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1.  Prevalence of unrecognized diabetes, prediabetes and metabolic syndrome in patients undergoing elective percutaneous coronary intervention 
Background
Diabetes mellitus (DM) and metabolic syndrome are important targets for secondary prevention in cardiovascular disease. However, the prevalence in patients undergoing elective percutaneous coronary intervention is not well defined. We aimed to analyse the prevalence and characteristics of patients undergoing percutaneous coronary intervention with previously unrecognized prediabetes, diabetes and metabolic syndrome.
Methods
Data were collected from 740 patients undergoing elective percutaneous coronary intervention between November 2010 and March 2013 at a tertiary referral center. Prevalence of DM and prediabetes was evaluated using Haemoglobin A1c (A1c ≥ 6.5% for DM, A1c 5.7–6.4% for prediabetes). A modified definition was used for metabolic syndrome [three or more of the following criteria: body mass index ≥30 kg/m2; triglycerides ≥ 150 mg/dL; high density lipoprotein <40 mg/dL in men and <50 mg/dL in women; systolic blood pressure ≥ 130 mmHg and/or diastolic ≥ 85 mmHg; and A1c ≥ 5.7% or on therapy].
Results
Mean age was 67 years, median body mass index was 28.2 kg/m2 and 39% had known DM. Of those without known DM, 8.3% and 58.5% met A1c criteria for DM and for prediabetes at time of percutaneous coronary intervention. Overall, 54.9% met criteria for metabolic syndrome (69.2% of patients with DM and 45.8% of patients without DM).
Conclusion
Among patients undergoing elective percutaneous coronary intervention, a substantial number were identified with a new DM, prediabetes, and/or metabolic syndrome. Routine screening for an abnormal glucometabolic state at the time of revascularization may be useful for identifying patients who may benefit from additional targeting of modifiable risk factors.
doi:10.1002/dmrr.2646
PMCID: PMC4694566  PMID: 25728823
diabetes; prediabetes; metabolic syndrome; Haemoglobin A1c; glucose intolerance; cardiac catheterization
2.  Clinician Update: Duration of Anticoagulation for Venous Thromboembolic Events 
Circulation  2014;130(25):2343-2348.
Case Presentation
A 68 year-old woman with a history of hypertension, hyperlipidemia, and diverticulitis presents to your office for follow-up care. Three months ago, she developed 3 days of pain and swelling in her right calf and thigh. Lower extremity venous ultrasonography demonstrated a deep vein thrombosis in the right femoral vein. No identifiable cause was noted. She was started on therapeutic enoxaparin as a bridge to warfarin anticoagulation for idiopathic venous thromboembolism. Since discharge, her international normalized ratio (INR) has been maintained between 2 and 3. She has no history of prior bleeding or thromboembolic events. She wants to know how long to continue anticoagulation, and what she can do to minimize her risk of recurrent venous thromboembolism.
doi:10.1161/CIRCULATIONAHA.114.010456
PMCID: PMC4279444  PMID: 25539522
Venous thromboembolism; deep vein thrombosis; pulmonary embolism; recurrence; anticoagulation; extended duration; bleeding
3.  Metal Pollutants and Cardiovascular Disease: Mechanisms and Consequences of Exposure 
American heart journal  2014;168(6):812-822.
Introduction
There is epidemiological evidence that metal contaminants may play a role in the development of atherosclerosis and its complications. Moreover, a recent clinical trial of a metal chelator had a surprisingly positive result in reducing cardiovascular events in a secondary prevention population, strengthening the link between metal exposure and cardiovascular disease (CVD). This is, therefore, an opportune moment to review evidence that exposure to metal pollutants, such as arsenic, lead, cadmium, and mercury, are significant risk factors for CVD.
Methods
We reviewed the English-speaking medical literature to assess and present the epidemiological evidence that 4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiologic and mechanistic links to atherosclerosis and CVD. Moreover, we briefly review how the results of the Trial to Assess Chelation Therapy strengthen the link between atherosclerosis and xenobiotic metal contamination in humans.
Conclusions
There is strong evidence that xenobiotic metal contamination is linked to atherosclerotic disease and is a modifiable risk factor.
doi:10.1016/j.ahj.2014.07.007
PMCID: PMC4254412  PMID: 25458643
metal; myocardial infarction; atherosclerosis; oxidative stress; chelation
4.  Platelet Activation Increases in Patients Undergoing Vascular Surgery 
Thrombosis research  2014;134(5):952-956.
Background
Platelets are a major contributor to atherothrombosis and may contribute to the heightened risk of perioperative cardiovascular events. We sought to examine changes in platelet activity in subjects undergoing vascular surgery.
Methods
Platelet activity in 18 patients (median age 74, 45% female) undergoing non-emergent open vascular surgery was assessed by light transmission aggregometry in response to saline, epinephrine and adenosine-5 diphosphate (ADP), and by flow cytometric analysis of monocyte-platelet aggregation (MPA). Platelet activity was assessed preoperatively (T1), 1-hour into the operation (T2), 1-hour (T3), 24-hours (T4) and 48-hours post-operatively (T5). Data were compared using the Wilcoxon Signed Ranks Test. Continuous variables are summarized as medians and (interquartile, IQR) ranges.
Results
Spontaneous platelet aggregation increased transiently during the surgical period (T1-5.8% [2.4, 10.8], T2-13.5% [9.3, 26.5], T3-7.5% [3.3, 17], T4-10.0% [7.3, 16.3], T5-7.25% [4.5, 29.9], P=0.002). Similar trends in perioperative platelet activity were noted for platelet aggregation in response to epinephrine (P=0.035) and ADP (P=0.036). Using flow cytometry, we found an increase in MPA during the perioperative period (P=0.047), which was most significant between T1 and T3 (P=0.005).
Conclusions
Platelet activity increases significantly during and following open vascular surgery. This data may help explain the pathophysiology of increased thrombotic risk during the perioperative period of vascular surgery.
doi:10.1016/j.thromres.2014.08.009
PMCID: PMC4533998  PMID: 25208456
5.  B-type Natriuretic Peptides Improve Cardiovascular Disease Risk Prediction in a Cohort of Women 
BACKGROUND
While N-terminal pro–B-type natriuretic peptide (NT-proBNP) has a strong relationship with incident cardiovascular disease (CVD), few studies have examined whether NT-proBNP adds to risk prediction algorithms, particularly in women.
OBJECTIVES
We sought to evaluate the relationship between NT-proBNP and incident CVD in women.
METHODS
Using a prospective case-cohort within the Women’s Health Initiative Observational Study, we selected 1,821 incident cases of CVD (746 myocardial infarctions, 754 ischemic strokes, 160 hemorrhagic strokes, and 161 other cardiovascular [CV] deaths) and a randomly selected reference cohort of 1,992 women without CVD at baseline.
RESULTS
Median (interquartile range) levels of NT-proBNP were higher at study entry among incident cases (120.3 [68.1 to 219.5]) than among controls (100.4 [59.7 to 172.6]; p <0.0001). Women in the highest quartile of NT-proBNP (≥ 140.8 ng/l) were at 53% increased risk of CVD versus those in the lowest quartile after adjusting for traditional risk factors (1.53 [1.21 to 1.94]; p-trend: <0.0001). Similar associations were observed after adjustment for Reynolds Risk Score (RRS) covariables (1.53 [1.20 to 1.95] p-trend <0.0001); the association remained in separate analyses of CV death (2.66 [1.48 to 4.81]; p-trend <0.0001), myocardial infarction (1.39 [1.02 to 1.88] p-trend = 0.008), and stroke (1.60 [1.22 to 2.11), p-trend <0.0001). When added to traditional risk covariables, NT-proBNP improved the c-statistic (0.765 to 0.774; p = 0.0003), categorical net reclassification (0.08; p <0.0001), and integrated discrimination (0.0105; p <0.0001). Similar results were observed when NT-proBNP was added to the RRS.
CONCLUSIONS
In this multiethnic cohort of women with numerous cardiovascular events, NT-proBNP modestly improved measures of CVD risk prediction.
doi:10.1016/j.jacc.2014.04.089
PMCID: PMC4294182  PMID: 25443700
biomarkers; multiethnic; prevention; risk prediction
6.  Use of Medicare Data to Identify Coronary Heart Disease Outcomes In the Women's Health Initiative (WHI) 
Background
Data collected as part of routine clinical practice could be used to detect cardiovascular outcomes in pragmatic clinical trials, or in clinical registry studies. The reliability of claims data for documenting outcomes is unknown.
Methods and Results
We linked records of Women's Health Initiative (WHI) participants aged 65 years and older to Medicare claims data, and compared hospitalizations that had diagnosis codes for acute myocardial infarction (MI) or coronary revascularization with WHI outcomes adjudicated by study physicians. We then compared the hazard ratios for active versus placebo hormone therapy based solely on WHI adjudicated events with corresponding hazard ratios based solely on claims data for the same hormone trial participants.
Agreement between WHI adjudicated outcomes and Medicare claims was good for the diagnosis for MI (kappa = 0.71 to 0.74), and excellent for coronary revascularization (kappa=0.88 to 0.91). The hormone:placebo hazard ratio for clinical MI was 1.31 (95% confidence interval (CI) 1.03 to 1.67) based on WHI outcomes, and 1.29 (CI 1.00 to 1.68) based on Medicare data. The hazard ratio for coronary revascularization was 1.09 (CI 0.88 to 1.35) based on WHI outcomes and 1.10 (CI 0.89 to 1.35) based on Medicare data. The differences between hazard ratios derived from WHI and Medicare data were not significant in 1,000 bootstrap replications.
Conclusion
Medicare claims may provide useful data on coronary heart disease outcomes among patients aged 65 years and older in clinical research studies.
Clinical Trials Registration Information
www.clinicaltrials.gov, Trial Number NCT00000611
doi:10.1161/CIRCOUTCOMES.113.000373
PMCID: PMC4548886  PMID: 24399330
outcomes research; research design; randomized controlled trials
7.  Greater Frequency of Nut Consumption is Associated with Lower Prevalence of, Peripheral Arterial Disease 
Preventive medicine  2014;72:15-18.
Nut consumption has been associated with lower risk of coronary heart disease and all-cause mortality. The association between nut intake and peripheral arterial disease (PAD) is uncertain.
Objective
We sought to investigate the association between nut consumption and presence of prevalent PAD in a large cross-sectional sample.
Methods
Self-referred participants at >20,000 US sites who completed a medical and lifestyle questionnaire were evaluated by screening ankle brachial indices for PAD. Multivariable logistic regression analysis was used to estimate odds of PAD in different nut consumption categories.
Results
Among 3,312,403 individuals, mean age was 63.6 ±10.6 years and 62.8% were female. There were 219,527 cases of PAD. After multivariable adjustment there was an inverse association of nut intake with PAD. Compared to subjects with consumption of nuts
Conclusion
These observations suggest the need for more rigorous testing evaluating the role of nuts in PAD prevention.
doi:10.1016/j.ypmed.2014.12.014
PMCID: PMC4518851  PMID: 25532677
peripheral arterial disease; nuts; nutrition
Objective
While the relationship between physical activity and coronary heart disease is well characterized, a paucity of data exists regarding physical activity and vascular disease in other arterial territories. This study examined the prevalence of peripheral artery disease (PAD) and carotid artery stenosis (CAS) in association with physical activity.
Approach and Results
The association between physical activity and vascular disease was examined in more than 3 million self-referred US participants in the United States from 2003–2008 who completed a medical and lifestyle questionnaire in the Life Line screening program. All subjects were evaluated by screening ankle brachial indices <0.90 for PAD and ultrasound imaging for CAS >50%. Multivariable logistic regression modeling was used to estimate odds of disease. Among 3,250,350 subjects, 63% of the population engaged in some leisure time vigorous physical activity. After adjustment for age, sex, race/ethnicity, hypertension, hypercholesterolemia, smoking status, diabetes, body mass index and family history of cardiovascular disease, subjects who reported any physical activity had a significantly lower odds of PAD (OR 0.64, 95% CI 0.63 – 0.65) and CAS (OR 0.80, 95% CI 0.79 – 0.81). The association between physical activity with PAD and CAS was robust when stratified by sex, race and age categories. Physical activity intensity frequency was associated with lower PAD and CAS in a graded manner (p trend <0.0001 for both). Findings appeared unaffected by confounding by comorbidity or indication.
Conclusions
In a large population based study, higher levels of physical activity were independently associated with lower odds of vascular disease in the lower extremities and carotid arteries.
doi:10.1161/ATVBAHA.114.304161
PMCID: PMC4518860  PMID: 25359858
Diabetes Care  2014;37(6):1636-1642.
OBJECTIVE
The aim of this study was to investigate the relationship between diabetes and different phenotypes of peripheral vascular disease (lower extremity peripheral artery disease [PAD], carotid artery stenosis [CAS], and abdominal aortic aneurysm [AAA]).
RESEARCH DESIGN AND METHODS
Prevalence of vascular disease was evaluated in 3,696,778 participants of the Life Line Screening survey between 2003 and 2008. PAD was defined as ankle-brachial pressure index <0.90 or prior revascularization, CAS as ≥50% stenosis or prior revascularization, and AAA as infrarenal aortic diameter ≥3 cm or prior repair. Odds ratios (ORs) and 95% CIs were assessed using logistic regression modeling.
RESULTS
Diabetes mellitus was present in 10.8% of participants (n = 399,884). Prevalence of PAD, CAS, and AAA was significantly higher (P < 0.0001) in participants with compared with those without diabetes. After multivariate adjustment for baseline demographics and clinical risk factors, a significant interaction existed between diabetes and vascular disease phenotype (P < 0.0001). Diabetes was associated with increased odds of PAD (OR 1.42 [95% CI 1.41–1.4]; P < 0.0001) and CAS (1.45 [1.43–1.47]; P < 0.0001) but decreased odds of AAA (0.86 [0.84–0.88]; P < 0.0001). The strength of association increased with increasing severity of disease in each vascular phenotype, and this association persisted in the population with asymptomatic vascular disease.
CONCLUSIONS
In a large population-based study, the association between diabetes and vascular disease differed according to vascular phenotype. Future studies exploring the mechanism for these vascular-specific differences are needed.
doi:10.2337/dc13-2432
PMCID: PMC4030086  PMID: 24705616
Background and Purpose
Since the diagnosis and treatment of carotid artery disease may reduce the rate of stroke, the aim of this study was to determine whether a diet intervention was associated with incident carotid artery disease.
Methods
Participants were 48,835 postmenopausal women aged 50 to 79 years who were randomly assigned to either the intervention or comparison group in the WHI Diet Modification Trial. Incident carotid artery disease was defined as an overnight hospitalization with either symptoms or a surgical intervention to improve flow.
Results
After a mean follow-up of 8.3 years from 1994 – 2005, there were 297 (0.61%) incident carotid artery events. Contrasted to the comparison group, the risk of incident carotid disease did not differ from those assigned to the intervention group (HR: 1.08, 95% CI: 0.9 - 1.4). In secondary analysis, there was no significant effect of the intervention on the risk for incident carotid disease during the five years of post-intervention follow-up from 2005 to 2010 (1.24, 0.9 - 1.7) and no significant effect during cumulative follow-up from 1994 to 2010 (1.13, 0.9 – 1.4).
Conclusions
Among postmenopausal women, a dietary intervention aimed at reducing total fat intake and encouraging increased intake of fruit, vegetables and grains, did not significantly change the risk for incident carotid artery disease.
doi:10.1161/STROKEAHA.114.005096
PMCID: PMC4259099  PMID: 24743440
diet; carotid artery disease; trial; women
Background
The primary aim of the present study was to determine the cumulative effect of a set of peripheral artery disease (PAD) risk factors among age, gender and race/ethnicity groups in the United States.
Methods
We examined data from a nationally representative sample of the US population (National Health and Nutrition Examination Survey [NHANES], 1999–2004). A total of 7058 subjects 40 years or older that completed the interview, medical examination and had ankle–brachial index (ABI) measurements were included in this study.
Results
The age- and sex-standardized prevalence of PAD was 4.6 % (standard error [SE] 0.3%).The highest prevalence of PAD was observed among elderly, non-Hispanic Blacks and women. In a multivariable age-, gender- and race/ethnicity-adjusted model hypertension, diabetes, chronic kidney disease, and smoking were retained as PAD risk factors (p ≤ 0.05 for each). The odds of PAD increased with each additional risk factor present from a non-significant 1.5-fold increase (O.R 1.5, 95% confidence interval [CI] 0.9–2.6) in the presence of one risk factor, to more than ten-fold (OR 10.2, 95% CI 6.4–16.3) in the presence of three or more risk factors. In stratified analysis, non-Hispanic Blacks (OR 14.7, 95% CI 2.1–104.1) and women (OR 18.6, 95% CI 7.1–48.7) were particularly sensitive to this cumulative effect.
Conclusion
In a large nationally representative sample, an aggregate set of risk factors that included diabetes mellitus, chronic kidney disease, hypertension and smoking significantly increase the likelihood of prevalent PAD. A cumulative risk factor analysis highlights important susceptibility differences among different population groups and provides additional evidence to redefine screening strategies in PAD.
doi:10.1177/2047487312452968
PMCID: PMC4436703  PMID: 22739687
Peripheral arterial disease; risk assessment; traditional cardiovascular risk factors; NHANES
The American journal of cardiology  2014;113(9):1474-1480.
Peri-procedural hyperglycemia is an independent predictor of mortality in patients undergoing percutaneous coronary intervention (PCI). However, peri-procedural management of blood glucose is not standardized. The effects of routinely continuing long-acting glucose-lowering medications prior to coronary angiography with possible PCI on peri-procedural glycemic control have not been investigated. Patients with diabetes mellitus (DM) (n=172) were randomized to continue (Continue group; n=86) or hold (Hold group; n=86) their clinically prescribed long-acting glucose-lowering medications prior to procedure. The primary endpoint was glucose level on procedural access. In a subset of patients (no DM group, n=25, Continue group, n=25, and Hold group, n=25), selected measures of platelet activity that change acutely were assessed. Patients with DM randomized to the Continue group had lower blood glucose levels on procedural access compared with those randomized to the Hold group (117 [97–151] vs 134 [117–172] mg/dL, p=0.002). There were 2 hypoglycemic events in the Continue group and none in the Hold group, and no adverse events in either group. Selected markers of platelet activity differed across the no DM, Continue, and Hold groups (leukocyte platelet aggregates: 8.1% [7.2–10.4], 8.7% [6.9–11.4], 10.9% [8.6–14.7], p=0.007; monocyte platelet aggregates: 14.0% [10.3–16.3], 20.8% [16.2–27.0], 22.5% [15.2–35.4], p<0.001; soluble p-selectin: 51.9ng/mL [39.7–74.0], 59.1ng/mL [46.8–73.2], 72.2ng/mL [58.4–77.4], p=0.014). In conclusion, routinely continuing clinically prescribed long-acting glucose-lowering medications prior to coronary angiography with possible PCI helps achieve peri-procedural euglycemia, appears safe, and should be considered as a strategy for achieving peri-procedural glycemic control.
doi:10.1016/j.amjcard.2014.01.428
PMCID: PMC4018663  PMID: 24630791
hyperglycemia; diabetes mellitus; coronary angiography; percutaneous coronary intervention
Journal of Immunology Research  2014;2014:234316.
OxLDL/β2GPI complexes have been implicated in the initiation and progression of atherosclerosis and associated with disease severity and adverse outcomes. We investigate the significance of anti-oxLDL/β2GPI antibodies and oxLDL/β2GPI complexes in patients with arterial and idiopathic venous disease. A cohort of 61 arterial disease patients, 32 idiopathic venous disease patients, and 53 healthy controls was studied. Because statins influence oxLDL/β2GPI, these complexes were analyzed on subjects not taking statins. Arterial and venous groups expressed higher levels of IgG anti-oxLDL/β2GPI antibodies than controls without any other significant clinical association. OxLDL/β2GPI complexes were significantly elevated in arterial (0.69 U/mL, P = 0.004) and venous disease (0.54 U/mL, P = 0.025) than controls (0.39 U/mL). Among arterial diseases, oxLDL/β2GPI was 0.85 U/mL for carotid artery disease, 0.72 U/mL for peripheral artery disease, and 0.52 U/mL for abdominal aortic aneurysm. There was a significant association with male gender, age, hypertension, and history of thrombosis. Subjects with oxLDL/β2GPI above the median (0.25 U/mL) were more likely to have arterial (OR 4.5, P = 0.004) or venous disease (OR 4.1, P = 0.008). Multivariate regression indicated that males (P = 0.021), high cholesterol (P = 0.011), and carotid disease (P = 0.023) were significant predictors of oxLDL/β2GPI. The coexistence of oxLDL/β2GPI in arterial and venous disease may suggest a common oxidative mechanism that independently predicts carotid artery disease.
doi:10.1155/2014/234316
PMCID: PMC4227323  PMID: 25405208
Journal of the American College of Cardiology  2013;62(9):10.1016/j.jacc.2013.03.080.
Objectives
This study sought to perform a systematic review and meta-analysis to understand the role of stress cardiac magnetic resonance imaging (CMR) in assessing cardiovascular prognosis in patients with known or suspected coronary artery disease (CAD).
Background
Although stress CMR is excellent for the diagnosis of obstructive CAD, the prognostic value of stress CMR has been less well described.
Methods
PubMed, Cochrane CENTRAL, and metaRegister of Controlled Trials were searched for stress CMR studies with >6 months of prognostic data. Primary endpoints were cardiovascular death, myocardial infarction (MI), and a composite outcome of cardiovascular death or MI during follow-up. Summary effect estimates were generated with random-effects modeling, and annualized event rates were assessed.
Results
Nineteen studies (14 vasodilator, 4 dobutamine, and 1 that used both) involved a total of 11,636 patients with a mean follow-up of 32 months. Patients had a mean age of 63 ± 12 years, 63% were male, and 26% had previous MI; mean left ventricular ejection fraction was 61 ± 12%; and late gadolinium enhancement was present in 29% and ischemia in 32%. Patients with ischemia had a higher incidence of MI (odds ratio [OR]: 7.7; p < 0.0001), cardiovascular death (OR: 7.0; p < 0.0001), and the combined endpoint (OR: 6.5; p < 0.0001) compared with those with a negative study. The combined outcome annualized events rates were 4.9% for a positive versus 0.8% for a negative stress CMR (p < 0.0001), 2.8% versus 0.3% for cardiovascular death (p < 0.0001), and 2.6% versus 0.4% for MI (p < 0.0005). The presence of late gadolinium enhancement was also significantly associated with a worse prognosis.
Conclusions
A negative stress CMR study is associated with very low risk of cardiovascular death and MI. Stress CMR has excellent prognostic characteristics and may help guide risk stratification of patients with known or suspected CAD.
doi:10.1016/j.jacc.2013.03.080
PMCID: PMC3863376  PMID: 23727209
late gadolinium enhancement; myocardial perfusion; prognosis; stress cardiac MRI
Background
Mechanisms for increased cardiovascular risk in HIV-1-infected adults are incompletely understood, but platelet activation and immune activation leading to a prothrombotic state have been proposed as significant contributors. Aspirin has antiplatelet and immunomodulatory properties. We explored whether 1 week of low-dose aspirin attenuates platelet activation and immune activation in HIV-1-infected and virologically suppressed adults on antiretroviral therapy.
Methods
Platelet activation and immune activation were measured in HIV-1-infected subjects virologically suppressed on antiretroviral therapy and controls before and after 1 week of low-dose aspirin.
Results
Compared with control subjects, HIV-1-infected subjects had increased platelet activation, as measured by spontaneous platelet aggregation and aggregation in response to adenosine diphosphate, collagen, and arachidonic acid. After aspirin therapy, percent aggregation decreased similarly in both HIV-1-infected and control subjects to all platelet agonists tested except aggregation in response to arachidonic acid, which remained elevated in the HIV-1-infected group. HIV-1-infected subjects exhibited increased markers of T-cell activation (CD38 and HLA-DR) and monocyte activation (sCD14), which decreased after 1 week of aspirin therapy. Moreover, leukocyte responses to Toll-like receptor stimulation were enhanced after 1 week of aspirin therapy. In vitro studies showed that HIV-1 plasma could activate healthy platelets, which in turn activated monocytes, implicating a direct role for activated platelets in immune activation.
Conclusions
Our data demonstrate that heightened platelet activation and immune activation in treated HIV-1 disease are attenuated by 1 week of aspirin therapy. Aspirin should be further studied for its antithrombotic and immunomodulatory benefits in treated HIV-1 disease.
doi:10.1097/QAI.0b013e31828a292c
PMCID: PMC3756489  PMID: 23406976
platelets; HIV-1; aspirin; immune activation; aggregation
Platelets  2013;25(3):188-192.
Some studies suggest that mean platelet volume (MPV) correlates with increased risk for cardiovascular morbidity and mortality. In this study, we aim to assess reproducibility, need for standardized measurements, effect of aspirin, and association with other established markers of platelet activity. Following an overnight fast, 48 healthy volunteers had weekly assessment of platelet activity and were administered aspirin 81 mg daily for 7 d between weeks 3 and 4. We investigated the influence of time between phlebotomy and MPV measurement (n=10). Reproducibility was assessed by coefficient of variation (CV) and intraclass correlation coefficient (ICC). MPV measurements were reproducible (Week 1: 10.6 fL [9.9–11], Week 2: 10.6 fL [10.0–10.9], Week 3: 10.6 fL [9.8–11]). CV was ≤4% and ICC>0.85 (p<0.001) for each comparison, indicating excellent reproducibility. There was no effect of aspirin on MPV (10.6 fL [9.8–11] versus 10.5 fL [9.9–11]; p=0.81). MPV significantly increased as time between phlebotomy and MPV measurement increased (Spearman’s rho=0.94, p=0.001). Increasing MPV tertiles was associated with collagen- and thrombin receptor-activated peptide-induced platelet aggregation but not with ADP- or arachidonic acid-induced or spontaneous platelet aggregation. In conclusion, when standardized, MPV is a reproducible marker of platelet size and not affected by low-dose aspirin. MPV is modestly associated with some, but not all, markers of platelet activity.
doi:10.3109/09537104.2013.793794
PMCID: PMC3809021  PMID: 23786366
Aspirin; mean platelet volume; platelet aggregation
American heart journal  2013;165(3):427-433.e1.
Background
Thrombotic and bleeding complications are major concerns during orthopedic surgery. Given the frequency of orthopedic surgical procedures and the limited data in the literature, we sought to investigate the incidence and risk factors for thrombotic (myocardial necrosis and infarction) and bleeding events in patients undergoing orthopedic surgery.
Methods and Results
We performed a retrospective cohort analysis of 3,082 consecutive subjects ≥ 21 years of age undergoing hip, knee, or spine surgery between November 1, 2008, and December 31, 2009. Patient characteristics were ascertained using ICD-9 diagnosis coding and retrospective review of medical records, and laboratory/blood bank databases. In-hospital outcomes included myocardial necrosis (elevated troponin), major bleeding, coded myocardial infarction (MI), and coded hemorrhage as defined by ICD-9 coding. Of the 3,082 subjects, mean age was 60.8 ± 13.3 years and 59% were female. Myocardial necrosis, coded MI, major bleeding, and coded hemorrhage occurred in 179 (5.8%), 20 (0.7%), 165 (5.4%), and 26 (0.8%) subjects, respectively. Increasing age (P<0.001), CAD (P<0.001), cancer (P=0.004), and chronic kidney disease (P=0.01) were independent predictors of myocardial necrosis, while procedure type (P<0.001), cancer (P<0.001), female sex (P<0.001), CAD (P<0.001), and COPD (P=0.01) were independent predictors of major bleeding.
Conclusion
There is a delicate balance between thrombotic and bleeding events in the perioperative period following orthopedic surgery. Perioperative risk of both thrombosis and bleeding deserve careful attention in preoperative evaluation and future prospective studies aimed at attenuating this risk are warranted.
doi:10.1016/j.ahj.2012.11.005
PMCID: PMC3595114  PMID: 23453114
arterial thrombosis; major bleeding; perioperative management
The American journal of cardiology  2012;111(2):185-189.
Increased platelet activity is associated with adverse cardiovascular events. Mean platelet volume (MPV) correlates with platelet activity but the relationship between MPV and long-term mortalityin patients undergoing percutaneous coronary intervention(PCI) is not well established. Furthermore, the role of change in MPV over time has not been previously evaluated. We evaluatedMPV at baseline, 30 days, 60 days, 90 days, 1 year, 2 years, and 3 years post-procedure in 1,512 patients who underwent PCI. The speed of change in MPV was estimated using slope of linear regression. Mortality was determined by query of social security death index. Over a median of 8.7 years, mortality was 49.3% post-PCI. There was no significant difference in mortality when stratified by MPV quartiles (1stquartile 50.1%, 2nd quartile 47.7%, 3rd quartile 51.3%, 4thquartile 48.3%, p=0.74). In patients with available data to determine a change in MPV over time post-PCI (n=839), mortality was 49.1% and significantly higher in patients with an increase (52.9%) compared to those with a decrease (44.2%) or no change (49.1%) in MPV over time (p<0.0001). In conclusion, there was no association between baseline MPV and long-term mortality in patients undergoing PCI. However, there was increased mortality when MPV increasedover time post-PCI. Monitoring MPV after coronary revascularization may play a role in risk stratification.
doi:10.1016/j.amjcard.2012.09.014
PMCID: PMC3538911  PMID: 23102880
Mean platelet volume; percutaneous coronary intervention; long-term mortality
Thrombosis and haemostasis  2012;109(1):85-92.
Summary
The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics to platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modeling. Stimulation with submaximal (2 μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.
doi:10.1160/TH12-03-0202
PMCID: PMC3582386  PMID: 23223800
Platelets; platelet activity; serotonin; epinephrine; transporter
American heart journal  2011;161(5):972-978.
Objective
Subjects with peripheral artery disease (PAD) are at increased risk of cardiovascular morbidity and mortality, perhaps in part, related to increased levels of inflammation, platelet activity, and lipids. We therefore sought to investigate the relationship between PAD and levels of inflammatory, platelet, and lipid biomarkers and the treatment effect of darapladib, a novel lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor.
Methods
This is a post hoc analysis of the 959 patients with coronary disease or their risk equivalent receiving atorvastatin who were randomized to receive darapladib or placebo to examine the effects of an Lp-PLA2 inhibitor on the biomarkers of cardiovascular risk. We conducted an exploratory analysis evaluating the levels of biomarkers in subjects with PAD (n = 172) compared with those without PAD (n = 787).
Results
After adjustment for age, sex, smoking, body mass index, and diabetes, subjects with PAD had greater levels of matrix metalloproteinase-9 (between group comparisons 22%, 95% confidence interval [10–31], P < .01), myeloperoxidase (12% [2–20], P = .01), interleukin-6 (13% [4–21], P = .01), adiponectin (17% [7–26], P < .01), intercellular adhesion molecule-1 (7% [2–11], P < .01), osteoprotegrin (6% [1–10], P = .02), CD40 ligand (15% [1–28], P = .04), high-sensitivity C-reactive protein (17% [1–31], P = .04), and triglycerides (11% [0.2–21], P = .05). No significant difference was detected for Lp-PLA2 activity, P-selectin, urinary 11-dehydrothroboxane B2, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between subjects with and without PAD. Darapladib produced highly significant inhibition of Lp-PLA2 activity when compared with placebo at weeks 4 and 12 (P < .01) in patients with and without PAD.
Conclusions
Subjects with PAD had elevated levels of matrix metalloproteinase-9, myeloperoxidase, interleukin-6, adiponectin, intercellular adhesion molecule-1, osteoprotegrin, CD40 ligand, high-sensitivity C-reactive protein, and triglycerides compared with those without PAD. Darapladib, a novel Lp-PLA2 inhibitor, was equally effective in reducing Lp-PLA2 activity levels in subjects with and without PAD.
doi:10.1016/j.ahj.2011.01.017
PMCID: PMC3750980  PMID: 21570531
Atherosclerosis  2010;213(2):586-591.
Objectives
We sought to determine whether mean platelet volume (MPV) is associated with the prevalence of peripheral artery disease (PAD).
Background
Platelets play a pivotal role in the pathogenesis of atherosclerosis and PAD. MPV, a measure of platelet size available in every blood count, is increasingly recognized as an important marker of platelet activity.
Methods
We analyzed data from 6354 participants aged 40 years and older from the 1999 to 2004 National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. PAD was defined as an ankle brachial index ≤0.90 in either leg. Odds ratios and 95% confidence intervals were estimated by logistic regression.
Results
The prevalence of PAD in the cohort was 5.7%. MPV was significantly associated with PAD prevalence (tertile 1 – 4.4%, tertile 2 – 6.1%, tertile 3 – 7.0%, P for trend = 0.003). After adjustment for age, sex, and race, the odds ratio of PAD comparing the highest tertile to the lowest tertile was 1.57 (95% confidence interval 1.15–2.13). After further adjustment for smoking status, hypertension, hypercholesterolemia, diabetes, glomerular filtration rate, body mass index, and platelet count the corresponding odds ratio was 1.58 (95% confidence interval 1.14–2.19). The addition of triglycerides, hemoglobin A1c, and C-reactive protein did not affect the results. The significant association between MPV and PAD was unchanged when MPV was used as a continuous variable.
Conclusions
Mean platelet volume is independently associated with PAD. These findings support the hypothesis that platelet size is an independent predictor of increased risk for PAD.
doi:10.1016/j.atherosclerosis.2010.09.010
PMCID: PMC3739454  PMID: 20940069
Mean platelet volume; Platelets; Peripheral artery disease; Epidemiology
Diabetes Care  2012;35(5):1074-1078.
OBJECTIVE
The association between platelet activity, diabetes, and glucometabolic control is uncertain. We aim to investigate mean platelet volume (MPV), a marker of platelet size and platelet activity, with the prevalence of diabetes, metabolic syndrome, and degree of glycemic control.
RESEARCH DESIGN AND METHODS
This is a retrospective analysis of 13,021 participants in the National Health and Nutrition Examination Survey from 1999 to 2004. Prevalence of diabetes was defined as nonfasting glucose >200 mg/dL, fasting glucose ≥126 mg/dL, or treatment with hypoglycemic agents. Presence of metabolic syndrome was determined by the National Cholesterol Education Program Adult Treatment Panel III definition. Odds ratios and 95% CIs were estimated by logistic regression.
RESULTS
MPV was significantly higher in subjects with diabetes (8.20 vs. 8.06 femtoliter [fL], P < 0.01) but not in subjects with metabolic syndrome (8.09 vs. 8.07 fL, P = 0.24). For the metabolic syndrome components, MPV was significantly higher in abdominal obesity (P = 0.03) and low HDL (P = 0.04), and not different in high blood pressure (P = 0.07), abnormal glucose metabolism (P = 0.71), or hypertriglyceridemia (P = 0.46). There was a significant correlation between MPV and glucose (P < 0.0001) and between MPV and hemoglobin A1c (P < 0.0001) in subjects with diabetes. These correlations were no longer significant in those without diabetes. The adjusted odds of diabetes rose with increasing MPV levels and were most pronounced in subjects with MPV levels exceeding the 90th percentile (≥9.31 fL). The association between MPV and diabetes was most apparent in those with the poorest glucose control.
CONCLUSIONS
Mean platelet volume is strongly and independently associated with the presence and severity of diabetes.
doi:10.2337/dc11-1724
PMCID: PMC3329806  PMID: 22410814
Background
Few studies simultaneously investigated lipids and lipoprotein biomarkers as predictors of ischemic stroke. The value of these biomarkers as independent predictors of ischemic stroke remains controversial.
Methods
We conducted a prospective nested case-control study among postmenopausal women from the Women’s Health Initiative Observational Study to assess the relationship between fasting lipids (total cholesterol, LDL-C, HDL-C, and triglycerides), lipoproteins (LDL, HDL and VLDL particle number and size, IDL particle number, and lipoprotein [a]) and risk of ischemic stroke. Among women free of stroke at baseline, 774 ischemic stroke patients were matched according to age and race to controls using a 1:1 ratio.
Results
In bivariate analysis, baseline triglycerides (P<0.001), IDL particles (P<0.01), LDL particles (P<0.01), VLDL triglyceride (P<0.001), VLDL particles (P<0.01), VLDL size (P<0.001), LDL size (P=0.03), and total/HDL cholesterol ratio (P<0.01) were significantly higher among women with incident ischemic stroke, while levels of HDL-C (P<0.01) and HDL size (P<0.01) were lower. No significant baseline difference for total cholesterol (P=0.15), LDL-C (P=0.47), and lipoprotein (a) (P=0.11) was observed. In multivariable analysis, triglycerides, (OR for the highest vs lowest quartile, 1.56; 95% CI, 1.13-2.17, P for trend =0.02), VLDL size (OR 1.59, 95% CI, 1.10-2.28, P for trend =0.03) and IDL particle number (OR 1.46, 95% CI, 1.04-2.04, P for trend =0.02) were significantly associated with ischemic stroke.
Conclusion
Among a panel of lipid and lipoprotein biomarkers, baseline triglycerides, VLDL size and IDL particle number were significantly associated with incident ischemic stroke in postmenopausal women.
doi:10.1161/STROKEAHA.111.641324
PMCID: PMC3547588  PMID: 22308251
Lipids; Lipoproteins; Ischemic Stroke; Women; Triglycerides

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