Luis H. Eraso

Mean platelet volume and prevalence of peripheral artery disease, the National Health and Nutrition Examination Survey, 1999-2004

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.

Peripheral arterial disease, prevalence and cumulative risk factor profile analysis

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.

Association of Lower Plasma Fetuin-A Levels with Peripheral Arterial Disease in Type-2 Diabetes

OBJECTIVE Fetuin-A is an inhibitor of vascular calcification and a mediator of insulin resistance. This study evaluated the association of plasma fetuin-A and peripheral arterial disease (PAD). RESEARCH DESIGN AND METHODS A total of 738 individuals with type 2 diabetes (mean age 58.7 years, 37.1% female) without known cardiovascular or kidney disease were included in this cross-sectional analysis. RESULTS Subjects with PAD had a significantly lower fetuin-A (264.3 vs. 293.4 ng/dl, P < 0.001). In multivariable analysis, a 1-SD decrease in fetuin-A increased the odds of PAD (odds ratio 1.6, P = 0.02). Subgroup analysis revealed an increased odds even in subjects with glomerular filtration rate >80 (odds ratio 1.9, P = 0.05) or high-sensitivity C-reactive protein <3 mg/dl (odds ratio 2.7, P = 0.002). CONCLUSIONS Lower circulating fetuin-A is associated with PAD in type 2 diabetes beyond traditional and novel cardiovascular risk factors. Our findings suggest a potentially unique role for fetuin-A deficiency as a biomarker of PAD in patients with type 2 diabetes.

Implications of new anticoagulants in primary practice

Background:  Effective prophylaxis and treatment of thromboembolic disorders remain suboptimal in many healthcare systems, partly owing to limitations of traditional anticoagulants. New oral anticoagulants have been developed and among these, rivaroxaban, apixaban and dabigatran etexilate are in the most advanced stage of clinical development.

Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium

BACKGROUND Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI. METHODS AND RESULTS We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance. RESULTS In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. CONCLUSIONS Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

Non-compressible arterial disease and the risk of coronary calcification in type-2 diabetes

OBJECTIVE Ankle-brachial index (ABI) screening is recommended for the detection of asymptomatic peripheral arterial disease (PAD) in at-risk populations, including diabetics. A low ABI identifies obstructive lower extremity vascular disease and predicts CVD events and increased mortality. A high ABI represents non-compressible arterial disease (NCAD), and is also associated with increased mortality and vascular events. Our objective is to investigate whether low and high ABI have distinct patterns of association with cardiovascular disease (CVD) risk factors and subclinical atherosclerosis in individuals with type-II diabetes mellitus. METHODS The Penn Diabetes Heart Study (PDHS) is a prospective observational cohort of diabetic individuals without clinically evident CVD. Multivariate logistic and Tobit linear regression were used to compare CVD risk factors and coronary artery (CAC) among 1863 subjects with PAD (ABI ≤ 0.9), NCAD (ABI ≥ 1.4 or non-compressible) or normal ABI (0.91-1.39). RESULTS Compared to those with normal ABI, PAD was associated with smoking, obesity, and lower HDL-c; while diabetes duration and reduced renal function were associated with NCAD. Both PAD and NCAD were independently associated with increased CAC compared to those with normal ABI, and these relationships were not attenuated in multiply adjusted models. CONCLUSION NCAD bears a distinct relationship to traditional CVD risk factors among diabetics, though like PAD is independently associated with increased CAC. These findings support the recognition of NCAD as a high-risk phenotype and provide additional relevance to ABI screening in diabetics.

Evaluation of trans sodium crocetinate on safety and exercise performance in patients with peripheral artery disease and intermittent claudication

Trans sodium crocetinate (TSC) is a synthetic carotenoid that improves the diffusion of oxygen in animal models of ischemia/hypoxia. This study evaluated multiple doses of TSC in patients with peripheral artery disease (PAD) and hypothesized that a preliminary dose–response relationship could be identified on peak walking time (PWT). Forty-eight patients with symptomatic PAD and an ankle–brachial index < 0.90 were included, while critical limb ischemia, recent revascularization, and exercise limited by symptoms other than claudication were exclusionary. Patients were randomized to placebo or eight dosing levels of TSC ranging from 0.25 mg/kg to 2.0 mg/kg given intravenously once daily for 5 days. Subjects were tested on a graded treadmill protocol to claudication-limited PWT with the change to Day 5 as primary. A cubic regression was fit to detect a pre-specified inverted U-shaped dose–response relationship (65% power). Patient-reported walking distance from the Walking Impairment Questionnaire was a secondary endpoint. Adverse events were not predominant on any drug dose relative to placebo. Changes in PWT demonstrated a cubic trend for dose (p = 0.07, r = 0.39, r2 = 0.15) with morphologic signals of benefit at doses above 1.00 mg/kg after both the first and fifth dosing days. Similar improvements occurred with the walking distance score at doses above 1.00 mg/kg. In conclusion, TSC was safe and well tolerated at all doses. Notable signals of benefit were observed at higher doses for both PWT and patient-perceived walking distance. These results support a phase II study to define the optimal dose for longer-term therapy with TSC. Clinical Trial Registration – URL:http://www.clinicaltrials.gov. Unique identifier: NCT00725881

Emerging diagnostic and therapeutic molecular imaging applications in vascular disease

Assessment of vascular disease has evolved from mere indirect and direct measurements of luminal stenosis to sophisticated imaging methods to depict millimeter structural changes of the vasculature. In the near future, the emergence of multimodal molecular imaging strategies may enable robust therapeutic and diagnostic (‘theragnostic’) approaches to vascular diseases that comprehensively consider structural, functional, biological and genomic characteristics of the disease in individualized risk assessment, early diagnosis and delivery of targeted interventions.This review presents a summary of recent preclinical and clinical developments in molecular imaging and theragnostic applications covering diverse atherosclerosis events such as endothelial activation, macrophage inflammatory activity, plaque neovascularization and arterial thrombosis. The main focus is on molecular targets designed for imaging platforms commonly used in clinical medicine including magnetic resonance, computed tomography and positron emission tomography. A special emphasis is given to vascular ultrasound applications, considering the important role this imaging platform plays in the clinical and research practice of the vascular medicine specialty.

Hemorrhagic bullous dermatosis: a rare heparin-induced cutaneous manifestation

ABSTRACT Heparin is one of the most widely prescribed medications. Cutaneous reactions distant to the injection site are rare and under-reported in the literature. We present an elderly man with history of CNS lymphoma who underwent treatment of a deep venous thrombosis with enoxaparin and subsequently developed well demarcated bullous lesions within days of heparin initiation. The exact pathophysiology is not well understood. Hemorrhagic bullous dermatosis is a rare cutaneous reaction that is temporally associated with the initiation of heparin products. The handful of cases thus far suggest that regression of these seemingly benign lesions may or may not be associated with dose reduction or discontinuation of heparin products and typically occur within a few weeks. Elderly age appears to be one potential risk factor for development of these rare asymptomatic lesions. Malignancy may have some contributing factor and differentiation between this rare cutaneous manifestation from heparin products and other dermatological findings in patients with malignancy is key. Because of the asymptomatic and self-limiting nature of hemorrhagic bullous dermatoses in the setting of heparin product use, we presume that the reported incidence does not reflect true clinical practice.

Ascending and descending thoracic aorta calcification in type 2 diabetes mellitus

BACKGROUND Calcification of the thoracic aorta is a risk factor for cardiovascular disease and peripheral arterial disease but has not been well studied in diabetics. In addition, many studies consider aortic calcium as a single anatomic entity, whereas calcification of the ascending and descending portions of the thoracic aorta may represent separate phenotypes. We sought to characterize the prevalence of ascending and descending aortic calcium among diabetics and to assess their associations with cardiovascular risk factors, coronary artery calcium, and peripheral arterial disease. METHODS Within the Penn Diabetes Heart Study, a cross-sectional study of subjects with type 2 diabetes mellitus but without coronary or renal disease, we quantified Agatston scores of the ascending and descending thoracic aorta in 1739 subjects (63% male, 61% Caucasian). Multivariate logistic and Tobit regressions were used to assess associations with cardiovascular risk factors, coronary calcium, and peripheral arterial disease. RESULTS Of all subjects, 54% had thoracic aortic calcium; of these, 37% had calcium solely in the ascending thoracic aorta and 20% solely in the descending thoracic aorta. In multivariate regression, age, Caucasian race, systolic blood pressure, low-density lipoprotein cholesterol, smoking, and diabetes duration were independently associated with calcium of both the ascending and descending thoracic aorta (P < .001 for all). Ascending and descending aortic calcium were each independently associated with coronary calcium in multivariate regression, but only calcification of the descending thoracic aortic was associated with low ankle-brachial index. CONCLUSION Ascending and descending thoracic aortic calcium have similar associations with traditional cardiovascular risk factors in diabetics and are independently associated with coronary artery calcium. Only calcium in the descending aorta is associated with peripheral arterial disease. Delineation of both phenotypes may provide information about the individualized vascular disease and risk profile of patients with type 2 diabetes mellitus.