Novel Plasma Biomarkers Associated with Future Peripheral Atherosclerotic Disease and Abdominal Aortic Aneurysm-Insights from Contemporary Prospective Studies from the Malmö Diet and Cancer Study.

INTRODUCTION: The potential utility of inflammatory and hemodynamic plasma biomarkers for the prediction of incident lower extremity arterial disease (LEAD), carotid artery stenosis (CAS), isolated atherosclerotic disease without concomitant abdominal aortic aneurysm (AAA), and isolated AAA without concomitant atherosclerotic disease has not yet been integrated in clinical practice. The main objective of this prospective study was to find predictive plasma biomarkers for cardiovascular disease and to evaluate differences in plasma biomarker profiles between asymptomatic and symptomatic CAS, as well as between isolated atherosclerotic disease and isolated AAA. METHODS: Blood samples collected at baseline from participants in the prospective Malmö Diet and Cancer study (MDCS) cardiovascular cohort (n = 5550 middle-aged individuals; baseline 1991-1994) were used for plasma biomarker analysis. Validation of each incident cardiovascular diagnosis was performed by random sampling. Cox regression analysis was used to calculate hazard ratios (HRs) per one standard deviation increment of each respective log-transformed plasma biomarker with 95% confidence intervals (CI). RESULTS: Adjusted lipoprotein-associated phospholipase A2 (Lp-PLA2) activity (HR 1.33; CI 1.17-1.52) and mass (HR 1.20; CI 1.05-1.37), C-reactive protein (CRP) (HR 1.55; CI 1.36-1.76), copeptin (HR 1.46; CI 1.19-1.80), N-terminal pro-B-type natriuretic peptide (N-BNP) (HR 1.28; 1.11-1.48), and cystatin C (HR 1.19; 95% 1.10-1.29) were associated with incident symptomatic LEAD. Adjusted N-BNP (HR 1.59; CI 1.20-2.11), mid-regional proadrenomedullin (HR 1.40; CI 1.13-1.73), cystatin C (HR 1.21; CI 1.02-1.43), and CRP (HR 1.53; CI 1.13-1.73) were associated with incident symptomatic but not asymptomatic CAS. Adjusted HR was higher for Lp-PLA2 (mass) for incident isolated AAA compared to for isolated atherosclerotic disease. CONCLUSIONS: Plasma biomarker profile data support that subclinical vascular inflammation and cardiovascular stress seem to be relevant for the development of atherosclerotic disease and AAA.

A population-based study on hyperinsulinaemia and arterial stiffness in men with and without abdominal aortic aneurysm.

Objectives: Patients with type 2 diabetes mellitus (DM) run lower risk for abdominal aortic aneurysm (AAA, aortic diameter ≥ 30 mm) and its complications. We aimed to evaluate associations between disturbances in glucose metabolism and arterial stiffness, AAA, and abdominal aortic diameter in 65-year-old men. Methods: Forty-eight 65-year-old men with screening-detected AAA and 115 men with normal abdominal aortic diameter underwent examination of glucose metabolism and arterial stiffness. Results: Men with AAA had higher BMI, waist-hip ratio (WHR), frequency of DM, haemoglobin A1c, smoking exposure, and plasma insulin levels at 0, 60 and 120 min during OGTT compared to those without. The increase in p-insulin (P < 0.001) after OGTT was also higher in men with AAA, adjusted for smoking, WHR, and nadir value of p-insulin. In analyses adjusted for smoking, use of lipid-lowering agents, and WHR, the increase in p-insulin at 2-hours (P = 0.006) after OGTT and p-homocysteine were associated with abdominal aortic diameter. There were no differences between groups in aortic stiffness or skin autofluorescence Advanced Glycation End products. Conclusion: In this population-based study hyperinsulinaemia as a marker of insulin resistance, but not hyperglycaemia or aortic stiffness, was associated with AAA and abdominal aortic diameter in 65-year-old men.

Circulating Biomarkers Predict Symptomatic but Not Asymptomatic Carotid Artery Stenosis.

BACKGROUND: Subjects exposed to risk factors such as age, gender, hypertension, diabetes mellitus, and smoking are prone to atherosclerotic events. AIMS: The main aim of this longitudinal cohort study was to determine whether the role of novel plasma biomarkers for atherosclerotic carotid artery disease is different in subjects developing symptomatic carotid artery stenosis (CAS), as opposed to those with incident asymptomatic CAS. METHODS: The following biomarkers were measured in 5,550 middle-aged subjects in a population-based cohort study: C-reactive protein (CRP), lipoprotein-associated phospholipase A2 mass and activity, proneurotensin, midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), N-terminal pro-B-type natriuretic peptide (NT pro-BNP), copeptin, and cystatin C. After exclusion of those with prevalent CAS, subjects were thereafter followed in national patient registers for 23.4 (interquartile range 19.5-24.3) years regarding incident symptomatic and asymptomatic CAS. RESULTS: Among 110 patients with confirmed incident CAS, 56 were symptomatic and 54 were asymptomatic. When including conventional risk markers in a Cox regression analysis, NT pro-BNP (hazard ratio [HR] 1.59; 95% confidence interval [CI]: 1.20-2.11), MR-proADM (HR 1.40; CI: 1.13-1.73), cystatin C (HR 1.21; CI: 1.02-1.43), and CRP (HR 1.53; CI: 1.13-1.73) were independently associated with incident symptomatic CAS, whereas no plasma biomarker was associated with incident asymptomatic CAS. CONCLUSION: Plasma biomarkers NT pro-BNP, MR-proADM, cystatin C, and CRP were independently associated with incident symptomatic CAS, whereas no such association could be demonstrated with incident asymptomatic CAS. As these biomarkers indicate future development of clinically relevant atherosclerotic CAS, their potential utility in relation to intensified preventive measures and selection of potential candidates for carotid surgery should be further evaluated.

Vasoactive Biomarkers Associated With Long-Term Incidence of Symptomatic Peripheral Arterial Disease and Mortality.

We evaluated if plasma biomarkers can predict incident peripheral arterial disease (PAD) and mortality in a longitudinal cohort study. Men (n = 3618) and women (n = 1542) were included in the Malmö Preventive Project and underwent analysis of: C-terminal endothelin-1 (CT-proET-1), N-Terminal prosomatostatin (NT-proSST), midregional proatrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and copeptin. Participants were followed up for incident PAD and mortality until December 31, 2016. Median follow-up was 11.2 years (interquartile range 9.4-12.2). Cumulative incidence of PAD was 4.3% (221/5160), 4.5% in men (164/3618) and 3.7% in women (57/1542; P = .174). In an adjusted Cox proportional hazards regression model, higher CT-proET-1 (hazard ratio [HR] 1.8; 95% confidence interval [CI] 1.4-2.3), NT-proSST (HR 1.5; 95% CI 1.2-2.0), and MR-proANP (HR 1.7; 95% CI 1.3-2.3) were independently associated with incident PAD, and higher CT-proET-1 (HR 1.3; 95% CI 1.2-1.5), NT-proSST (HR 1.2; 95% CI 1.1-1.3), MR-proANP (HR 1.4; 95% CI 1.3-1.6), PCT (HR 1.1; 95% CI 1.0-1.2), and copeptin (HR 1.2; 95% CI 1.1-1.4) were independently associated with mortality. Increased levels of CT-proET-1, NT-proSST, and MR-proANP were independently associated with incident PAD, whereas all the vasoactive biomarkers were independently associated with mortality during follow-up.

Prospective Comparison of Plasma Biomarker and Traditional Risk Factor Profiles for Incident Isolated Atherosclerotic Disease and Incident Isolated Abdominal Aortic Aneurysm.

Background: Traditional risk factors for atherosclerotic disease (AD) are well-known, of which some are relevant also for abdominal aortic aneurysms (AAA). The present study compares the importance of plasma biomarkers and traditional risk factor profiles for incident AD without concomitant AAA (isolated AD) and AAA without concomitant AD (isolated AAA) during long-term follow-up. Methods: In the Malmö Diet and Cancer Study-cardiovascular cohort, 5,381 participants were free from atrial fibrillation or flutter, AD (coronary artery disease, atherothrombotic ischemic stroke, carotid artery disease, or peripheral artery disease), and AAA underwent blood sampling under standardized fasting conditions between 1991 and 1994. Cox proportional hazards regression analysis was used to calculate hazard ratios (HR) with 95% CIs. Results: During a median follow-up of 23.1 years, 1,152 participants developed isolated AD, and 44 developed isolated AAA. Adjusted HR for lipoprotein-associated phospholipase A2 (mass) (HR 1.53, 95% CI 1.14-2.04 vs. HR 1.05, 95% CI.99-1.12) was higher for incident isolated AAA compared to incident isolated AD, respectively. Mid-regional pro-adrenomedullin (MR-proADM) was associated with incident isolated AD (HR 1.17, 95% CI 1.1-1.25) and incident isolated AAA (HR 1.47, 95% CI 1.15-1.88). MR-proADM was correlated (r = 0.32; p < 0.001) to body mass index (BMI), and BMI was associated with increased risk of incident isolated AAA (HR 1.43, 95% CI 1.02-2). No participant with diabetes mellitus (DM) at baseline developed isolated AAA (0/44), whereas DM was associated with an increased risk of isolated AD (HR 2.57, 95% CI 2.08-3.18). Adjusted HR for male sex (HR 4.8, 95% CI 2.42-9.48, vs. HR 1.76, 95% CI 1.56-1.98) and current smoking (HR 4.79, 95% CI 2.42-9.47 vs. HR 1.97, 95% CI 1.73-2.23) were higher in the incident isolated AAA group compared to the incident isolated AD group, respectively. Conclusions: The data supports the view that components of vascular inflammation and cardiovascular stress drives AAA development, whereas glycated cross-links in abdominal aortic wall tissue may have a plausible role in reducing AAA risk in individuals with DM.

Pro B-type Natriuretic Peptide and Midregional Proadrenomedullin are Associated with Incident Carotid Stenosis During Long Term Follow-up.

BACKGROUND: Plasma biomarkers may be useful to detect healthy individuals at increased risk for atherosclerotic manifestations, such as carotid artery stenosis. The aim of this longitudinal cohort study was to evaluate new biomarkers in relation to C-reactive protein and conventional risk factors for carotid artery stenosis during long term follow-up METHODS: The following markers were measured in 5550 middle-aged subjects: C-reactive protein, lipoprotein-associated phospholipase A2, proneurotensin, midregional pro-adrenomedullin, midregional pro-atrial natriuretic peptide, N-terminal pro B-type natriuretic peptide, copeptin, and cystatin C. Subjects with prevalent carotid artery stenosis were excluded. Subjects were followed in national patient registers for 23.4 (interquartile range 19.5-24.3) years regarding incident carotid artery stenosis, both operated and non-operated. RESULTS: When including conventional risk markers in Cox regression, N-terminal pro B-type natriuretic peptide (Hazard ratio 1.36; 95% confidence interval 1.12-1.65; p = 0.002) was independently associated with incident carotid artery stenosis, whereas there were trends for C-reactive protein (HR 1.20; 95% confidence interval 0.98-1.48; p = 0.071), and midregional pro-adrenomedullin (Hazard ratio 1.21; 95% confidence interval 0.99-1.47; p = 0.061). Midregional pro-adrenomedullin (Hazard ratio 1.30; 95% confidence interval 1.03-1.65; p = 0.029) was independently associated with incident surgery for carotid artery stenosis, whereas there was a trend for N-terminal pro B-type natriuretic peptide (Hazard ratio 1.31; 95% confidence interval 1.00-1.72; p = 0.052). CONCLUSIONS: N-terminal pro B-type natriuretic peptide and midregional pro-adrenomedullin can be used as predictors for clinically detected carotid artery stenosis during long-term follow-up of healthy subjects.

Healthy diet and fiber intake are associated with decreased risk of incident symptomatic peripheral artery disease - A prospective cohort study.

Peripheral artery disease (PAD) is caused by atherosclerosis and associated with an increased risk of leg amputation, cardiovascular disease, and death. A healthy diet has been shown to reduce the risk of cardiovascular events, but relationships between diet, fiber intake, and incidence of PAD are virtually unknown. The aim was to investigate the long-term impact of diet on the development of PAD among 26,010 middle-aged individuals in the prospective Malmö Diet and Cancer study (MDCS). Data on dietary intake were collected through a 7-day food diary combined with a food questionnaire and a 1-hour interview. Adherence to a recommended intake of six dietary components - saturated fat, polyunsaturated fat, fish and shellfish, fiber, fruit and vegetables, and sucrose - was scored (sum 0-6 points) to assess a diet quality index, adjusting for potential confounders. Cox regression analysis was used to estimate associations between diet variables and PAD incidence expressed in hazard ratios (HR) with 95% CI. During a median follow-up of 21.7 years, 1122 participants developed PAD. Diet score was associated with a reduced risk of PAD in multivariable analysis (p = 0.03). When mutually adjusting for all dietary variables, only adherence to recommended levels of fiber intake was associated with a reduced risk of incident PAD (HR 0.84; 95% CI 0.72-0.99). In this prospective, population-based study including 26,010 participants with over 20 years of follow-up, a healthy diet, especially a high intake of fiber, was associated with a reduced risk of PAD. Primary prevention programs directed against PAD should therefore include a fiber recommendation.

Copeptin, B-type natriuretic peptide and cystatin C are associated with incident symptomatic PAD.

Purpose: The aim of this study is to evaluate plasma biomarkers as predictors for peripheral arterial disease (PAD). Materials and methods: Prospective longitudinal cohort study of middle-aged individuals from the cardiovascular cohort of the Malmö Diet and Cancer study (MDCS) (n = 5550; 1991-94). Cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional proatrial natriuretic peptide (MR-proANP), mid-regional proadrenomedullin (MR-proADM), and conventional risk factors were measured at baseline. The diagnosis of symptomatic PAD was validated in 97% of the cases. Results: Cumulative incidence of PAD during median follow up of 23.4 years was 4.4% (men 5.9%, women 3.3%). Adjusted for age, sex, smoking, body mass index, hypertension, diabetes mellitus and total cholesterol, copeptin (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.19-1.80), N-BNP (HR 1.28; 95% CI 1.11-1.48), and cystatin C (HR 1.19; 95% CI 1.10-1.29) were independently associated with incident PAD. Subjects with the three biomarkers copeptin, N-BNP, and cystatin C in the highest quartiles, ran a high risk of incident PAD (HR 3.29; 95% CI 1.76-6.17) compared to those with no biomarker in the highest quartile. Conclusion: Copeptin, N-BNP, and cystatin C were associated with incident symptomatic PAD, implying that these biomarkers are sensitive indicators of early subclinical PAD. Clinical significance First prospective longitudinal cohort study evaluating Cystatin C, copeptin, N-terminal pro-B-type natriuretic peptide (N-BNP), midregional proatrial natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) as predictors for peripheral arterial disease (PAD). Copeptin, N-BNP, and Cystatin C where independently associated with incident symptomatic PAD after adjustment for conventional risk factors. Copeptin, N-BNP, and Cystatin C seem to be sensitive indicators of early subclinical PAD.

Lp-PLA2 activity and mass and CRP are associated with incident symptomatic peripheral arterial disease.

Long follow up is needed in prospective cohort study evaluation of plasma biomarkers for incident peripheral arterial disease (PAD) Middle-aged PAD-free individuals from the cardiovascular cohort of the Malmö Diet and Cancer study (n = 5550; 1991-94) were followed prospectively for a median time of 23.4 years. The plasma biomarkers lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass, proneurotensin, and CRP, were studied in relation to incidence of PAD until December 31st, 2016. The diagnosis of PAD could be validated and confirmed in 98%. Cox regression was used to calculate hazard ratios (HR) per 1 standard deviation increment of each respective log transformed plasma biomarker. Cumulative incidence of PAD was 4.4% (men 5.9%, women 3.3%). Adjusting for age, gender, smoking, body mass index, hypertension, diabetes mellitus, Lp-PLA2 activity (HR 1.33; 95% CI 1.17-1.52), Lp-PLA2 mass (HR 1.20; 95% CI 1.05-1.37) and CRP (HR 1.55; 95% CI 1.36-1.76) remained independently associated with incident PAD. The plasma biomarkers Lp-PLA2 activity and mass, and CRP were markers of PAD risk, implying that they might be useful biomarkers for subclinical atherosclerosis and atherosclerotic disease.