Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease.

BACKGROUND: No study has compared pharmacologic properties of ticagrelor and clopidogrel in non-dialysis patients with stage 4-5 chronic kidney disease (CKD). METHODS: We conducted a double-blind RCT to compare effects of ticagrelor and clopidogrel in 48 CKD, with the primary outcome of ADP-induced platelet aggregation (WBPA) after 2 weeks of DAPT. In a parallel arm, we compared effects of 2 weeks of ticagrelor plus aspirin on mean changes in WBPA and markers of thromboinflammation among non-CKD controls (n = 26) with that of CKD in the ticagrelor-arm. RESULTS: Average age of CKD was 53.7 years, with 62% women, 54% African American, and 42% with stage 5 CKD. Ticagrelor generated statistically lower WBPA values post treatment [median 0 Ω (IQR 0, 2)] vs. clopidogrel [median 0 Ω (IQR 0, 5)] (P = 0.002); percent inhibition of WBPA was greater (87 ± 22% vs. 63 ± 50%; P = 0.04; and plasma IL-6 levels were much lower (8.42 ± 1.73 pg/ml vs. 18.48 ± 26.56 pg/ml; P = 0.04). No differences in mean changes in WBPA between CKD-ticagrelor and control groups were observed. Ticagrelor- DAPT reduced levels of IL-1α and IL-1ß in CKD-ticagrelor and control groups, attenuated lowering of TNFα and TRAIL levels in CKD-ticagrelor (vs controls), and had global changes in correlation between various cytokines in a subgroup of CKD-ticagrelor subjects not on statins (n = 10). Peak/trough levels of ticagrelor/metabolite were not different between CKD-ticagrelor and control groups. CONCLUSIONS: We report significant differences in platelet aggregation and anti-inflammatory properties between ticagrelor- and clopidogrel-based DAPT in non-dialysis people with stage 4-5 CKD. These notable inflammatory responses suggest ticagrelor-based DAPT might lower inflammatory burden of asymptomatic patients with stage 4 or 5 CKD. (clinicaltrials.gov # NCT03649711).

LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse.

We hypothesized that lectin-like oxidized LDL receptor-1 (LOX-1) deletion may inhibit oxidative stress signals, reduce collagen accumulation and attenuate cardiac remodeling after chronic ischemia. Activation of LOX-1 plays a significant role in the development of inflammation, apoptosis and collagen signals during acute ischemia. Wild-type and LOX-1 knockout (KO) mice were subjected to occlusion of left coronary artery for 3 weeks. Markers of cardiac hypertrophy, fibrosis-related signals (collagen IV, collagen-1 and fibronectin) and oxidant load (nicotinamide adenine dinucleotide phosphate oxidase expression, activity of mitogen-activated protein kinases and left ventricular (LV) tissue thiobarbituric acid reactive substances) were analyzed. In in vitro experiments, HL-1 cardiomyocytes were transfected with angiotensin II (Ang II) type 1 receptor (AT1R) or type 2 receptor (AT2R) genes to determine their role in the cardiomyocyte hypertrophy. LOX-1 KO mice had 25% improvement in survival over the 3-week period of chronic ischemia. LOX-1 deletion reduced collagen deposition and cardiomyocyte hypertrophy (∼75%) in association with a decrease in oxidant load and AT1R upregulation (all P<0.05). The LOX-1 KO mice hearts exhibited a disintegrin and metalloproteinase 10 (ADAM10) and a disintegrin and metalloproteinase 17 (ADAM17) expression and matrix metalloproteinase 2 activity, and increased AT2R expression (P<0.05). Attenuation of cardiac remodeling was associated with improved cardiac hemodynamics (LV ±dp/dt and cardiac ejection fraction). In vitro studies showed that it is AT1R, and not AT2R overexpression that induces cardiomyocyte hypertrophy. We demonstrate for the first time that LOX-1 deletion reduces oxidative stress and related intracellular signaling, which leads to attenuation of the positive feedback loop involving AT1R and LOX-1. This results in reduced chronic cardiac remodeling.

Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo.

Atherosclerosis is an inflammatory disorder of arteries. Atherosclerotic plaque, in its early to intermediate stages, is composed largely of lipid-engorged foam cells. These foam cells are derived from the trafficking of monocytes (Mo) into the arterial intima, attracted to the site by chemoattractants. Given that foam cells are derived from the trafficking of Mo, the use of Netrin-1, an Mo chemorepellent, may be useful in limiting Mo accumulation and subsequent plaque formation. To investigate the potential of Netrin-1 for limiting atherosclerosis, we systemically delivered its human (h) cDNA by adeno-associated virus type 8 (AAV8, single-stranded structure) delivery into low-density lipoprotein receptor knockout (LDLR-/-) mice and placed the animals on a high cholesterol diet (HCD). Compared with control neomycin resistance (Neo) gene delivery/HCD, hNetrin-1 delivery resulted in a significant reduction in plaque formation, as determined by larger aortic lumen size, thinner intima-media thickness and lower blood velocity than the Neo/HCD control (all statistically significant). Indices of monocyte/macrophage (Mo/MΦ) accumulation, CD68, integrin, alpha M (ITGAM) and egf-like module containing, mucin-like, hormone receptor-like 1 (EMR-1), were reduced in hNetrin-1/HCD-treated animal's aortas and spleens compared with Neo/HCD-treated animals. Unexpectedly, CD25 and foxp3 (regulatory T cells (Tregs)) in the aorta were strongly upregulated. This is the first time the Mo/MΦ chemorepellent approach, and specific Netrin-1 gene delivery, has been performed for the reduction of Mo/MΦ burden and atherosclerosis. In addition, Netrin-1 has never before been linked to altered Treg levels. These data strongly suggest that hNetrin-1 gene delivery can reduce Mo/MΦ accumulation, inflammation and subsequent plaque formation.

Evolution of interventions for complex coronary lesions.

The exponential growth of percutaneous coronary intervention (PCI) has in large part been due to expansion of the indications to include the procedure in patients with extensive coronary disease, multiple risk factors, older age and comorbidities. Improvement in PCI equipment, development of new interventional techniques, and availability of myocardial and systemic support techniques have all contributed to this growth. With these advances, patients once considered high risk for PCI are no longer considered high risk. This article reviews the complex coronary lesions challenges, various interventional and pharmacologic strategies for optimal results and novel technology.

Overexpression of TGFbeta1 by adeno-associated virus type-2 vector protects myocardium from ischemia-reperfusion injury.

Transforming growth factor beta(1) (TGFbeta(1)) has been purported to protect tissues from ischemia-reperfusion (I-R) injury. This study was designed to examine if overexpression of TGFbeta(1) using adeno-associated virus type 2 (AAV) protects cardiomyocytes from reoxygenation injury. TGFbeta(1) was overexpressed in cultured HL-1 mouse cardiomyocytes by transfection with AAV/TGFbeta(1)(Latent) or with AAV/TGFbeta(1)(ACT) (active TGFbeta(1)). TGFbeta(1) upregulation reduced cardiomyocyte apoptosis and necrosis induced by 24 h of hypoxia followed by 3 h of reoxygenation concomitant with reduction in reactive oxygen species release, activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and NF-kappaB expression. Transfection with AAV/TGFbeta(1)(ACT) was superior to that with AAV/TGFbeta(1)(Latent). To determine if AAV/TGFbeta(1)(ACT) upregulation in vivo would induce cardioprotection from I-R injury, rat hearts were injected with AAV/TGFbeta(1)(ACT) or phosphate-buffered saline (PBS). Six weeks later, TGFbeta(1)(ACT) was upregulated throughout the myocardium. Following I-R, AAV/TGFbeta(1)(ACT)-overexpressing rats had much smaller infarct size (P<0.01 vs PBS group), which was also related to reduced activation of NADPH oxidase and NF-kappaB, and lower levels of malondialdehyde in I-R tissues. These data demonstrate that overexpression of TGFbeta(1) by AAV can protect cardiac tissues from reperfusion injury, possibly via antioxidant mechanism. These findings suggest potential of TGFbeta(1)(ACT) gene therapy for cardioprotection from I-R injury.

Traditional risk factors and acute myocardial infarction in patients hospitalized with cocaine-associated chest pain.

BACKGROUND: Cocaine causes coronary artery constriction and may cause acute myocardial infarction (AMI). The role of traditional coronary risk factors in cocaine-associated myocardial infarction is unclear. HYPOTHESIS: We hypothesized that traditional risk factors play a major role in predicting AMI in patients admitted with cocaine-associated chest pain METHODS: After reviewing 165 admissions for chest pain in patients with a history of recent cocaine use and/or a positive drug screen from January 2001 to December 2004, we identified 151 patients with information available on at least 6 of the following 7 risk factors: gender, hypertension, hyperlipidemia, diabetes, smoking, family history of coronary artery disease (CAD) and known CAD. AMI was diagnosed using WHO criteria. A risk score was calculated on the basis of the number of risk factors, gender and age. Association of AMI was evaluated with the individual risk factors and with the risk score. RESULTS: AMI was identified in 21 patients (14%). All patients diagnosed with AMI were smokers. Continuous risk score (p < 0.0001), highest vs. lowest quartile of risk score (p = 0.007), known CAD, age, hyperlipidemia and family history of CAD were individually associated with the diagnosis of AMI (p>or=0.05). Each quartile of risk score was associated with increased odds of the diagnosis of AMI and score of 8 or higher was statistically significant. CONCLUSION: Several traditional risk factors are associated with the diagnosis of AMI among patients hospitalized with cocaine-associated chest pain and increasing risk factor score was associated with increasing odds of AMI diagnosis.

[New insights in atherosclerosis research: LOX-1, leading actor of cardiovascular diseases]. / Nuovi approfondimenti nella ricerca su l'ateroslerosi: LOX-1, un primo attore nelle malattie cardiovascolari.

The OLR1 gene encodes a cell-surface endocytosis receptor (LOX-1) for oxidized low density lipoprotein (OxLDL). LDL is oxidized in vascular endothelial cells to a highly injurious product that results in endothelial cell injury, which is implicated in the development of atherosclerosis. Vascular endothelial cells also internalize and degrade oxLDL though the OLR1 receptor. This receptor is upregulated by ox-LDL itself and by angiotensin II, endothelin, cytokines, and shear stress, important factors of atherosclerosis. This receptor is upregulated in the arteries of hypertensive, dyslipidemic, and diabetic animals. Two independent studies have demonstrated genetic association between polymorphisms in the OLR1 gene and myocardial infarction. Based on genetic and functional studies we propose LOX-1 as a novel biomarker and target in cardiovascular disease diagnosis and prevention.

Transforming growth factor-beta(1) modulates oxidatively modified LDL-induced expression of adhesion molecules: role of LOX-1.

Oxidatively modified LDL (ox-LDL) activates a lectin-like receptor, LOX-1, which results in the expression of adhesion molecules on endothelial surface. We investigated the regulation of the expression of transforming growth factor-beta(1) (TGF-beta(1)) and its receptors by ox-LDL and the functional significance of this interaction with regard to adhesion molecule expression in human coronary artery endothelial cells (HCAECs). Ox-LDL, in a time- and concentration-dependent manner, upregulated the expression of all 3 subtypes (1, 2, and 3 [including endoglin]) of TGF-beta(1) receptors and decreased active TGF-beta(1) synthesis (all P<0.05 versus control and native-LDL-treated cells). Treatment of HCAECs with a monoclonal antibody to LOX-1 attenuated ox-LDL-mediated upregulation of TGF-beta(1) receptors and decrease in TGF-beta(1) synthesis (P<0.05 versus ox-LDL alone). Ox-LDL also enhanced the expression of P-selectin and ICAM-1 as well as monocyte adhesion to HCAECs (P<0.05 versus control untreated cells). Pretreatment with recombinant TGF-beta(1) attenuated the enhanced expression of adhesion molecules and monocyte adhesion to HCAECs (P<0.05 versus ox-LDL alone). Effects of recombinant TGF-beta(1) were blocked by antibody to TGF-beta(1) receptor type 2, but not by antibody to endoglin. Thus ox-LDL, via activation of LOX-1, increases the expression of TGF-beta(1) receptors and decreases TGF-beta(1) synthesis in HCAECs. Recombinant TGF-beta(1), by binding to TGF-beta(1) type 2 receptors, modulates ox-LDL-mediated expression of adhesion molecules and monocyte adhesion to HCAECs.

Influence of statins on postoperative wound complications after inguinal or ventral herniorrhaphy.

The lipid-lowering agents, statins, are the most commonly prescribed class of drugs in the western world. Because of their widespread use, many patients undergo surgical procedures while on statins. Statins, in addition to cholesterol-lowering effects, also have anticoagulant, immunosuppressive, and antiproliferative properties that may affect the risk of local wound complications. This study investigated the relationship between statins and postoperative wound complications in a large cohort of patients undergoing inguinal or ventral hernia repair. Data mining was performed in the Veterans Integrated Service Network (VISN)16 Data Warehouse. This database contains clinical and demographic information about all veterans cared for at the ten VA Medical Centers that comprise the South Central VA Healthcare Network in the mid-south region of the US. Aggregate data (age, body mass index, smoking history, gender, race, history of diabetes, statin use, and postoperative wound complications) were obtained for all patients who underwent inguinal or ventral hernia repair during the period October 1, 1996-November 30, 2004. During the period of the query, 10,782 patients (10,676 male, 106 female), 1,242 (11.5%) of whom received statins, underwent herniorrhaphy. Statin use did not affect the risk of wound infection or delayed wound healing. Statin use was, however, associated with an increased rate of local postoperative bleeding complications (P=0.01). When the type of hernia, age, smoking, diabetes, and body mass index were included in a multivariate analysis, statins remained borderline significant as an independent predictor of wound hematoma/postoperative bleeding (P=0.04), odds ratio 1.6 (95% CI 1.03-2.44). Patients who undergo inguinal herniorrhaphy while on statins have an increased risk of postoperative wound hematoma/hemorrhage. Focus on additional factors that may affect the propensity to postoperative bleeding and on meticulous intraoperative hemostasis are particularly important in such patients.

Antisense to LOX-1 inhibits oxidized LDL-mediated upregulation of monocyte chemoattractant protein-1 and monocyte adhesion to human coronary artery endothelial cells.

BACKGROUND: We have recently demonstrated a lectin-like receptor for oxidized (ox)-LDL (LOX-1) in human coronary artery endothelial cells (HCAECs). This receptor is upregulated by ox-LDL. The present study examined the significance of LOX-1 in monocyte adhesion to HCAECs and endothelial injury in response to ox-LDL. METHODS AND RESULTS: HCAECs were incubated in the presence of antisense oligodeoxynucleotides to the 5'-coding sequence of the human LOX-1 gene (0.5 microm/L). Basal LOX-1 mRNA and protein were suppressed by antisense LOX-1. Ox-LDL-mediated upregulation of LOX-1 was also suppressed by antisense LOX-1. Incubation of HCAECs with ox-LDL (40 microg/mL) for 24 hours markedly increased monocyte chemoattractant protein-1 (MCP-1) mRNA and protein expression as well as monocyte adhesion to HCAECs (P<0.01). After 48 hours of preincubation of HCAECs with antisense LOX-1, ox-LDL-mediated upregulation of MCP-1 and monocyte adhesion to HCAECs both were suppressed (P<0.01), whereas sense LOX-1 had no effect. Whereas antisense or sense LOX-1 alone (both 0.5 nmol/L) did not injure the cells, antisense LOX-1, but not sense LOX-1, reduced ox-LDL-mediated HCAEC injury, determined as LDH release (P<0.01). Activation of mitogen-activated protein kinase (MAPK) may play a critical role in signal transduction in ox-LDL-mediated alteration in MCP-1 expression, since antisense LOX-1, but not the sense LOX-1, completely inhibited the ox-LDL-induced MAPK activation. CONCLUSIONS: These observations with the first use of a specific antisense to human LOX-1 mRNA suggest that LOX-1 is a key factor in ox-LDL-mediated monocyte adhesion to HCAECs.

Relationship of Chlamydia pneumoniae infection to severity of human coronary atherosclerosis.

BACKGROUND: Infection with Chlamydia pneumoniae has been postulated to play a pathogenic role in atherosclerosis. We examined the role of infection with C pneumoniae in relation to the extent of coronary atherosclerosis. METHODS AND RESULTS: Coronary atherosclerosis was graded microscopically on a postmortem basis in a blinded fashion in 60 subjects as mild (n=18) or severe (n=42) atherosclerosis. Serum antibodies to C pneumoniae were measured by microimmunofluorescence test. Paraffin-embedded coronary artery specimens were examined for the presence of chlamydia by use of a genus-specific direct immunofluorescence monoclonal antibody. Frozen coronary artery specimens were examined by immunoperoxidase for the presence of C pneumoniae by use of a specific monoclonal antibody RR-402. Direct immunofluorescence was reactive in 86% of cases with severe atherosclerosis but in only 6% of cases with mild atherosclerosis (P<0.01), whereas immunoperoxidase staining was reactive in 80% and 38% of cases with severe and mild atherosclerosis, respectively (P<0. 01). Elevated IgG and IgA levels against C pneumoniae were not different in cases with severe and mild atherosclerosis (61% and 30% for severe atherosclerosis and 67% and 42% for mild atherosclerosis, respectively). CONCLUSIONS: This study supports the hypothesis that intracellular infection with C pneumoniae may relate to the severity of atherosclerosis in some subjects. Serum antibody titers against C pneumoniae do not differentiate between severe and mild atherosclerosis.

Oxidized LDL upregulates angiotensin II type 1 receptor expression in cultured human coronary artery endothelial cells: the potential role of transcription factor NF-kappaB.

BACKGROUND: We demonstrated earlier that angiotensin II (Ang II), by AT(1) receptor activation, upregulates oxidized LDL (ox-LDL) endothelial receptor LOX-1 gene expression and uptake of ox-LDL in human coronary artery endothelial cells (HCAECs). In this study, we investigated the regulation of Ang II receptors (AT1R and AT2R) by ox-LDL and the role of the redox-sensitive transcription factor NF-kappaB in this process. METHODS AND RESULTS: HCAECs were incubated with ox-LDL for 24 hours. Ox-LDL (10 to 40 microg protein/mL) upregulated AT1R but not AT2R, mRNA, or protein. Ox-LDL degraded IkappaBalpha in cytoplasm and activated transcription factor NF-kappaB (P65) in HCAEC nuclear extract. Treatment of cells with the antioxidant alpha-tocopherol (10 to 50 micromol/L) attenuated ox-LDL-mediated degradation of IkappaBalpha and activation of NF-kappaB (P65) and inhibited the upregulation of AT1R mRNA and protein. The role of NF-kappaB signal transduction was further examined by use of an NF-kappaB inhibitor, caffeic acid phenethyl ester (CAPE). Pretreatment of cells with CAPE inhibited ox-LDL-mediated degradation of IkappaBalpha and NF-kappaB activation and inhibited ox-LDL-induced upregulation of AT1R expression. Incubation of cells with both ox-LDL and Ang II increased cell injury, measured as cell viability and LDH release, compared with either ox-LDL or Ang II alone. alpha-Tocopherol as well as the specific AT1R blocker CV11974 (candesartan) attenuated the cell-injurious effects of ox-LDL. CONCLUSIONS: These observations suggest an important role of ox-LDL-mediated AT1R upregulation in cell injury. In this process, NF-kappaB activation seems to play a critical role in signal transduction. These findings provide a basis for the use of antioxidants and AT1R blockers in designing therapy of atherosclerosis.

Protection of myocytes from hypoxia-reoxygenation injury by nitric oxide is mediated by modulation of transforming growth factor-beta1.

BACKGROUND: Reoxygenation injury is a result of several complex events, including release of reactive oxygen species, protein kinase C (PKC) activation, and altered expression of transforming growth factor-beta1 (TGF-beta(1)). Nitric oxide (NO) generally protects tissues from reperfusion injury. METHODS AND RESULTS: We examined the modulation of TGF-beta1 expression and activity and PKC activation in cultured rat heart myocytes exposed to a brief period of hypoxia-reoxygenation (H-R) by NO donor 3-morpholino-sydnonimine (SIN-1). H-R resulted in an increased expression of total TGF-beta1 (mRNA and protein) but a decrease in the release of active TGF-beta1. Myocyte PKC-alpha protein level was not altered by H-R, but its phosphorylation was augmented. Pretreatment of myocytes with SIN-1 diminished myocyte injury quantified as lactate dehydrogenase release. Simultaneously, release of active TGF-beta1 increased and total TGF-beta1 expression decreased (all P<0.05 versus H-R alone). PKC-alpha phosphorylation increased further in cells treated with SIN-1. The effects of SIN-1 were blocked by the NO scavenger phenyl-tetramethyl-imidazoline-oxyl-oxide as well as by the PKC inhibitor staurosporine. To examine if another NO donor would have a similar effect, cardiomyocytes were treated with nitroglycerin before H-R. With nitroglycerin treatment, similar to SIN-1 treatment, myocyte injury was diminished, TGF-beta1 release increased, and total TGF-beta1 expression decreased. CONCLUSIONS: These observations suggest modulation of TGF-beta1 expression as a novel mechanism of salutary effect of NO donors. PKC-alpha activation may play an important role in the protective effect of NO against H-R injury.

Evaluation of venous and arterial conduit patency by 16-slice spiral computed tomography.

BACKGROUND: Computed tomography has been shown to be useful in the evaluation of aortocoronary bypass grafts (CABG). This is the first prospective study to evaluate the accuracy of a new-generation scanner in the detection of patency and significant stenoses (>50% decrease in diameter) of venous and arterial grafts in patients with previous CABG. METHODS AND RESULTS: In 96 patients (80 males, mean age 62 years) with previous CABG, a multislice computed tomography (MSCT) scan was performed (collimation 16x0.625 mm). Patients with atrial fibrillation, renal failure, severe respiratory disease, severe heart failure, heart rate >70 bpm despite therapy, or unstable angina were excluded. A total of 285 conduits implanted on the native coronary arteries at the time of CABG were evaluated. MSCT data were analyzed by 2 independent radiologists and compared with the results of conventional angiography. Three patients were excluded from analysis. All conduits were judged evaluable in 84 patients. Among these patients, MSCT correctly diagnosed 54 occluded grafts and 4 significant stenoses on the body of the grafts. Of the 17 significant anastomotic lesions, MSCT correctly diagnosed 15. For these 84 patients, diagnostic accuracy was 99%, sensitivity was 97%, and specificity was 100%. When all 93 patients were considered, the sensitivity of MSCT in diagnosing significant stenoses was 96%. CONCLUSIONS: MSCT with the new-generation scanner allows for accurate assessment of venous and arterial conduits in patients with previous CABG with a high degree of sensitivity and specificity. Exclusion criteria and radiation exposure remain limitations of the method.

Endothelial, platelet and leukocyte interactions in ischemic heart disease: insights into potential mechanisms and their clinical relevance.

Recent investigations of the complex interactions among vascular endothelium, platelets and leukocytes have relevance to the pathogenesis of atherosclerosis and ischemic heart disease. Perturbations in the hemodynamic equilibrium maintained by these cellular elements may lead to vasospasm, in vivo thrombosis and a reduction in blood flow. Recent advances in the understanding of these interactions in health and disease states are summarized. The effect of pharmacologic agents on these cell-cell interactions are discussed to provide the reader with a general understanding of the relevance of these interactions in cardiovascular disease.

Neutrophils as potential participants in acute myocardial ischemia: relevance to reperfusion.

An interaction among leukocytes, platelets and endothelial cells is important in atherogenesis and in maintenance of blood flow and vascular tone. These complex cell-cell interactions are mediated by release of such metabolic substances as arachidonic acid metabolites, growth factors, oxygen free radicals and endothelium-derived relaxing factor. These substances participate in the regulation of blood flow in health and disease, and perturbation in the delicate equilibrium among various cellular elements may lead to evolution and propagation of myocardial ischemia. During reperfusion of ischemic myocardium, neutrophils together with platelets cause capillary plugging in the coronary microcirculation and exert detrimental effects on endothelial function resulting in the "no reflow" phenomenon, ventricular arrythmias, loss of coronary vascular reserve and, perhaps, extension of cellular injury. This review addresses the mechanisms of cell-cell interactions with special reference to myocardial ischemia and the potential for development of improved therapy to protect and preserve ischemic myocardium.

Interactive role of infection, inflammation and traditional risk factors in atherosclerosis and coronary artery disease.

Although first suggested at the turn of the 20th century, there is a renewed interest in the infectious theory of atherosclerosis. Studies done in many laboratories around the world over the past several years have shown an association between markers of inflammation and coronary atherosclerosis with an exacerbation of the inflammatory process during acute myocardial ischemia, particularly in the early stages of reperfusion. It is also being recognized that the traditional risk factors, such as smoking, dyslipidemia, hypertension and diabetes mellitus, do not explain the presence of coronary atherosclerosis in a large proportion of patients. We believe that in certain genetically susceptible people, infection with very common organisms, such as Chlamydia pneumoniae or cytomegalovirus, may lead to a localized infection and a chronic inflammatory reaction. Persistence of infection may relate to the degree of inflammation and severity of atherosclerosis. Early trials with appropriate antibiotic agents in some patients with a recent history of acute myocardial infarction have led to very salutary results. If patients with an infectious basis of atherosclerosis can be identified, a therapy directed at eradication of the offending organism may be appropriate.

Differential effects of alpha- and gamma-tocopherol on low-density lipoprotein oxidation, superoxide activity, platelet aggregation and arterial thrombogenesis.

OBJECTIVES: This study was designed to examine the differential effects of alpha- and gamma-tocopherol on parameters of oxidation-antioxidation and thrombogenesis. BACKGROUND: Experimental studies have shown that antioxidants, such as vitamin E (alpha-tocopherol), improve atherosclerotic plaque stability and vasomotor function, and decrease platelet aggregation and tendency to thrombus formation. METHODS: Sprague Dawley rats were fed chow mixed with alpha- or gamma-tocopherol (100 mg/kg/day) for 10 days. A filter soaked in 29% FeCl3 was applied around the abdominal aorta to study the patterns of arterial thrombosis. The aortic blood flow was observed and continuously recorded using an ultrasonic Doppler flow probe. ADP-induced platelet aggregation, low-density lipoprotein oxidation induced by phorbol 12-myristate 13-acetate (PMA)-stimulated leukocytes, superoxide anion generation and superoxide dismutase (SOD) activity were also measured. RESULTS: Both alpha- and gamma-tocopherol decreased platelet aggregation and delayed time to occlusive thrombus (all p < 0.05 vs. control). Both alpha- and gamma-tocopherol decreased arterial superoxide anion generation, lipid peroxidation and LDL oxidation (all p < 0.05 vs. control), and increased endogenous SOD activity (p < 0.05). The effects of gamma-tocopherol were more potent than those of alpha-tocopherol (p < 0.05). CONCLUSIONS: This study indicates that both alpha- and gamma-tocopherol decrease platelet aggregation and delay intraarterial thrombus formation, perhaps by an increase in endogenous antioxidant activity. Gamma-tocopherol is significantly more potent than alpha-tocopherol in these effects.

Platelet function and biosynthesis of prostacyclin and thromboxane A2 in whole blood after aspirin administration in human subjects.

Small doses of aspirin have been shown to inhibit platelet thromboxane A2 while sparing vascular prostacyclin synthesis. Because leukocytes generate prostacyclin and participate in thrombosis along with platelets, the effects of three different doses of aspirin (40, 325 and 650 mg) on platelet function as well as on endogenous biosynthesis of thromboxane A2 and prostacyclin in whole blood were examined. In normal volunteers given a single 40 mg dose of aspirin, platelet aggregation and adenosine triphosphate release were inhibited for 24 hours. In contrast, platelet function was inhibited for 4 to 7 days in volunteers given 325 or 650 mg of aspirin. Platelet and whole blood generation of thromboxane A2 was inhibited less than 60% by the 40 mg dose, but almost completely by both the 325 and 650 mg doses. Likewise, whole blood generation of prostacyclin was inhibited 70% by the 40 mg dose and over 90% by the larger doses. Inhibition of thromboxane A2 as well as of prostacyclin was evident for 4 days with the 40 mg dose and for 7 days with the larger doses. Decreases in whole blood thromboxane A2 and prostacyclin with any dose of aspirin were of similar magnitude. These data indicate that aspirin in doses of 40 to 650 mg inhibits platelet function and biosynthesis of thromboxane A2 and prostacyclin in whole blood in human beings in a dose-dependent fashion.