Peripheral artery disease, biomarkers, and darapladib

Abstract

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.

Biological variation of established and novel biomarkers for atherosclerosis: Results from a prospective, parallel-group cohort study

“…In contrast to our results, de Maat and coworkers reported no difference in within-subject-and betweensubject variation of CRP and PAI-I between a group of healthy young adults versus patients with clinically stable angina pectoris [56]. These conflicting results might be explained by the higher inflammatory activity in patients with PAD than in patients with coronary disease as reported by Berger and coworkers [15].…”

“…A pathophysiological explanation for this observation could be subclinical inflammatory bouts as a marker of plaque instability [3]. Interestingly, Berger and coworkers reported in a cohort of patients with coronary artery disease or its risk equivalent, that those patients with concomitant PAD had higher levels of hs-CRP, IL-6, MMP-9, ICAM-1 than patients without PAD [15]. These biomarkers are likely to be of particular importance in the pathophysiology of atherosclerotic PAD and might therefore be of particular interest for diagnosis, subclinical disease monitoring or prognostic stratification [24,55].…”

“…In a cohort of patients with coronary artery disease, those with concomitant PAD had higher inflammatory biomarkers than those without PAD [15]. The risk of cardiovascular events in PAD patients is 2 to 4 times higher compared to those without PAD, even after adjustment for the Framingham risk score [16].…”

Association between arterial stiffness and peripheral artery disease as measured by radial artery tonometry

“…Finally, many of the biomarkers associated with stiffness are also associated with PAD, such as CRP, osteoprotegrin, and MMP-9. 27, 34, 35 …”

Fasting Serum Long-Acting Natriuretic Peptide Correlates With the Ankle Brachial Index in Renal Transplant Recipients

“…Peripheral artery disease patients also had elevated serum levels of triglyceride compared with those without PAD. [17][18][19] A higher serum triglyceride level has been shown to be associated with a low ABI value in asymptomatic patients between 50 and 70 years of age. 20 Our results also identified higher serum total cholesterol and higher triglyceride levels in the low ABI group, and the serum triglyceride level was negatively correlated with the ABI value for renal transplant recipients.…”