History Of Atherosclerotic Disease Research Articles

Are all people with diabetes and cardiovascular risk factors or microvascular complications at very high risk? Findings from the Risk and Prevention Study.

To verify whether it is possible, in people with diabetes mellitus (DM) considered at very high cardiovascular (CV) risk, stratify this risk better and identify significant modifiable risk factor (including lifestyle habits) to help patients and clinicians improve CV prevention. People with DM and microvascular diseases or one or more CV risk factors (hypertension, hyperlipidemia, smoking, poor dietary habits, overweight, physical inactivity) included in the Risk and Prevention study were selected. We considered the combined endpoint of non-fatal acute myocardial infarction and stroke and CV death. A multivariate Cox proportional analysis was carried out to identify relevant predictors. We also used the RECPAM method to identify subgroups of patients at higher risk. In our study, the rate of major CV events was lower than expected (5% in 5years). Predictors of CV events were age, male, sex, heart failure, previous atherosclerotic disease, atrial fibrillation, insulin treatment, high HbA1c, heart rate and other CV diseases while being physically active was protective. RECPAM analysis indicated that history of atherosclerotic diseases and a low BMI defined worse prognosis (HR 4.51 95% CI 3.04-6.69). Among subjects with no previous atherosclerotic disease, men with HbA1c more than 8% were at higher CV risk (HR 2.77; 95% CI 1.86-4.14) with respect to women. In this population, the rate of major CV events was lower than expected. This prediction model could help clinicians identify people with DM at higher CV risk and support them in achieving goals of physical activity and HbA1c.

The role of the history of coronary heart disease among second degree relatives for predicting coronary artery disease

Introduction: The history of atherosclerotic disease among second degree family members of patients as a risk factor has not been properly explained. The present study aimed to assess this role in the Iranian population. Methods: This case-control study was performed on 500 consecutive patients, who were candidates for coronary angiography. The presence of Coronary Heart Disease (CHD) history among first and second degree relatives were determined by interviewing the participants. Results: In total, 450 patients were shown to have CHD as the case group and 50 without CHD as the control group. Family history of CHD among first degree relatives was 39.1% for cases and 22.0% for the controls with a significant difference (P = 0.018), however the history of CHD among second degree relatives was not statistically different in the case group and the control group (17.8% vs. 8.0%, P = 0.079). In total, 80 patients had CHD with simultaneous history of disease among their second degree relatives, while 370 with CHD had no history of disease among their second degree relatives. Our study could not find a significant difference between the two CHD groups with and without history of disease among second degree relatives in terms of cardiovascular risk profile. Conclusions: Despite the powerful effect of the presence of family history of CHD in first degree relatives on risk of CHD and its severity, the presence of this history among second degree relatives cannot predict the risk for CHD.

Improving cardiovascular prevention in general practice: Results of a comprehensive personalized strategy in subjects at high risk.

Although high cardiovascular risk patients should be the main target of preventive strategies, modifiable risk factors are often inadequately controlled. To assess feasibility and results of a comprehensive personalized method for cardiovascular prevention in high risk patients followed by their general practitioner. Between 2004 and 2007, 12,513 patients (mean age 64.0 ± 9.5 years; 61.5% males) with multiple cardiovascular risk factors or history of atherosclerotic disease were identified and followed for five years. If control of major modifiable cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, smoking, unhealthy diet, physical inactivity) was sub-optimal, at baseline and yearly thereafter general practitioners planned with patients, with the help of a brief checklist, preventive interventions to improve the global risk profile. Main outcome was the control of the seven major modifiable cardiovascular risk factors during follow-up. Secondary outcome was the incidence of cardiovascular deaths and hospitalization for cardiovascular reasons according to the improvement in global cardiovascular risk profile during the first year. Control of all major modifiable risk factors except physical inactivity improved gradually and significantly (p < 0.0001) during follow-up.The improvement in the global cardiovascular risk profile during the first year was independently and significantly associated with a lower rate of major cardiovascular events in the following years (hazard ratio 0.939; 95% confidence interval 0.887-0.994, p = 0.03). Our comprehensive, personalized method for cardiovascular risk prevention in people at high risk appears feasible in general practice. The improvement in the global cardiovascular risk profile was associated with a better prognosis.

Revision using distal inflow is a safe and effective treatment for ischemic steal syndrome and pathologic high flow after access creation

Ischemic steal syndrome (ISS) and pathologic high flow (HF) are a complications after hemodialysis access creation. Their management is complex and varied with most requiring surgical revision for correction of symptoms. Revision using distal inflow (RUDI) has been described in small series for the treatment of ISS. We present our experience with RUDI for the treatment of ISS and pathologic HF. We retrospectively reviewed consecutive patients who underwent RUDI for ISS from April, 2010 to March, 2014. Data collection included demographic characteristics, medical histories, subsequent procedures, volume flows, access usage, limb salvage, and patient survival. We performed 29 RUDI procedures in 28 patients (16 women, 12 men). Indications for surgery were pathologic HF in 13 and ISS in 19. Ten percent had previous banding for ISS or HF. Sixty-nine percent of patients had a history of diabetes. Fifty-two percent had a history of atherosclerotic disease. Mean time to intervention from creation was 40 months (range, 6-88 months). Accesses included 1 upper arm graft and 27 brachial artery-based fistulas. Outflow included 25 cephalic veins and 3 basilic veins. Distalization targets were 19 radial arteries and 10 ulnar arteries. Mean flow reduction was 1191 mL/min. Primary assisted patency at 1 year was 74%. Secondary patency at 1 year was 87%. A single access was ligated for continued heart failure after RUDI. ISS symptom resolution was reported as complete in 69% and partial in 31%. RUDI is an effective and durable treatment of ISS and HF comparable with reported experiences with distal revascularization-interval ligation, proximalization of the arterial inflow, and banding. Patient selection is key for optimizing relief of symptoms and maintaining use of the access.

Carotid intima media thickness is independently associated with urinary sodium excretion in patients with chronic kidney disease

Atherosclerosis-induced premature vascular diseases are the leading cause of mortality among patients with chronic kidney disease (CKD). The pathogenetic mechanism of atherosclerosis in patients with CKD has not been fully explained. Experimental studies have demonstrated that high dietary sodium intake not only increases circulatory volume and blood pressure, but also facilitates development of atherosclerosis by reducing production-bioavailability of nitric oxide due to oxidative stress and accordingly by enhancing endothelial and arterial stiffness. In this study, we investigated the relationship between sodium consumption and carotid artery intima-media thickness, which is the indicator of atherosclerosis, by determining daily urinary sodium excretion, which is a reliable indicator of sodium consumption, in our patient group. Our patient group included 193 patients with stage 2–4 non-diabetic CKD and without a history of atherosclerotic disease. We determined that 77% of our patients have been consuming more than 2 g of sodium per day, which is the upper limit of sodium consumption recommended for patients with CKD. We determined a positive linear correlation between carotid artery intima-media thickness and patient age (p < 0.001), C-reactive protein (p < 0.001), urinary sodium excretion (p < 0.001), body mass index (p = 0.002), systolic blood pressure (p = 0.002), hemoglobin (p = 0.030), triglycerides (p = 0.043), and diastolic blood pressure (p = 0.049). We also found a negative linear correlation between carotid artery intima-media thickness and glomerular filtration rate (p = 0.008). We found that urinary sodium excretion is the determinant of intima-media thickness even if all factors associated with intima-media thickness are adjusted, and that intima-media thickness increases by 0.031 (0.004–0.059) mm per 2 g increase in daily sodium excretion, independent from overall factors (p = 0.025). Our results reveal a relation between urinary sodium excretion and carotid artery intima-media thickness and suggest that excessive sodium consumption predisposes development of atherosclerosis in patients with CKD.

Revision Using Distal Inflow: A Safe and Effective Treatment for Ischemic Steal Syndrome After Access Creation

Ischemic steal syndrome (ISS) is a dreaded complication after hemodialysis access creation. Its management is complex and varied, with most requiring surgical revision for correction of symptoms. Revision using distal inflow (RUDI) has been described in small series for the treatment of ISS. We present our experience with RUDI for the treatment of ISS and pathologic high flow (HF). We retrospectively reviewed consecutive patients who underwent RUDI for ISS from April 2010 to March 2014. Data collection included demographics, medical histories, subsequent procedures, volume flows, access usage, limb salvage, and patient survival. We performed 32 RUDI procedures in 31 patients (18 women, 13 men). Indications for surgery were pathologic HF in 15 and ISS in 21. Sixteen percent had prior plication for ISS or HF. Seventy-one percent of patients had a history of diabetes, and 52% had a history of atherosclerotic disease. Time to intervention from creation was 40 months (range, 6-88 months). Accesses included one upper arm graft and 30 brachial artery-based fistulas. Outflow included 26 cephalic veins and four basilic veins. Distalization targets were 20 radial arteries, nine ulnar arteries, and three distal brachial arteries. Mean flow reduction was 994 mL/min. Primary assisted patency at 1 year was 73%, and secondary patency was 88%. The RUDI in one patient was revised from a distal brachial to radial inflow. A single access was ligated for continued heart failure after RUDI. ISS symptom resolution was reported as complete in 81% and partial in 19%. RUDI is an effective and lasting treatment of ISS and HF and comparable to reported experiences with distal revascularization-interval ligation, proximalization of the arterial inflow, and plication. Patient selection is key for optimizing relief of symptoms and maintaining use of the access.

Is there a relationship between serum paraoxonase level and epicardial fat tissue thickness?

This study aimed to show the relationship between serum paraoxonase 1 level and the epicardial fat tissue thickness. Two hundred and seven patients without any atherosclerotic disease history were included in this cross-sectional observational study. Correlation analysis was performed to determine the correlation between epicardial fat tissue thickness, which was measured by echocardiography and serum paraoxonase 1 level. Also correlation analysis was performed to show correlation between patients' clinical and laboratory findings and the level of serum paraoxonase 1 (PON 1) and the epicardial fat tissue thickness. Pearson and Spearman test were used for correlation analysis. No linear correlation between epicardial fat tissue thickness and serum PON 1 found (correlation coefficient: -0.127, p=0.069). When epicardial fat tissue thickness were grouped as 7 mm and over, and below, and 5 mm and over, and below, serum PON 1 level were significantly lower in ≥7 mm group (PON1 : 168.9 U/L) than <7 mm group (PON 1: 253.9 U/L) (p<0.001). Also hypertension prevalence was increased in ≥7 mm group (p=0.001). Serum triglyceride was found to be higher in ≥7 mm group (p=0.014), body mass index was found higher in ≥5 mm group (p=0.006). Serum PON 1 level is not correlated with the epicardial fat tissue thickness. But PON 1 level is lower in patients with epicardial fat tissue thickness 7 mm and over. Therefore, increased atherosclerosis progression can be found among patients with 7 mm and higher epicardial fat tissue thickness.

Carotid and popliteal artery intima-media thickness in patients with poor oral hygiene and the association with acute-phase reactants

The aim of this study was to evaluate whether poor oral hygiene is associated with carotid and popliteal arterial intima-media thickness, which is one of the predictors of future progression of sub-clinical atherosclerosis, and highsensitivity C-reactive protein (hsCRP) and fibrinogen levels. A specialised dentist checked the patients and selected 550 patients during periodontal examinations, according to their oral hygiene. The patients had no history of atherosclerotic disease. Carotid and popliteal artery B-mode ultrasonographic examinations and hsCRP and fibrinogen levels were analysed at baseline and after a mean of 6.2 months. The patients were scored on the DMFT index for the number of decayed (D), missing (M), and filled (F) teeth (T). We also used the Silness-Loe plaque index (SLI) to evaluate oral hygiene and dental plaque. The patients were divided into two groups using the DMFT and SLI criteria. Group I had a DMFT index score from 0 to 3 and SLI index score of 0 or 1. Group II had a DMFT index score from 4 to 28 and SLI index score of 2 or 3. A significant association was observed between dental status, oral hygiene, carotid and popliteal artery intima-media thickness and hsCRP level. Patients with increasing DMFT and SLI scores correlated with increasing carotid artery intima-media thickness. The results clearly showed that chronic poor oral hygiene and tooth loss are related to sub-clinical atherosclerotic changes in the carotid arteries and may be indicative of future progression of atherosclerosis.

Does Oral Hygiene Trigger Carotid Artery Intima-Media Thickness?

The aim of this study was to evaluate whether poor oral hygiene is associated with the intima-media thickness of the carotid arteries, which is one of the predictors of future progression of subclinical atherosclerosis. We selected 108 patients during periodontal examinations according to their oral hygiene. The patients had no history of atherosclerotic disease. The results of carotid artery B-mode ultrasonography examinations were analyzed at baseline and after a mean of 7.8 months. Patients were scored on the DMFT index for the number of decayed (D), missing (M), and filled (F) teeth (T). We also used the Silness-Loe plaque index (SLI) to evaluate oral hygiene and dental plaque. The patients were divided into 2 groups according to DMFT and SLI criteria. Group I had a DMFT index of 0 to 3 and an SLI score of 0 or 1; group II had a DMFT index of 4 to 28 and an SLI score of 2 or 3. Dental status and oral hygiene were significantly associated with carotid artery intima-media thickness. Patients with increasing DMFT and SLI indices were correlated with intima-media thickness of the carotid artery. Chronic poor oral hygiene and tooth loss are related to subclinical atherosclerotic changes in the carotid arteries and might be indicative of future progression of atherosclerosis.

Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation

Background— The role of concomitant aspirin (ASA) therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant ASA use and its association with clinical outcomes among AF patients treated with OAC. Methods and Results— The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry enrolled 10 126 AF patients from 176 US practices from June 2010 through August 2011. The study population was limited to those on OAC (n=7347). Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant ASA therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% of AF patients (n=2543) on OAC also received ASA (OAC+ASA). Patients receiving OAC+ASA were more likely to be male (66% versus 53%; P &lt;0.0001) and had more comorbid illness than those on OAC alone. More than one third of patients (39%) receiving OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding risk scores (≥5). Major bleeding (adjusted hazard ratio, 1.53; 95% confidence interval, 1.20–1.96) and bleeding hospitalizations (adjusted hazard ratio, 1.52; 95% confidence interval, 1.17–1.97) were significantly higher in those on OAC+ASA compared with those on OAC alone. Rates of ischemic events were low. Conclusions— Patients with AF receiving OAC are often treated with concomitant ASA, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant ASA outweigh the risks in AF patients already on OAC. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Metabolic Syndrome in the Spectrum of Hair Grayness

Background: hair graying is an aging sign; it is associated with ischemic heart disease. Metabolic syndrome often associates with increased risk for atherosclerotic arterial disease.Objective: To test retrospectively the association between onset of hair graying and risk of metabolic syndrome.Methods: Four hundred and eighty one gray hair individuals, with no history of atherosclerotic diseases were included. The individuals have been divided into metabolic syndrome and control groups. Each individual was asked about the decade (2nd-6th) of onset of hair grayness.Results: Patients with metabolic syndrome had peak onset of hair grayness in the 4th decade which was statistically higher than the control group (p values= 0.045). While the peak onset in the control group was in the 5th decade which was different from the metabolic syndrome group (p-value = 0.024). The difference was not significant in the 2nd, 3rd and 6th decades of life.Conclusion: Patients with metabolic syndrome had an earlier age of onset of hair grayness.

Antigens of persistent Chlamydia pneumoniae within coronary atheroma from patients undergoing heart transplantation

AimsIn order for Chlamydia pneumoniae to play a causative role in chronic human disease, it would need to persist within infected tissue for extended periods of time. Current theory suggests...

Improving interMediAte Risk management. MARK study

BackgroundCardiovascular risk functions fail to identify more than 50% of patients who develop cardiovascular disease. This is especially evident in the intermediate-risk patients in which clinical management becomes difficult. Our purpose is to analyze if ankle-brachial index (ABI), measures of arterial stiffness, postprandial glucose, glycosylated hemoglobin, self-measured blood pressure and presence of comorbidity are independently associated to incidence of vascular events and whether they can improve the predictive capacity of current risk equations in the intermediate-risk population.Methods/DesignThis project involves 3 groups belonging to REDIAPP (RETICS RD06/0018) from 3 Spanish regions. We will recruit a multicenter cohort of 2688 patients at intermediate risk (coronary risk between 5 and 15% or vascular death risk between 3-5% over 10 years) and no history of atherosclerotic disease, selected at random. We will record socio-demographic data, information on diet, physical activity, comorbidity and intermittent claudication. We will measure ABI, pulse wave velocity and cardio ankle vascular index at rest and after a light intensity exercise. Blood pressure and anthropometric data will be also recorded. We will also quantify lipids, glucose and glycosylated hemoglobin in a fasting blood sample and postprandial capillary glucose. Eighteen months after the recruitment, patients will be followed up to determine the incidence of vascular events (later follow-ups are planned at 5 and 10 years). We will analyze whether the new proposed risk factors contribute to improve the risk functions based on classic risk factors.DiscussionPrimary prevention of cardiovascular diseases is a priority in public health policy of developed and developing countries. The fundamental strategy consists in identifying people in a high risk situation in which preventive measures are effective and efficient. Improvement of these predictions in our country will have an immediate, clinical and welfare impact and a short term public health effect.Trial RegistrationClinical Trials.gov Identifier: NCT01428934

All-cause mortality in hemodialysis patients with heart valve calcification.

Calcification of the mitral and aortic valves is common in dialysis patients (CKD-5D). However, the prognostic significance of valvular calcification (VC) in CKD is not well established. 144 adult CKD-5D patients underwent bidimensional echocardiography for qualitative assessment of VC and cardiac computed tomography (CT) for quantification of coronary artery calcium (CAC) and VC. The patients were followed for a median of 5.6 years for mortality from all causes. Overall, 38.2% of patients had mitral VC and 44.4% had aortic VC on echocardiography. Patients with VC were older and less likely to be African American; all other characteristics were similar between groups. The mortality rate of patients with calcification of either valve was higher than for patients without VC. After adjustment for age, gender, race, diabetes mellitus, and history of atherosclerotic disease, only mitral VC remained independently associated with all-cause mortality (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.03 to 2.91). Patients with calcification of both valves had a two-fold increased risk of death during follow-up compared with patients without VC (HR, 2.16; 95% CI, 1.14 to 4.08). A combined CT score of VC and CAC was strongly associated with all-cause mortality during follow-up (HR for highest versus lowest tertile, 2.21; 95% CI, 1.08 to 4.54). VC is associated with a significantly increased risk for all-cause mortality in CKD-5D patients. These findings support the use of echocardiography for risk stratification in CKD-5D as recently suggested in the Kidney Disease Improving Global Outcomes guidelines.

Depression, Hypothalamic Pituitary Adrenal Axis, and Hippocampal and Entorhinal Cortex Volumes—The SMART Medea Study

Structural brain changes have often been found in major depressive disorder (MDD), and it is thought that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity may explain this relation. We investigated the association of MDD and history of depression with hippocampal and entorhinal cortex volumes and whether HPA axis activity explained this association. In 636 participants with a history of atherosclerotic disease (mean age 62 ± 9 years, 81% male) from the second Manifestation of ARTerial disease-Memory depression and aging (SMART-Medea) study, a 12-month diagnosis of MDD and history of depression were assessed. Age of first depressive episode was classified into early-onset depression (< 50 years) and late-onset depression (≥ 50 years). HPA axis regulation was assessed by four morning saliva samples, two evening samples, and one awakening sample after .5 mg dexamethasone. Hippocampus and entorhinal cortex volume were manually outlined on three-dimensional T1-weighted magnetic resonance images. General linear models adjusted for demographics, vascular risk, antidepressant use, and white matter lesions showed that ever having had MDD was associated with smaller hippocampal volumes but not with entorhinal cortex volumes. Remitted MDD was related to smaller entorhinal cortex volumes (p < .05). Participants with early-onset depression had smaller hippocampal volumes than those who were never depressed (p < .05), whereas participants with late-onset depression had smaller entorhinal cortex volumes (p < .05). HPA axis activity did not explain these differences. We found differential associations of age of onset of depression on hippocampal and entorhinal cortex volumes, which could not be explained by alterations in HPA axis regulation.

Low-Dose Aspirin Therapy in Patients With Type 2 Diabetes and Reduced Glomerular Filtration Rate

OBJECTIVEType 2 diabetes accompanied by renal damage is a strong risk factor for atherosclerotic events. The purpose of this study was to investigate the efficacy of low-dose aspirin therapy on primary prevention of atherosclerotic events in patients with type 2 diabetes and coexisting renal dysfunction.RESEARCH DESIGN AND METHODSThe Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial was a prospective, randomized, open-label trial conducted throughout Japan that enrolled 2,539 type 2 diabetic patients without a history of atherosclerotic diseases. Patients were assigned to the aspirin group (81 mg/day or 100 mg/day) or the nonaspirin group and followed for a median of 4.37 years. The primary end points were atherosclerotic events of fatal and nonfatal ischemic heart disease, stroke, and peripheral arterial disease.RESULTSThe analysis included 2,523 patients who had serum creatinine measured. In 1,373 patients with baseline estimated glomerular filtration rate (eGFR) 60–89 mL/min/1.73 m2, the incidence of primary end points was significantly lower in the aspirin group than in the nonaspirin group (aspirin, 30/661; nonaspirin, 55/712; hazard ratio 0.57 [95% CI 0.36–0.88]; P = 0.011). Low-dose aspirin therapy did not reduce primary end points in patients with eGFR ≥90 mL/min/1.73 m2 (aspirin, 9/248; nonaspirin, 11/270; 0.94 [0.38–2.3]) or those with eGFR <60 mL/min/1.73 m2 (aspirin, 29/342; nonaspirin, 19/290; 1.3 [0.76–2.4]). The Cox proportional hazard model demonstrated a significant interaction between mild renal dysfunction (eGFR 60–89 mL/min/1.73 m2) and aspirin (P = 0.02).CONCLUSIONSThese results suggest a differential effect of low-dose aspirin therapy in diabetic patients with eGFR 60–89 mL/min/1.73 m2.

Intakes of Vitamin B6 and Dietary Fiber and Clinical Course of Systemic Lupus Erythematosus: A Prospective Study of Japanese Female Patients

BackgroundIntakes of selected vitamins and dietary fiber may influence the clinical course of systemic lupus erythematosus (SLE). Using a cohort study method, we investigated the associations of dietary intake of vitamin B6 and B12, folate, and dietary fiber with the risk of active disease and atherosclerotic vascular events in SLE.MethodsThe study included female SLE patients in the Miyagi Lupus Cohort, which was founded in 1995. Dietary nutrients at baseline were estimated by a semiquantitative food frequency questionnaire. The association of each nutrient intake with the risk of active disease was investigated in 216 patients who had inactive disease at baseline. The association with atherosclerotic vascular events was assessed in 196 women who had inactive disease and no history of atherosclerotic diseases at baseline.ResultsForty-three cases of active disease were identified during 9966 person-months of follow-up (1995–1999). During 19 575 person-months of follow-up (1995–2005), 20 atherosclerotic vascular events were documented. The Cox proportional hazards model revealed an inverse association between vitamin B6 intake and the risk of active disease (hazard ratio for the highest as compared with the lowest tertile, 0.41; 95% confidence interval, 0.18–0.97; P for trend = 0.04). An inverse association was also found for dietary fiber intake (P for trend = 0.01). However, no significant association was observed between intakes of these nutrients and the risk of atherosclerotic vascular events.ConclusionsHigher intake of vitamin B6 and dietary fiber may prevent the occurrence of active disease in SLE.

Depression, stress, and risk for Alzheimer's disease

It has frequently been hypothesized that depression can cause Alzheimer's disease through hypersecretion of glucocorticoids, which would have deleterious effects on hippocampal structures. However, no large-scale studies in humans examined the direct relation between depression, hypothalamic-pituitary-adrenal (HPA) axis activity and hippocampal structures. The aim of this study was to examine the associations between depression, HPA-axis activity, and hippocampal and entorhinal cortex volumes. Cross-sectional analyses within 636 participants (mean age 62±9 years, 81% male) from the Second Manifestation of ARTerial disease-Memory depression and aging (SMART-Medea) study, an ancillary study to the SMART-MR study, aimed to investigate brain changes associated with psychosocial stressors in patients with a history of atherosclerotic disease. Twelve-month diagnosis of major depressive disorder (MDD), early-onset depression (EOD) (<50 years) and late-onset depression (LOD) (≥50 years) were assessed. HPA-axis activity was measured with 6 saliva samples, collected at awakening and 30, 45 and 60 minutes thereafter, and at 10PM and 11PM. Suppression of the HPA-axis was defined as the cortisol value at awakening after ingestion of 0.5 mg dexamethasone at 11PM. Volumetric measurements of the hippocampus and entorhinal cortex were performed on a 3-dimensional FFE T1-weighted 1.5 Tesla MRI scan with isotropic voxels. Regression models adjusted for demographics, vascular risk, antidepressant use and white matter lesions showed that MDD was not significantly associated with hippocampal or entorhinal cortex volumes. However, participants with EOD had significantly smaller hippocampal volumes than those never depressed, whereas participants with LOD had smaller entorhinal cortex volumes. Participants with higher evening cortisol levels and reduced suppression after dexamethasone had smaller hippocampal volumes. Higher evening cortisol levels were also associated with smaller right, but not left, entorhinal cortex volume. The cortisol awakening response was not significantly associated with hippocampal or entorhinal cortex volumes. Cortisol levels did not, however, explain the associations found between age of onset of depression with hippocampal or entorhinal cortex volumes. Although we found several associations between depression, HPA-axis activity, and hippocampal or entorhinal cortex volumes, from our studies it seems unlikely that hypersecretion of glucocorticoids is an explanation for the frequently observed association between depression, hippocampal atrophy, and Alzheimer's disease.

Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: Design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial

Thrombin potently activates platelets via interaction with the protease-activated receptor 1. SCH 530348 is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin via antagonism of the protease-activated receptor 1. Because SCH 530348 does not interfere with other pathways for hemostasis, it is possible that SCH 530348 reduces thrombosis with less increase in bleeding than do other potent antiplatelet agents. TRA 2 degrees P-TIMI 50 is a phase III, randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the efficacy and safety of SCH 530348 during long-term treatment of patients with established atherosclerotic disease receiving standard therapy (up to 27,000). Eligible patients with a history of myocardial infarction, ischemic stroke, or peripheral arterial disease are randomized 1:1 to SCH 530348 2.5 mg daily or matched placebo until the end of study. Randomization is stratified by the qualifying disease and planned use of a thienopyridine. The primary end point is the composite of cardiovascular death, myocardial infarction, stroke, or urgent coronary revascularization. The major secondary end point is the composite of cardiovascular death, myocardial infarction, or stroke. The evaluation of long-term safety includes bleeding defined by the GUSTO and TIMI criteria. Recruitment began in September 2007. The trial will continue until 2,279 primary end points and 1,400 secondary end points are recorded with expected completion in 36 to 44 months from first enrollment. TRA 2 degrees P-TIMI 50 is evaluating whether a new approach to platelet inhibition via interruption of thrombin-mediated platelet activation reduces major cardiovascular events with a favorable safety profile in patients with established atherosclerosis.