Risk Factor For Vascular Events Research Articles

Significance of MTHFR gene mutation with normal homocysteine level in vascular events

e20520 Background: Hyperhomocysteinemia, due to a combination of genetic and environmental factors, is considered to be a risk factor for vascular disease. Two common variations of the MTHFR gene (C677T and A1298C) result in amino acid substitutions and enhanced thermolability of the enzyme. Individuals with MTHFR gene mutations appear to have raised plasma level of homocysteine which may lead to increased risk of vascular events. However, significance of MTHFR gene mutations with normal homocysteine levels is unknown. Objective: To assess the relation of MTHFR gene mutations with normal homocysteine level and risk of Vascular events (deep venous thrombosis (DVT), pulmonary embolism (PE), Ischemic Heart disease (IHD), cerebrovascular accidents (CVA),recurrent fetal loss). Methods: We reviewed the records of 90 patients referred to our benign hematology clinic for thrombophilia evaluation between 2006 and 2008. All available medical history for risk factors and laboratory test results, obtained from first vascular event through time of consultation, including genetic testing, were reviewed. Anti-cardiolipin antibody, MTHFR genotyping and Protein C and Protein S assays were performed at Warde Medical Laboratory, Ann Arbor, MI. Results: 61 patients with documented vascular events were tested for MTHFR gene mutations. Forty one of these patients also had homocysteine levels available. Thirty-eight of these 41 (92 %) patients had an MTHFR gene mutation with normal homocysteine levels. Eighteen (47%) of these 38 patients had only an MTHFR gene mutation with normal homocysteine level and no other congenital or acquired risk factors for vascular events identified. Conclusions: In our clinic population, many patients with documented vascular events had MTHFR gene polymorphisms with normal homocysteine levels with no other thrombophilia risk factors identified, raising the question of whether MTHFR gene polymorphisms alone, without hyperhomocysteinemia, may somehow contribute to thrombophilia. [Table: see text] No significant financial relationships to disclose.

The Influence of Hyperlipidemia on Platelet Activity Markers in Patients after Ischemic Stroke

Background: To investigate the relationship between hyperlipidemia and platelet activation markers – platelet and soluble P-selectin (sP-selectin), and platelet-derived microparticles (PDMPs) – in patients after ischemic stroke. Methods: 41 patients after ischemic stroke (>3 months) confirmed by CT were divided into 2 groups: with hyperlipidemia (HL, n = 21) and normolipidemia (NL, n = 20). Twenty healthy subjects served as controls. CD62P-positive platelets and PDMPs in whole blood were analyzed by the use of a flow cytometer and anti-CD61 and anti-CD62P monoclonal antibodies. Platelets were activated by thrombin (0.08 units). The level of sP-selectin in serum was measured by ELISA. Results: We observed a significantly higher CD62P expression and percentage of CD62P-positive resting and thrombin-activated platelets in the HL as compared to the NL group. The sP-selectin concentration was also significantly higher in HL than NL subjects (p < 0.05). Moreover, we observed a significantly higher percentage of PDMPs in patients after stroke (NL: p < 0.05; HL: p = 0.005) in comparison with the control group. Conclusions: Patients after stroke present symptoms of platelet hyperreactivity. HL in the patients may be a risk factor for vascular events due to the increase in platelet activation.

Blood pressure control, risk factors and cardiovascular prognosis in patients with diabetes: 30 years of progress

Hypertension is a major co-morbidity for type 2 diabetes, and an important modifiable risk factor for vascular events. Therefore, treatment of diabetes and its risk factors is important to minimize complications, and much progress has been made over the past 30 years. The UKPDS trial showed that intensive glycaemic and blood pressure control reduced the risk of vascular events. In the HOT study, the addition of aspirin to patients with diabetes and controlled hypertension decreased the risk of myocardial infarction. Blood pressure control with angiotensin-converting enzyme inhibitors in MICRO-HOPE also showed significant reductions in the risk of vascular complications, and blockers of the renin-angiotensin system produced substantial renal protective effects in patients with hypertension and diabetes. Statin therapy in the HPS and CARDS studies was effective in the primary prevention of cardiovascular disorders. Finally, an intensive multifactorial intervention achieved sustained reduction in the risk of vascular complications and death in patients with type 2 diabetes in the Steno-2 study. Nevertheless, the major coronary event risk remains high in type 2 diabetes patients, and the results of the ADVANCE trial provided a step forward in treatment.

Contrôle tensionnel, facteurs de risque et pronostic cardiovasculaire du patient diabétique: 30 ans de progrès

Hypertension is a major co-morbidity for type 2 diabetes, and an important modifiable risk factor for vascular events. Therefore, treatment of diabetes and its risk factors is important to minimize complications, and much progress has been made over the past 30 years. The UKPDS trial showed that intensive glycaemic and blood pressure control reduced the risk of vascular events. In the HOT study, the addition of aspirin to patients with diabetes and controlled hypertension decreased the risk of myocardial infarction. Blood pressure control with angiotensin-converting enzyme inhibitors in MICRO–HOPE also showed significant reductions in the risk of vascular complications, and blockers of the renin–angiotensin system produced substantial renal protective effects in patients with hypertension and diabetes. Statin therapy in the HPS and CARDS studies was effective in the primary prevention of cardiovascular disorders. Finally, an intensive multifactorial intervention achieved sustained reduction in the risk of vascular complications and death in patients with type 2 diabetes in the Steno-2 study. Nevertheless, the major coronary event risk remains high in type 2 diabetes patients, and the results of the ADVANCE trial provided a step forward in treatment.

Lymphotoxin-alpha C804A polymorphism is a risk factor for stroke. The PROSPER study

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint ( p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes ( p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.

Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larrán A et al.

Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larran A et al.

Reply to Westerman et al.: ‘Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larrán A et al. Leukemia 2007; 21: 1218–1223’

Reply to Westerman et al. : ‘Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larran A et al. Leukemia 2007; 21: 1218–1223’

Reply to ‘Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larrán et al. Leukemia 2007; 21: 1218–1223’

Reply to ‘Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larran et al. Leukemia 2007; 21: 1218–1223’

Reply to ‘Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larrán A et al.’ by Westerman et al.

Reply to ‘Re: Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients. Alvarez-Larran A et al. ’ by Westerman et al.

Essential thrombocythemia in young individuals: frequency and risk factors for vascular events and evolution to myelofibrosis in 126 patients

The frequency of vascular events and evolution to myelofibrosis (MF) in young individuals with essential thrombocythemia (ET) is not well known. The incidence and predisposing factors to such complications was studied in 126 subjects diagnosed with ET at a median age of 31 years (range: 5-40). Overall survival and probability of survival free of thrombosis, bleeding and MF were analyzed by the Kaplan-Meier method and the presence of the Janus Kinase 2 (JAK2) V617F mutation correlated with the appearance of such complications. The JAK2 mutation (present in 43% of patients) was associated with higher hemoglobin (Hb) (P<0.001) and lower platelets at diagnosis. With a median follow-up of 10 years (range: 4-25), 31 thrombotic events were registered (incidence rate: 2.2 thromboses/100 patients/year). When compared with the general population, young ET patients showed a significant increase in stroke (odds ratio 50, 95% CI: 21.5-115) and venous thromboses (odds ratio 5.3, 95% CI: 3.9-10.6). Thrombosis-free survival was 84% at 10 years, with tobacco use being associated with higher risk of thrombosis. Actuarial freedom from evolution to MF was 97% at 10 years. In conclusion, young ET patients have thrombotic events, especially stroke and venous thrombosis, more frequently than generally considered, whereas they rarely transform to MF.

The course of vascular risk factors and the occurrence of vascular events in patients with symptomatic peripheral arterial disease

Previous studies have documented an undertreatment of vascular risk factors, and patients with symptomatic peripheral arterial disease (PAD) are at increased risk of recurrent vascular events. We examined which baseline variables are related to future vascular events, investigated the course of vascular risk factors, and compared the number of vascular risk factors at baseline and at follow-up to determine whether risk factor management could be further improved. This study involved 461 patients with Fontaine classification II to IV who were enrolled in the SMART study (Second Manifestations of ARTerial disease) from September 1996 to December 2000. Patients underwent a standardized screening program for risk factors and were invited for a follow-up measurement during September 2003 to March 2005, after a mean follow-up of 5.5 years (SD, 1.3 years). In the interim period between baseline and follow-up measurement, patients received usual care. During follow-up, vascular events (mortality, ischemic stroke, and myocardial infarction) and PAD-related events (vascular surgery, interventions, and amputations) were documented in detail. In 2739 person-years of follow-up, 91 vascular events occurred, resulting in a 29.1% (95% confidence interval [CI], 22.8%-35.4%) cumulative incidence proportion of recurrent vascular events. Older age, increased homocysteine levels, impaired renal function, and a history of coronary heart disease at baseline were related to an increased risk of new vascular events. Of the 461 patients, 108 patients died, 20 patients were lost to follow-up, and 333 patients were eligible for follow-up measurement, in which 221 (66%) patients wished to participate. In 8 of the 221 patients, a nonfatal vascular event occurred during follow-up. The prevalence of hypertension increased from 51% to 70% (95% CI, 10%-28%), the prevalence of obesity increased from 54% to 67% (95% CI, 3%-21%), and the prevalence of diabetes mellitus increased from 8% to 16% (95% CI, 2%-14%). At follow-up, fewer patients were current smokers (59% to 37%; 95% CI, -13% to -31%), and fewer patients had increased lipid levels (96% to 73%; 95% CI, -29% to -16%). Medication use increased in all drug categories during follow-up. Age, increased homocysteine levels, impaired renal function, and a history of coronary heart disease were independent risk factors for vascular events in patients with symptomatic PAD. The prevalence of most risk factors, except for smoking and hyperlipidemia, increased over a 5.5-year period even though medication use increased over the same period.

Essential Thrombocythemia in Young Individuals: Frequency and Risk Factors for Vascular Events and Evolution to Myelofibrosis in 126 Patients.

Vascular events and evolution to either myelofibrosis (MF) and acute leukemia (AL) are the main causes of morbidity and mortality in individuals with essential thrombocythemia (ET). However, the frequency of these complications in young ET patients is not well known. The objective of the present study was to assess the frequency of vascular events and the incidence of MF and AL in young patients with ET and to identify the factors associated with the development of such complications. In 126 subjects diagnosed with ET at a median age of 31 years (range: 5–40), overall survival and probability of survival free of either thrombosis, bleeding, MF, AL, and polycythemia vera (PV) were analyzed by the Kaplan-Meier method, followed by the log-rank test. With a median follow-up of eleven years (range: 4–25) three patients have died, being the probability of survival 98% at ten years. A total of 31 thrombotic events were registered in 25 patients; thrombosis-free survival (TFS) was 84% at ten years. Tobacco use was the only factor associated with an increased thrombotic risk, since TFS at 10 years was 72% in smokers versus 90% in non-smokers (p=0.03). Severe hemorrhagic complications were observed in 11 patients, and the estimated probability of bleeding-free survival was 92% at ten years. Evolution to MF was seen in 6 patients, four of whom had never received treatment for ET. MF-free survival was 97% at 10 years, with the risk being higher in patients showing an increased reticulin network in the bone marrow biopsy performed at diagnosis of ET (p=0.005). Transformation to AL was registered in one patient. JAK2 was mutated in 33 out of the 87 assessable patients (38%) and the mutation was associated with higher Hb values at diagnosis (p = 0.001). ET evolved into PV in five patients, being the probability of evolution into PV of 15% in JAK2 V617F positive patients versus 0% in JAK2 V617F negative patients (p=0.01). In conclusion, severe vascular complications are not infrequent in young subjects with ET, whereas transformation to MF or AL is a rare event.

The Combined Use of Hydroxyurea and Anagrelide Allows Better Hematologic Control in Patients with Chronic Myeloproliferative Disorders and Thrombocytosis. A Report on 13 Patients with Poor Tolerance to Hydroxyurea Monotherapy.

Background: Anagrelide has proven effective in selectively lowering platelet count in patients with chronic myeloproliferative disorders (CMPD). It has been approved for the control of thrombocytosis in patients with CMPD and in patients with essential thrombocytemia (ET) refractory or intolerant to hydroxyurea (HU). In spite of their different mechanisms of action, its use in combination with other active agents, particularly HU, has not been explored.Aim of the study: We have reviewed the records of patients with CMPD treated at our Institution and report herein on the combined use of anagrelide and HU in a series of 13 patients, mean age 66,7 years, followed for 1–21 years. Their diagnoses were: essential thrombocythemia (7), polycythemia vera (3), chronic myeloid leukaemia (CML) (1), and idiopathic myelofibrosis (1). Previous treatments included HU (13), phlebotomy (2), busulphan (4), r-interferon (1), imatinib mesylate (1). All had thrombocytosis (mean platelet count: 948.9 × 109/L), with coexistent risk factors for vascular events in 11 of 13.Results: Anagrelide was started because of poor platelet control by a HU daily dose of 0,5– 3 g (median: 1,5 g), which caused anemia (Hb < 10,5 g/dL) (3 transfusion-dependent) and/or leukopenia (WBC < 4.0 × 109/L) in 12/13 cases and because of HU-related cutaneous ulcers in 1. Initial anagrelide daily dose was 0,5 – 2 mg. It was associated with HU at the significantly reduced daily dose of 0,25 – 2 g (median 1g) (Wilcoxon: P<0.001). After a median of 1 month on combined therapy (range 0,5 – 4) the mean peripheral blood cell (PBC) count changes compared to treatment with HU alone were as follows: platelets: 507.5 vs 948.9 × 109/L (P=0.013); WBC: 8.392 vs 5047 × 109/L (P=0.039); hemoglobin: 11,28 vs 10,15 g/dL (P:=0.026) (1 vs 3 pts transfused). In 6 patients HU was stopped after a median of 1,5 months and anagrelide was continued as monotherapy. In 1 CML patient in accelerated phase anagrelide was associated with imatinib mesylate to control thrombocytosis, without side effects. In 6 patients anagrelide and HU combined treatment has been carried on for 19 – 40+ months (median 28 months) by modulating doses according to PBC counts. Anagrelide's dosage had to be reduced in 1 patient because of fatigue. Further mild side effects included peripheral edema (1) dyspepsia and abdominal meteorism (1), dyarrhoea (2). Three patients had gastrointestinal bleeding from duodenal ulcer (1), intestinal polyps (1), stomach angiodysplasia while on oral anticoagulation (1). One patient had cerebral TIA during a transient thrombocytosis rebound after haemorrhage. Their CMPD did not show evidence of progressive disease. In one pt a marrow trephine biopsy after 18 months showed a slight increase of fibrosis from grade 1–2 focal to grade 1–2 diffuse. Two patients died, both of comorbid conditions.Conclusion: This preliminary clinical experience shows that the association of anagrelide and hydroxyurea allows a significant reduction of the dose of HU needed to control thrombocytosis and causes significant less toxicity on the erythroid series. Compared to anagrelide monotherapy it should allow costs saving as well as a better control of WBC count, whose correlation with thrombotic risk is currently debated. The combination was well tolerated, although the frequency of gastrointestinal bleeding needs careful monitoring. This innovative therapeutic approach merits further investigation.

Metabolism of collagen is altered in hypertensives with increased intima media thickness

Background. Increased intima media thickness (IMT) of common carotid arteries (CCAs) and left ventricular mass index (LVMI) are independent risk factors for vascular events and may be related to accumulation of extracellular proteins due to altered metabolism of collagen. Methods. IMT and LVMI were measured ultrasonographically in 50 males with newly diagnosed, untreated, essential hypertension (HTN, 37.7±13.1 years), and 14 controls (C, 32.6±9.7 years). Serum levels of procollagen type I carboxy‐terminal propeptide (PICP), procollagen type III amino‐terminal propeptide (PIIINP), carboxy‐terminal telopeptide (ICTP), matrix metalloproteinase (MMP‐1) and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) were determined using immunoassays. Results. IMT was significantly higher in HTN than in C (0.6±0.1 vs 0.4±0.1 mm, p<0.001) as well as LVMI (119.5±39.9 vs 106.8±18.7 g/m2, p = 0.04) and serum TIMP‐1 (in HNT 691.7±124.6 ng/ml; in C 577.5±70.8 ng/ml, p<0.001). Other parameters did not differ between these groups. The sum of PICP and ICTP was higher in HTN (165.0±46.9 µg/l), than in C (147.1±26.0 µg/l, p = 0.03). TIMP‐1 correlated with IMT (r = 0.33, p = 0.02) in hypertensives. Conclusions. We suggest that the collagenase–anticollagenase system is abnormal in essential hypertension and contributes to cardiovascular remodeling. Increased IMT may be related to the accumulation of extracellular proteins due to altered metabolism of collagen.

Silent cerebral infarction predicts vascular events in hemodialysis patients

Cardiovascular disease is the leading cause of death in hemodialysis (HD) patients. We have previously reported a higher incidence of silent cerebral infarction (SCI) in HD patients compared with the control group using MRI studies. In the present study, we examined whether or not SCI could predict vascular events in HD patients. Cranial magnetic resonance imaging (MRI) was performed on 119 HD patients without symptomatic cerebrovascular disease. SCI was detected by MRI, and the patients were prospectively followed up. The end points of the study were the incidence of major events related to vascular events (cerebral events, cardiac events, and sudden deaths). We investigated the prognostic role of SCI in cerebral, cardiac, and vascular events by using the Kaplan-Meier method and Cox proportional hazards analysis. The prevalence of SCI was 49.6% in HD patients. During a follow-up period of maximum 60 months, vascular events, which included 13 cerebral events, 5 cardiac events, and 3 sudden deaths, occurred in 21 patients. The presence of SCI was predictive for a higher cerebral and vascular morbidity compared to the absence of SCI [18.6% (N= 11) vs. 3.3% (N= 2), P= 0.0169, and 30.5% (N= 18) vs. 5.0% (N= 3), P= 0.0006, respectively]. By multivariate Cox proportional hazards analysis, SCI remained a powerful independent predictor of cerebral and vascular events (hazard ratio for cerebral events 7.33, 95% CI 1.27-42.25: for vascular events 4.48, 95% CI 1.09-18.41). The findings of the present study indicate that the presence of SCI is a new risk factor for vascular events in HD patients.

Carotid stiffness and the risk of new vascular events in patients with manifest cardiovascular disease. The SMART study

To study whether arterial stiffness is related to risk of new vascular events in patients with manifest arterial disease and to examine whether this relation varies between patients who differ with respect to baseline vascular risk, arterial stiffness, or systolic blood pressure (SBP). The study was performed in the first consecutive 2183 patients with manifest arterial disease enrolled in the SMART study (Second Manifestations of ARTerial disease), a cohort study among patients with manifest arterial disease or cardiovascular risk factors. Common carotid distension (i.e. the change in carotid diameter in systole relative to diastole) was measured at baseline by ultrasonography. With the distension, several stiffness parameters were determined. In the entire cohort, none of the carotid artery stiffness parameters was related to the occurrence of vascular events. However, decreased stiffness was related to decreased vascular risk in subjects with low baseline SBP. The relation of carotid stiffness with vascular events did not differ between tertiles of baseline risk and carotid stiffness. Carotid artery stiffness is no independent risk factor for vascular events in patients with manifest arterial disease. However, in patients with low SBP, decreased carotid stiffness may indicate a decreased risk of vascular events.

Fenofibrate: Metabolic and Pleiotropic Effects

Disturbances of lipoprotein metabolism represent one of the most important risk factors for vascular events. However, dyslipidaemic patients often have a number of additional abnormalities (such as endothelial dysfunction, hypertension, low-grade inflammation, haemostatic abnormalities and hyperuricaemia) that may accelerate the atherosclerotic process. Thus, the ideal lipid-modifying drug, along with exerting beneficial effects on lipoprotein metabolism, should also improve these coexisting disturbances. Fibric acid derivatives (fibrates) are a class of lipid-modifying drugs mainly used in patients with elevated triglyceride levels. These drugs mainly exert their actions via the activation of specific nuclear receptors called peroxisome proliferator-activated receptors alpha (PPARalpha). In this review, we summarize the current evidence suggesting that fenofibrate, one of the most widely used fibric acid derivatives, along with its well established actions on lipids also exerts several other antiatherogenic actions. Based on recently published studies, fenofibrate is a useful option for patients with primary combined dyslipidaemias or secondary dyslipidaemias, such as those associated with diabetes mellitus, metabolic syndrome or HIV infection. Additionally, in cases of refractory dyslipidaemia, the combination of fenofibrate with statins is a therapeutic option.

Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXIII. Baseline predictors of vascular events

To determine the baseline (time 0) risk factors associated with the subsequent occurrence of vascular events in a multiethnic US cohort (LUMINA [LUpus in MInorities: NAture versus nurture]) of patients with systemic lupus erythematosus (SLE). Five hundred forty-six LUMINA patients were assessed at time 0 for traditional and nontraditional (disease-related) risk factors for vascular events. These were defined as 1) cardiovascular (myocardial infarction and/or definite or classic angina and/or the undergoing of a vascular procedure for myocardial infarction [coronary artery bypass graft]), 2) cerebrovascular (stroke), and 3) peripheral vascular (arterial claudication and/or gangrene or significant tissue loss and/or arterial thrombosis in peripheral arteries). The observation time (followup time in the cohort) was the interval between time 0 and the last visit. The unit of analysis was the patient and not each vascular event. Variables at time 0 and vascular events were examined by univariable and multivariable (logistic and Cox proportional hazards regression) analyses. Age, sex, ethnicity, followup time, and all known risk factors for the occurrence of vascular events were included in the model. Thirty-four patients (6.2%) developed one or more vascular event after time 0. The overall median duration of followup in the cohort was 73.8 months (range 10.8-111.3 months). Vascular events (13 cardiovascular, 18 cerebrovascular, 5 peripheral vascular) occurred in 7 Hispanics from Texas (6.5%), 1 Hispanic from Puerto Rico (1.2%), 15 African Americans (7.5%), and 11 Caucasians (7.1%). The mean total number of traditional risk factors was significantly higher in patients who developed vascular events than in those who did not (7.1 versus 5.6). Independent predictors of vascular events were older age, current smoking status, longer followup time, elevated serum levels of C-reactive protein (CRP), and the presence of any antiphospholipid antibody. The same variables were identified when time-dependent analyses were performed, although azathioprine use was also found to be a contributing factor. Smoking, previously not reported in SLE, emerged as a predictor of vascular events and should be strongly discouraged. Antiphospholipid antibodies and CRP support the role of inflammation and autoimmunity in the development of accelerated atherosclerosis in SLE. Ethnicity was not associated with vascular events in our patients.

Atherosclerosis of the aorta: Risk factor, risk marker, or innocent bystander?: A prospective population-based transesophageal echocardiography study

The goal of this study was to investigate whether complex aortic atherosclerosis is associated with increased risk of vascular events in a non-selected population. In selected high-risk patients, aortic atherosclerosis is associated with increased risk of vascular events. We describe the relationship between simple versus complex (>4-mm thick or mobile debris) aortic atherosclerotic plaques and vascular events during follow-up in a random sample of 585 persons (age > or =45 years) using 1993 to 2000 data from the Stroke Prevention: Assessment of Risk in a Community (SPARC), a prospective population-based longitudinal study. At five-year median follow-up (range, 0.5 to 6.5 years), cardiac events (death, non-fatal myocardial infarction, coronary revascularization, heart failure associated with coronary artery disease) and cerebrovascular events (ischemic fatal and non-fatal strokes, transient ischemic attacks) had occurred in 95 subjects and 41 subjects, respectively. Age, male gender, prior coronary artery disease, higher pulse pressure, and diabetes were significant cardiovascular predictors. Age, prior myocardial infarction, and a history of atrial fibrillation were significant cerebrovascular predictors. Simple aortic plaques (253 persons) were not independently associated with either cardiac or cerebrovascular events. Complex plaques (44 persons) were marginally associated with cardiac events, adjusting for age and gender (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.11 to 4.68; p = 0.053 for two degrees of freedom [complex and simple plaques vs. no plaques]) but not after adjusting for additional clinical risk factors (HR, 1.22; 95% CI, 0.57 to 2.62; p = 0.64). Complex plaques were associated with cerebrovascular events only univariately. Aortic atherosclerotic plaques are not associated with future cardiac or cerebrovascular events. Aortic atherosclerosis may not be an independent risk factor for vascular events in the general population.

AMPK activation may suppress hepatic production of C-reactive protein by stimulating nitric oxide synthase

The utility of C-reactive protein (CRP) as an independent risk factor for vascular events may be attributable, at least in part, to a direct adverse impact of CRP on endothelial function. In particular, modestly elevated concentrations of CRP have been shown to decrease the expression of the endothelial isoform of nitric oxide synthase (eNOS) in endothelial cells; the implication of this for vascular health is evident. Strategies for decreasing elevated CRP include administration of statins, thiazolidinediones, and metformin; moderate alcohol consumption and appropriate weight loss are also helpful in this regard. Metformin's antidiabetic efficacy is now known to reflect activation of AMP-activated kinase (AMPK); AMPK can stimulate eNOS, which is expressed in hepatocytes. A recent study shows that nitric oxide suppresses the activation of Stat3 by interleukin-6 in hepatocytes; Stat3 is crucial for the IL-6-mediated induction of CRP and various other acute phase reactants. Thus, it is proposed that metformin – or AMPK – inhibits hepatic CRP production by boosting hepatic nitric oxide synthesis, which in turn impedes Stat3 activation and CRP transcription. This hypothesis should be readily testable in cultured hepatocytes. Although the impact of metformin on plasma IL-6 levels has not been reported, the possibility that AMPK activation could influence adipocyte secretion of this cytokine also merits scrutiny.