively as a risk factor for coronary artery disease (CAD). We investigated polymorphism frequencies, allelic associations and the effect of the resulting MTHFR genotypes on total plasma homocysteine (tHcy) levels and on coronary risk in a case-control study with 1000 angiographically confirmed Middle-European CAD patients and 1000 matched controls. Three out of four theoretically possible MTHFR haplotypes were detected: *1 (677C, 1298A), *2 (677T, 1298A), and *3 (677C, 1298C). The frequencies were *1: 36.4 and 34.4%; *2: 30.8 and 32.3%; and *3: 32.8 and 33.3%, in cases and controls, respectively. Only one patient was heterozygous for 1317C. None of the six resulting genotypes showed significant influence on tHcy levels. Moreover, there was no significant association with CAD risk or with disease severity or early disease manifestation. In the subgroup presenting with acute coronary syndromes, MTHFR genotypes *2/*3 and *3/*3 were surprisingly underrepresented (relative risk of *3/*3, 0.40; 95% confidence interval 0.20-0.79, P=0.009). We conclude from our genotype-based analysis that, in this well-fed Middle-European population, the observed common allelic variants of the MTHFR gene have no significant influence on tHcy levels or on the chronic process of CAD development.

Cellular adhesion molecules play a pivotal role in the pathogenesis of atherosclerosis by mediating the adherence of blood leukocytes. Since hyperhomocysteinemia appears to be an independent risk factor for the development of atherosclerosis, in this study we investigated the effect of homocysteine on basal and TNF-alpha-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) on human umbilical-vein endothelial cells. Incubation of endothelial cells with homocysteine resulted in dose-dependent reduction in TNF-alpha-induced (5 ng/ml) expression of VCAM-1, E-selectin, and ICAM-1 (the latter less pronounced). This effect was found to be specific since other thiol compounds-cysteine and glutathione-did not mimic homocysteine activity. Homocysteine attenuated TNF-alpha-stimulated U-937 adhesion to the endothelial monolayer and reduced TNF-alpha-induced activation of the transcription factor NF-kappaB, indicating that NF-kappaB inhibition may play a role in inhibiting expression of adhesion molecules in endothelial cells., (Copyright 2001 Academic Press.)

Background: Since hyperhomocysteinaemia is an independent risk factor for development of atherosclerosis as well as for arterial and venous thrombosis we investigated whether elevated homocysteine levels are associated with procedural excess risk which complicates coronary interventions including coronary angioplasty (PTCA), stenting, or directional coronary atherectomy (DCA)., Design: Consecutive cases receiving coronary catheter interventions., Setting: Tertiary referral centre in Germany., Methods: Fasting total plasma homocysteine levels (tHcy) were determined in 648 consecutive coronary artery disease patients who underwent catheter interventions (272 PTCA, 102 DCA, and 274 stenting). Hyperhomocysteinaemia was defined as tHcy >/=15 micromol/l. The patients were investigated for a 30-day composite endpoint, including need for target-vessel revascularization, myocardial infarction, and death., Results: Among the 648 patients, 78 (12%) demonstrated elevated tHcy levels. The composite endpoint occurred in 41 patients (6.3%). For the entire intervention group there was no evidence that hyperhomocysteinaemia was associated with excess procedural risk (odds ratio [OR]: 1.27; 95% confidence interval [CI]=0.52 to -3.13; P=0.62). In further analyses according to device, hyperhomocysteinaemia also failed to predict complications in the device related subgroups., Conclusion: The results indicate that hyperhomocysteinaemia is not a major risk factor for 30-day adverse events complicating PTCA, DCA, or stenting.

Background: The role of plasma and neutrophils in endothelial dysfunction following myocardial ischemia was investigated., Methods: Isolated rabbit hearts were perfused at constant pressure with a modified Krebs-Henseleit solution. After a 30-minute global ischemia the hearts were perfused at the onset of reperfusion for 10 minutes with either NaCl (group I, n = 6), autologous plasma alone (group II, n = 5), autologous polymorphonuclear leukocytes alone (PMN, group III, n = 6), or PMN and plasma in combination (group IV, n = 5). Before and after ischemia the effects of intracoronary endothelial dependent and independent vasodilation by acetylcholine (1 x 10(-7)mol/L) and glycerol trinitrate (1 x 10(-6) mol/L) were investigated., Results: A similar increase in coronary flow was induced in groups I, II, and III by acetylcholine and glycerol trinitrate before and after ischemia. In contrast, in group IV the endothelial dependent vasodilation was significantly depressed (p < 0.05). In groups II and IV a moderate but significant reduction in the recovery of the left ventricular pressure was observed after ischemia and reperfusion., Conclusions: These results suggest that after myocardial ischemia, plasma is required for neutrophil-mediated endothelial dysfunction.

Background: A five-fold increase in risk of stent thrombosis in carriers of A1/A2 (Leu33Pro) polymorphism of glycoprotein Illa has been described. Whether this increased procedural risk applies to other coronary interventions is unknown. We investigated the role of A1/A2 polymorphism as a putative risk factor., Methods: We genotyped 1000 consecutive patients with angiographically confirmed coronary-artery disease and 1000 controls matched for age and sex. 653 of the 1000 patients received interventions (271 coronary angioplasty, 102 directional coronary atherectomy, and 280 stenting) and were assessed for a 30-day composite endpoint of need for target-vessel revascularisation, myocardial infarction, and death., Findings: The composite endpoint occurred in 41 (6.3%) patients. There was no evidence that the A2 allele was associated with excess procedural risk (relative risk 1.36 [95% CI 0.70-2.70], p=0.37). Nor, in subgroup analyses, did A2 predict events that complicated coronary angioplasty (1.17 [0.40-2.70]), directional coronary atherectomy (1.50 [0.30-8.70]), or stenting (1.45 [0.60-3.50]). Neither heterozygotes (A1/A2) nor homozygotes (A2/A2) were over-represented in any subgroup, including those with acute coronary syndromes, early disease manifestation (age <40 years), and histories of myocardial infarction., Interpretation: A1/A2 polymorphism is not a major risk factor for 30-day adverse events that complicate coronary angioplasty, directional coronary atherectomy, or stenting. Furthermore, A1/A2 polymorphism has no apparent impact on more chronic processes such as atherogenesis of the coronary arteries.