Risk Of Atherothrombotic Disease Research Articles

The artificial sweetener erythritol and cardiovascular event risk.

Artificial sweeteners are widely used sugar substitutes, but little is known about their long-term effects on cardiometabolic disease risks. Here we examined the commonly used sugar substitute erythritol and atherothrombotic disease risk. In initial untargeted metabolomics studies in patients undergoing cardiac risk assessment (n = 1,157; discovery cohort, NCT00590200 ), circulating levels of multiple polyol sweeteners, especially erythritol, were associated with incident (3 year) risk for major adverse cardiovascular events (MACE; includes death or nonfatal myocardial infarction or stroke). Subsequent targeted metabolomics analyses in independent US (n = 2,149, NCT00590200 ) and European (n = 833, DRKS00020915 ) validation cohorts of stable patients undergoing elective cardiac evaluation confirmed this association (fourth versus first quartile adjusted hazard ratio (95% confidence interval), 1.80 (1.18-2.77) and 2.21 (1.20-4.07), respectively). At physiological levels, erythritol enhanced platelet reactivity in vitro and thrombosis formation in vivo. Finally, in a prospective pilot intervention study ( NCT04731363 ), erythritol ingestion in healthy volunteers (n = 8) induced marked and sustained (>2 d) increases in plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential in in vitro and in vivo studies. Our findings reveal that erythritol is both associated with incident MACE risk and fosters enhanced thrombosis. Studies assessing the long-term safety of erythritol are warranted.

Patients’ knowledge about psoriasis and comorbidities; their participation in treatment decisions

Background Psoriasis is a common chronic inflammatory disease. Having more information about psoriasis and comorbid diseases means that patients have more involvement in treatment. Aim Evaluate the knowledge levels of psoriasis patients about the disease and comorbidities and also to determine participation in treatment decisions. Methods Totally 103 patients over the age of 18 with diagnosed psoriasis were included into the study. A questionnaire including items on knowledge about disease and treatment options, comorbid diseases were filled out by the patients. Total knowledge score (TKS) was found by giving 1 point to the questions that the patients knew correctly. Results Patients were well informed about their risk of depression (64.1%), but were less well informed about their risk of atherothrombotic disease (14.6%). About 50.4% of the patients thought that psoriasis may be due to an internal organ disease. There was a negative correlation between the patient’s age, the age of diagnosis and TKS. About 42.7% wanted to leave the decision entirely to the physician. Conclusion The results of this study showed that majority of patients with psoriasis are not aware of the increased risk of comorbid diseases and do not have enough knowledge about psoriasis.

Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation.

Neutrophils and neutrophil extracellular traps (NETs) have a robust relationship with atherothrombotic disease risk, which led to the idea that interfering with the release of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute coronary events and the pro-thrombotic state cause markedly elevated levels of circulating deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency and showed a significant benefit for atherothrombotic disease in experimental mouse models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms underlying NET release and atherogenic inflammation have come from transgenic mouse studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic disease has been shown and linked to profound pro-inflammatory and pro-thrombotic effects, complement activation and endothelial dysfunction. Recent studies have shown that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects against atherosclerosis burden, propagation of its thrombotic complications and notably macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol accumulation have emerged as important factors driving NET release, likely involving mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for cardiovascular diseases.

Managing Clopidogrel Hypersensitivity without Interrupting Therapy: The Toronto Approach.

Clopidogrel remains a widely used antiplatelet agent for patients with established or high risk of atherothrombotic disease, particularly those treated with coronary, carotid or peripheral endovascular stenting. Clopidogrel hypersensitivity is an uncommon but well established adverse drug reaction presenting a challenge for patient management. The clinical presentation ranges from focal or diffuse cutaneous manifestations in most patients to angioedema in some and a systemic immune response in rare cases. The treatment options include drug discontinuation with or without desensitization therapy, switching to alternate ADP receptor antagonists or administration of oral steroids while continuing clopidogrel in patients at high risk of adverse events with clopidogrel discontinuation. In this review the author describes the phenomenon of clopidogrel hypersensitivity, various treatment strategies.

α(1,3)-Fucosyltransferases FUT4 and FUT7 Control Murine Susceptibility to Thrombosis

The α(1,3)-fucosyltransferases, types IV and VII (FUT4 and FUT7, respectively), are required for the synthesis of functional selectin-type leukocyte adhesion molecule ligands. The selectins and their ligands modulate leukocyte trafficking, and P-selectin and its ligand, P-selectin glycoprotein ligand-1, can modulate hemostasis and thrombosis. Regulation of thrombosis by FUT4 and/or FUT7 activity was examined in mouse models of carotid artery thrombosis and collagen/epinephrine-induced thromboembolism. Mice lacking both FUT4 and FUT7 (Fut(-/-) mice) had a shorter time to occlusive thrombus formation in the injured carotid artery and a higher mortality due to collagen/epinephrine-induced pulmonary thromboemboli. Mice lacking P-selectin or P-selectin glycoprotein ligand-1 did not have a prothrombotic phenotype. Whole blood platelet aggregation was enhanced, and plasma fibrinogen content, clot weight, and clot strength were increased in Fut(-/-) mice, and invitro clot lysis was reduced compared with wild type. Fut4(-/-), but not Fut7(-/-), mice had increased pulmonary thromboembolism-induced mortality and decreased thromboemboli dissolution invivo. These data show that FUT4 and FUT7 activity regulates thrombosis in a P-selectin- and P-selectin glycoprotein ligand-1-independent manner and suggest that FUT4 activity is important for thrombolysis.

This Month in Gastroenterology

This Month in Gastroenterology

Blood Sugar Levels are Not Necessary to Predict the Population at Risk for Atherothrombotic Disease

Blood Sugar Levels are Not Necessary to Predict the Population at Risk for Atherothrombotic Disease

Predicting the Risk of Atherothrombotic Disease with Lipid Ratios

Predicting the Risk of Atherothrombotic Disease with Lipid Ratios

The Influence of Body Mass Index on Mortality and Bleeding Among Patients with or at High-Risk of Atherothrombotic Disease

Conclusions: In patients with or at risk for atherothrombotic disease, adverse cardiovascular events and bleeding complications occur more frequently in those with a low body mass index (BMI). Summary: The effect of obesity in predisposing to hypertension, cardiovascular diseases, and type 2 diabetes is serving to negate the gains in life expectancy achieved over the past decades. A meta-analysis of 40 studies involving 250,152 patients with coronary artery disease has demonstrated that low BMI (<20.0 kg/m2) is associated with higher total and cardiovascular mortality than patients with normal BMI (range, 20.0-24.9 kg/m2). In fact, total and cardiovascular mortality was lowest among those who are overweight but not obese, defined as a BMI between 25.0 and 29.9 kg/m2 (Lancet 2006;368:666-78). In this study, the authors explored the relationship between BMI and cardiovascular events in patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study. CHARISMA was a multinational double-blinded, placebo-controlled, randomized, clinical trial that evaluated the efficacy of clopidogrel in patients with atherothrombotic disease or multiple risk factors for atherothrombotic disease who were also receiving aspirin. This is a subanalysis of the CHARISMA data stratified for BMI. Primary end points included cardiovascular death, myocardial infarction, or stroke as well as all-cause mortality and bleeding complications. Follow-up was for a median of 28 months. Varying the patients with the highest BMI quartile to those with the lowest BMI quartile, the primary end point, cardiovascular, and all-cause mortality all were more frequent in those in the lowest BMI quartile. The cutoff for all cause mortality and continuous BMI was 29.9 kg/m2. Comment: The relationship between BMI and cardiovascular outcomes is surprisingly complex. Mortality rates in the general population are highest among those who are overweight and underweight. In the Physicians' Health Study of 5010 middle-aged men, relative risk for all-cause mortality was 1.4 among those who had a BMI <22.0 kg/m2 compared with those with BMIs between 22 and 24.9 kg/m2 (Arch Intern Med 2004;164:2326-32). It may be that the relationship between obesity and mortality differs between individuals with and without cardiovascular disease. Certainly the data do not imply obesity is protective in patients with cardiovascular disease, but it does appear that being underweight is detrimental to those with cardiovascular disease.

Abstract 1514: Effect of Prior Medication on Clinical Characteristics and Hospital Outcome of Acute Coronary Syndromes

Background: Patients (Pts) with acute coronary syndrome (ACS) are often on medication at time of admission, because of risk factors and/or prior history of cardiovascular disease. We assessed the influence of prior medication on mode of presentation and prognosis of ACS. Methods: We studied 18,400 Pts included in a nationwide prospective registry of ACS and determined the influence of prior medication with aspirin (ASA), beta-blockers (BB), angiotensin converting enzyme inhibitors (ACEI), and statins (Stat) on type of ACS and its effect on all-cause hospital mortality. Results: ACS presentation was more benign in Pts previously medicated with ASA, BB, ACEI or Stat (Table ). Pts on prior medication with these drugs were older, more often female, less often smokers, and more often presented BMI &gt;=25, diabetes, hypertension, hypercholesterolemia, and prior history of cerebrovascular or peripheral arterial disease, MI or myocardial revascularization. Of the 3453 Pts with prior MI, 63.9% were on ASA, 42.0% BB, 47.6% ACEI, and 49.4% Stat. Of the 2946 diabetics, 29.6% were on ASA, 32.5% ACEI, and 25.7% Stat. Of the 1275 Pts with prior stroke/TIA, 36.3% were on ASA and 24.2% Stat. Of the 382 Pts with peripheral arterial disease, 38.8% were on ASA and 33.7% Stat. Overall, 344 (3.4%) of the 9980 non-ST-elevation ACS and 703 (8.3%) of the 8420 ST-elevation MI Pts died. Prior BB was an independent predictor of hospital mortality in non-ST-elevation ACS (adjusted OR = 1.58; 95% CI, 1.09–2.29; p=0.016), but not ST-elevation MI. Prior medication with ASA, an ACEI or a Stat did not influence outcome of either type of ACS. Conclusions: In the real world, Pts at high risk for atherothrombotic disease are insufficiently medicated with ASA, BB, ACEI and/or Stat. Prior medication with these drugs is associated with a more benign clinical presentation of ACS. Further studies are required to clarify the mechanisms conferring increased hospital mortality in Pts with non-ST-elevation ACS admitted on a BB.

Nanomaterials Induce Oxidized Low-Density Lipoprotein Cellular Uptake in Macrophages and Platelet Aggregation

Nanomaterials have numerous potential benefits for society, but the potential hazards of nanomaterials on human health are poorly understood. Nanomaterials are known to pass into the circulatory system in humans, causing vascular injuries that might play a role in the development of atherosclerosis. The present study aimed to determine the effects of chronic exposure to nanomaterials on macrophage phenotype and platelet aggregation. Cultured macrophages (RAW264.7) were treated with carbon black (CB) and water-soluble fullerene (C60(OH)24) from 7 to 50 days. Individually, CB had no significant effects on RAW264.7 cell growth, whereas C60(OH)24 alone or CB and C60(OH)24 together with oxidized low-density lipoprotein (Ox-LDL) (100 microg/ml) induced cytotoxic morphological changes, such as Ox-LDL uptake-induced foam cell-like formation and decreased cell growth, in a dose-dependent manner. C60(OH)24 induced LOX-1 protein expression, pro-matrix metalloprotease-9 protein secretion, and tissue factor mRNA expression in lipid-laden macrophages. Although CB or C60(OH)24 alone did not induce platelet aggregation, C60(OH)24 facilitated adenosine diphosphate (ADP)-induced platelet aggregation. Furthermore, C60(OH)24 acted as a competitive inhibitor of ADP receptor antagonists in ADP-mediated platelet aggregation. The present study confirmed novel effects of nanomaterials in macrophages and platelets. These effects suggest that exposure to nanomaterials might be a risk for atherothrombotic diseases.

TREATMENT OF DYSLIPIDEMIA

TREATMENT OF DYSLIPIDEMIA

LETTER TO THE EDITOR

I read with interest the editorial by John LaRosa, MD, concerning the newest NCEP guidelines.1 I concur that the guidelines have gotten more complex, and said so in a letter to the editor of JAMA.2 I have published a (global) risk-factor graph that accurately predicts the population at risk for atherothrombotic disease (ATD) (Figure). The lipid predictor balances the proatherogenic lipids (mainly low-density lipoprotein [LDL]) and antiatherogenic lipids (mainly high-density lipoprotein [HDL]) in the form of a fraction, the cholesterol retention fraction (CRF, or [LDL - HDL]/LDL), which is placed on the ordinate of the graph. The systolic blood pressure (SBP) in mm Hg is placed on the abscissa. A threshold line has been drawn, with loci at CRF-SBP plots (0.74, 100) and (0.49, 140). In the Bowling Green Study (BGS) database, 85% of all ATD patients will have CRF-SBP plots above the threshold line. Of the 15% of ATD patients who develop ATD despite a CRF-SBP plot below the threshold line, most are cigarette smokers. This leaves only 6% of all ATD patients in the BGS database that could not be predicted by a CRF-SBP plot above the threshold line and/or cigarette smoking status.3 The Bowling Green Study graph. CRF=cholesterol retention fraction ([low-density lipoprotein {LDL} - high-density lipoprotein]/LDL). Reproduced with permission from J Cardiovasc Risk. 2000;7:415–423. In a meta-analysis of eight published angiographic regression trials (over 2000 angiograms), involving all the usual treatments for dyslipidemia, any therapy that brought the patient's CRF-SBP plot below the threshold line resulted in angiographic stabilization or reversal of coronary plaque in a minimum average of 75% of cases. (Had the Program on Surgical Control of Hyperlipidemia [POSCH] been structured to control blood pressure, many more patients' CRF-SBP plots would have come below the threshold line and the average rate of plaque stabilization or regression would have approached 95%.3) I have shown a graph that plots the percentage of people's CRF-SBP plots per age group that transgress the threshold line vs. the percentage of people per age group, in that same population, who develop some form of clinical ATD. The curves, both for men and women, more or less run parallel, with a 40-year gap between the curves for men and a 20-year gap between the curves for women.4 Hence, the graph also tells the physician when the clock starts to tick. The people who develop ATD despite a CRF-SBP plot below the threshold line, in the absence of any history of cigarette smoking, are quite old when that ATD event occurs—at an average age of 78 years for men and 75 years for women. Moreover, the men don't die until an average age of 94 years, and the women don't die until an average age of 84 years.4 A CRF-SBP plot position below the threshold line, in the absence of any history of cigarette smoking, implies virtual invulnerability to ATD, and hence should be the goal of ATD treatment. I should like to note that HDL is unable to compensate for unlimited LDL. In our regional lab, the breakpoint of LDL above which HDL begins to lose its compensatory ability is 170 mg/dL (or 4.4 mmol/L). The more that LDL exceeds this breakpoint, the less that HDL can compensate. At LDL levels of 250 mg/dL (6.5 mmol/L), HDL is virtually unable to compensate. Even so, the lower the CRF, the older the person will be when the ATD event occurs. This scenario is much more likely to occur in women than in men. Hence, I also treat any LDL level ≥170 mg/dL to bring it below this level, regardless of CRF value. The BGS graph was initially presented to the medical community at the 1983 Annual Scientific Assembly of the American Academy of Family Physicians, was modified in 1988 to include an initial threshold line for primary prevention, and finally modified (threshold line lowered) to include secondary prevention in 2000. The BGS graph is simple to use and utilizes a global risk factor approach. It provides support for early screening for ATD risk factors, and gives the physician and patient an easy means of guiding therapy to maximally stabilize or reverse coronary (and by extension, cerebral, and peripheral vascular) plaque. The author does not intend to further modify the BGS graph.

Type 2 Diabetes: An Atherothrombotic Syndrome

Insulin resistance is found in around 80-90% of subjects with older onset (type 2) diabetes and in approximately 25% of the general population. Insulin resistance prior to the development of frank type 2 diabetes and type 2 diabetes itself is associated with a significant increase in the risk of atherothrombotic disease, which is due in part to a disruption in the balance of factors regulating coagulation and fibrinolysis. Both insulin resistance and type 2 diabetes are associated with the development of endothelial dysfunction, and enhanced platelet aggregation and activation. Whilst the plasma levels of many clotting factors including fibrinogen, FVII, FVIII, FXII, FXIII b-subunit are elevated, the fibrinolytic system is relatively inhibited as a consequence of an increase in plasminogen activator inhibitor type-1 (PAI-1) levels. These changes favour the development of a hypercoagulable pro-thrombotic state, which may in turn enhance cardiovascular risk by increasing the likelihood of developing an occlusive thrombus within a coronary/cerebral artery, and/or contributing to the development of atherosclerotic lesions. This article reviews the current published evidence of the pro-thrombotic changes that occur in association with type 2 diabetes and insulin resistance, and the putative underlying mechanisms which lead to these changes.

Clinical relevance of hyperhomocysteinaemia in atherothrombotic disease.

High fasting plasma homocysteine levels (> 12 to 15 mumol/L) are commonly encountered in clinical practice and are associated with increased risk of atherothrombotic disease. Treatment with folic acid (1 to 5 mg/day) is inexpensive and effective in normalising plasma homocysteine levels. High plasma homocysteine levels after methionine loading (> 40 to 50 mumol/L) are also common and can be treated with pyridoxine-based regimens (50 to 250 mg/day). As compared with fasting plasma homocysteine levels, the association between high postmethionine loading plasma homocysteine levels and atherothrombotic disease has been less extensively studied. There is reasonable, but not clearly definitive, evidence that high plasma homocysteine levels are causally related to atherothrombotic disease. Results of randomised trials of homocysteine-lowering treatment with clinical end-points will be available in 4 to 6 years. At present, a reasonable policy for the practising clinician would be to consider homocysteine-lowering treatment in individuals at very high risk of atherothrombotic disease, such as patients with clinically manifest atherothrombotic disease with onset before 55 years of age, patients with end stage renal disease, and healthy subjects with a strong family history of early-onset atherothrombotic disease. Such a policy should be reassessed as the results of randomised trials become available.

Angiotensin-Converting Enzyme Gene Polymorphism and Plasminogen Activator Inhibitor 1 Levels in Subjects with Cerebral Infarction.

It has been suggested that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is an independent risk factor for coronary artery disease, but its relation to cerebral infarction is still controversial. Plasminogen activator inhibitor 1 (PAI-1) is also a predictor of risk of atherothrombotic disease. In this study we investigated the association of the ACE gene polymorphism and plasma PAI-1 levels in subjects with cerebral infarction. We evaluated the genotype of the ACE gene in 26 subjects with and 28 subjects without a history of ischemic stroke. The ACE genotype was analyzed by the polymerase chain reaction. Plasma PAI-1 antigen levels were measured by ELISA. There were no differences in accepted risk factors between the groups with or without cerebral infarction. However, the frequency of the D allele was significantly higher in subjects with cerebral infarction (0.63) than in those without infarction (0.39) (chi(2) = 6.306, P = 0.012). The frequency of the DD genotype of the ACE gene was also significantly higher in subjects with than in those without cerebral infarction (DD: 46.2%, ID: 34.6%, II: 19.2% vs. DD: 14.3%, ID: 50.0%, II: 35.7%, chi(2) = 6.689, P = 0.035). Plasma PAI-1 levels were not significantly different between groups with and without cerebral infarction. There was no association between the ACE genotype and PAI-1 levels. The DD genotype of the ACE gene is associated with cerebral infarction, which is independent of plasma PAI-1 level.

Lipoprotein(a) concentration and risk of atherothrombotic disease

To the Editor. —In their article, Dr Ridker and colleagues 1 reported that there was no prospective association between lipoprotein(a) [Lp(a)] concentration and the risk of stroke. The authors summarized briefly the results of prior prospective studies of as a risk factor for coronary artery disease; however, certain points raised in that discussion require clarification. Namely, two studies that used the arbitrary nomenclature apo for apolipoprotein (a) as opposed to Lp(a) were addressed separately. With one exception, 2 all studies to date have detected using immunoassays directed against apo(a). For example, Ridker et al 1 refer to Lp(a) and Wald et al 3 in the article cited by Ridker et al refer to apo(a); however, both groups used the Biopool ELISA (enzyme-linked immunosorbent assay). Thus, it is neither necessary nor appropriate to dichotomize studies based on differences in nomenclature. Therefore, among prior prospective studies of and

Lipoprotein(a) Concentration and Risk of Atherothrombotic Disease

Lipoprotein(a) Concentration and Risk of Atherothrombotic Disease