Serum Angiopoietin–Like Protein 2 Is a Novel Risk Factor for Cardiovascular Disease in the Community

Abstract

Objective-Angiopoietin-like protein 2 (ANGPTL2), a proinflammatory mediator, has been reported to accelerate the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. However, no cohort studies have examined the relationship between serum ANGPTL2 levels and the development of cardiovascular disease (CVD) in a general population. Approach and Results-A total of 3005 community-dwelling Japanese aged ≥40 years without a history of CVD were divided into 4 groups according to the quartiles of serum ANGPTL2 concentrations (Q1, lowest and Q4, highest) and followed up for 10 years. The hazards ratios and their 95% confidence intervals for the development of CVD (coronary heart disease or stroke) were estimated using a Cox proportional hazards model. During the follow-up, 219 first-ever CVD events were observed. The risk of CVD increased significantly with elevating ANGPTL2 levels after adjustment for age, sex, serum total cholesterol, use of lipid-lowering agents, ECG abnormalities, smoking habits, alcohol intake, and regular exercise (hazards ratios [ Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. ResultsThe baseline characteristics of the study population according to the quartiles of serum ANGPTL2 concentrations are shown in Table 1. The mean values of age, waist circumference, body mass index, systolic and diastolic blood pressures, fasting plasma glucose, and serum levels of low-density lipoprotein cholesterol, triglycerides, and hs-CRP increased significantly with elevating serum ANGPTL2 levels. The subjects with higher serum ANGPTL2 levels had significantly higher frequencies of antihypertensive medication, antidiabetic medication, lipid-lowering medication, ECG abnormalities, regular exercise, metabolic syndrome, and its components. In contrast, the mean values of serum high-density lipoprotein cholesterol and frequencies of current smoking and drinking decreased significantly with higher serum ANGPTL2 levels. Serum ANGPTL2 levels did not show a clear association with sex and total cholesterol levels. Figure I in the online-only Data Supplement shows the distributions of baseline serum ANGPTL2 concentrations in subjects with and without CVD events during the follow-up. The distribution of serum ANGPTL2 in subjects with CVD was significantly higher than in those without CVD (P<0.001). Figure demonstrates the age-and sex-adjusted incidence rates of CVD and its subtypes according to the serum ANGPTL2 levels. The incidence rates of total CVD and coronary heart disease increased significantly with elevating serum ANGPTL2 levels (P for trend=0.005 and 0.01, respectively). A similar but nonsignificant trend was observed for the incidence rate of stroke (P for trend=0.07). Table 2 and Figure II in the online-only Data Supplement show the hazard ratios (HRs) for the development of CVD and its subtypes according to the serum ANGPTL2 levels. In model 1 with adjustment for age and sex, higher serum ANGPTL2 levels were significantly associated...

ANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism

“…9e ). On the other hand, to date we and others have independently reported that circulating ANGPTL2 levels increase in various pathological conditions other than obesity accompanied by adipose tissue inflammation, such as atherosclerotic vascular disease and type 2 diabetes and that these levels are associated with disease severity 17 20 39 40 41 . Because, some of these conditions are risk factors for HF development, further studies are needed to investigate whether circulating ANGPTL2 affects cardiac function.…”

ANGPTL2 ― A New Causal Player in Accelerating Heart Disease Development in the Aging ―

“…21,29-35, 56 We found that serum ANGPTL2 levels are associated with obesity, as estimated by body mass index and abdominal circumference, in the general Japanese population. 17 Moreover, in overweight Japanese subjects, decreased serum ANGPTL2 levels reflect positive effects of lifestyle intervention in terms of weight loss and improved metabolic parameters, such as triglyceride (TG) and/or insulin activity and the homeostasis model assessment-insulin resistance (HOMA-IR) index.…”

“…59 A 10-year follow-up in an epidemiological study of the general Japanese population with no history of CVD revealed that elevated serum ANGPTL2 levels correlated with future de novo development of CVD, independent of risk factors such as high hs-CRP levels. 56 Moreover, in a prospective, monocentric cohort of European patients with type 2 diabetes but without end-stage renal disease (followed for a median of 6.0 years with death as a primary endpoint and major adverse CV events (known as MACE) such as death, myocardial infarction or stroke as a secondary endpoints), serum ANGPTL2 concentrations were independently associated with death and MACE. 60 Taken together with observations suggesting that ANGPTL2 promotes CVD development and progression in mice, 25 circulating ANGPTL2 levels could be viewed as a candidate biomarker for risk stratification relevant to CVD development and progression in both type 2 diabetic patients and…”

Endothelial Functions

“…In the Hisayama cohort study including 3005 Japanese general population aged ≥40 from 1988, serum levels of angiopoietin-like protein 2-a proinflammatory mediator that promotes endothelial dysfunction-were positively correlated with the risk for future cardiovascular disease. 78 Saita et al 79 showed that plasma levels of soluble endoglin-a transforming growth factor-β receptor highly expressed on proliferating endothelial cells-were inversely associated with the severity of coronary artery disease. Given that conflicting results have been reported earlier in diabetic patients, 80 whether endoglin can serve as a biomarker for coronary artery disease awaits further investigation.…”