Agnes Jager

Microalbuminuria and Peripheral Arterial Disease Are Independent Predictors of Cardiovascular and All-Cause Mortality, Especially Among Hypertensive Subjects Five-year Follow-up of the Hoorn Study

Microalbuminuria (MA) is associated with increased cardiovascular and all-cause mortality. It has been proposed that MA reflects generalized atherosclerosis and may thus predict mortality. To investigate this hypothesis, we studied the associations between, on the one hand, MA and peripheral arterial disease (PAD), a generally accepted marker of generalized atherosclerosis, and, on the other hand, cardiovascular and all-cause mortality in an age-, sex-, and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50 to 75 years followed prospectively for 5 years. At baseline, the albumin-to-creatinine ratio (ACR) was measured in an overnight spot urine sample; MA was defined as ACR >2.0 mg/mmol. PAD was defined as an ankle-brachial pressure index below 0.90 and/or a history of a peripheral arterial bypass or amputation. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). Both MA and PAD were associated with a 4-fold increase in cardiovascular mortality. After adjusting for age, sex, diabetes mellitus, hypertension, levels of total and HDL-cholesterol and triglyceride, body mass index, smoking habits, and preexistent ischemic heart disease, the relative risks (RR) (95% confidence intervals) were 3.2 (1.3 to 8.1) for MA and 2.4 (0.9 to 6.1) for PAD. When both MA and PAD were included in the multivariate analysis, the RRs were 2.9 (1.1 to 7.3) for MA and 2.0 (0.7 to 5.7) for PAD. MA and PAD were both associated with an about 2-fold increase in all-cause mortality. The RRs of all-cause mortality associated with MA and PAD were about 4 times higher among hypertensive than among normotensive subjects. We conclude that both MA and PAD are associated with an increased risk of cardiovascular mortality. MA and PAD are mutually independent risk indicators. The associations of MA and PAD with all-cause mortality are somewhat weaker. They are more pronounced in the presence of hypertension than in its absence. These data suggest that MA affects mortality risk through a mechanism different from generalized atherosclerosis.

von Willebrand Factor, C-Reactive Protein, and 5-Year Mortality in Diabetic and Nondiabetic Subjects The Hoorn Study

Increased levels of von Willebrand factor (vWf) and C-reactive protein (CRP) predict cardiovascular mortality in selected populations. It is uncertain whether vWf and CRP predict mortality in a general population and whether vWf and CRP predict mortality through similar pathways. This study investigated the association of vWf and CRP with cardiovascular and all-cause mortality among diabetic and nondiabetic subjects. An age-, sex-, and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50 to 75 years was followed prospectively for 5 years. After 5 years of follow-up, 58 subjects had died (24 of cardiovascular causes). vWf (>1.56 IU/mL) and CRP (>2.84 mg/L) levels in the upper tertile were associated with, respectively, a 3- and 2-fold increase in cardiovascular mortality after adjustment for age, sex, and glucose tolerance status. Analyses in nondiabetic and diabetic subjects separately gave similar results. After further adjustment for hypertension, levels of HDL cholesterol and triglyceride, smoking habits, ischemic heart disease, and peripheral arterial disease, the relative risks (RRs) were 3.0 (95% CI 1.2 to 7.9) for vWf and 1.4 (95% CI 0.6 to 3.5) for CRP. When both vWf and CRP were included in the latter multivariate analysis, the RRs were 3.0 (95% CI 1.1 to 7.9) for vWf and 1.3 (95% CI 0.5 to 3.4) for CRP. The association between vWf and risk of cardiovascular mortality was independent of blood group (O versus non-O) and, moreover, similar among subjects with different blood groups. Repeating the analyses for all-cause mortality gave similar results for CRP. For vWf, the RR was 2.0 (95% CI 1.1 to 3.5) after adjustment for all other risk factors. Increased levels of vWf are independently associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects. The association between increased levels of CRP and cardiovascular mortality was partly explained by other risk factors. Mutual adjustment of vWf and CRP did not markedly change the results, favoring the hypothesis that vWf and CRP predict mortality through different pathways.

Microalbuminuria is strongly associated with NIDDM and hypertension, but not with the insulin resistance syndrome: the Hoorn study

Summary Microalbuminuria is a strong predictor of cardiovascular disease. The aim of this study was to investigate whether microalbuminuria is part of a cluster of risk factors, the insulin resistance syndrome (IRS), or whether it is only associated with, and presumably a complication of, hypertension and non-insulin-dependent diabetes mellitus (NIDDM). An age-, sex- and glucose tolerance-stratified random sample from a 50–75 year old general population (n = 622) was investigated. The urinary albumin-to-creatinine ratio was measured in an early morning spot urine sample. Microalbuminuria was defined as an albumin-to-creatinine ratio greater than 2.0 mg/mmol. We considered, as IRS-related variables, fasting hyperinsulinaemia, insulin resistance (IR; calculated from the formula of the homeostasis model assessment), dyslipidaemia, glucose intolerance, hypertension and waist-to-hip ratio (WHR). Dyslipidaemia was defined as levels of HDL-cholesterol in the lowest and / or levels of triglyceride in the highest tertile. Fasting insulin levels, IR and WHR were divided into tertiles; the highest tertiles were compared to the lowest tertiles. Age-, sex- and glucose tolerance-adjusted analyses showed microalbuminuria to be significantly associated with hypertension, NIDDM and WHR. In multiple logistic regression analyses, microalbuminuria showed independent associations with hypertension, NIDDM and WHR, with odds ratios (ORs [95 % confidence interval]) of 3.33 (1.86–5.96), 2.26 (1.14–4.48) and 2.49 (1.09–5.70), respectively. No associations were found with impaired glucose tolerance, hyperinsulinaemia, IR or dyslipidaemia. Multiple logistic regression analyses in diabetic and non-diabetic subjects separately showed that microalbuminuria was independently associated only with hypertension (ORs 4.31 and 2.69). In this Caucasian population, microalbuminuria was associated with hypertension, NIDDM and WHR and not with other variables of the IRS. It is therefore likely that microalbuminuria is a complication of hypertension and NIDDM, and not an integral part of the IRS. [Diabetologia (1998) 41: 694–700]

C-Reactive Protein and Soluble Vascular Cell Adhesion Molecule-1 Are Associated With Elevated Urinary Albumin Excretion but Do Not Explain Its Link With Cardiovascular Risk

An elevated urinary albumin excretion rate (UAER) is associated with an increased risk of cardiovascular mortality, but the pathophysiological mechanism underlying this association is poorly understood. To investigate the role of endothelial dysfunction, leukocyte adhesion, and low-grade inflammation (1) in the development of elevated UAER (study I) and (2) in linking elevated UAER with risk of cardiovascular mortality (study II), we performed a prospective study in an age–, sex–, and glucose tolerance– stratified sample of a population-based cohort aged 50 to 75 years. High levels of von Willebrand factor, soluble vascular cell adhesion molecule-1 (sVCAM-1), and C-reactive protein (CRP) were used as markers of endothelial dysfunction, leukocyte adhesion, and low-grade inflammation, respectively. For study I, subjects who had normal UAER at baseline (n=316 subjects, 66 with type 2 diabetes) were reexamined after a mean follow-up of 6.1 years. The development of elevated UAER was defined as a mean albumin-to-creatinine ratio >2.0 mg/mmol at follow-up. Age–, sex–, and glucose tolerance– adjusted logistic regression analyses showed the development of elevated UAER to be significantly associated with levels of sVCAM-1 and CRP (odds ratio 1.14 [95% CI 1.02 to 1.27] per 10% increase of sVCAM-1 and odds ratio 1.17 [95% CI 1.04 to 1.32] per 50% increase of CRP). The results were not materially different after additional adjustment for hypertension, body mass index, cardiovascular disease, and creatinine clearance or stratification by the presence of diabetes. For study II, the vital status of all subjects (n= 575) was determined after a mean follow-up of 6.6 years. Eighty-one of 575 subjects died (30 died of cardiovascular disease). The presence of elevated UAER at baseline was associated with a 4.1-fold (1.94 to 8.73) increased risk of cardiovascular death after adjustment for age, sex, and glucose tolerance status. Adjustment for levels of von Willebrand factor, sVCAM-1, or CRP did not materially affect the results, nor did additional adjustment for the presence of hypertension, retinopathy, and cardiovascular disease and for levels of homocysteine, triglycerides, and high density lipoprotein cholesterol. Leukocyte adhesion (sVCAM-1) and low-grade inflammation (CRP) are determinants of the development of elevated UAER. However, these determinants do not explain the association between elevated UAER and cardiovascular mortality.

Serum Homocysteine Levels Are Associated With the Development of (Micro)albuminuria: The Hoorn Study

Abstract—Microalbuminuria is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Slightly increased levels of homocysteine, an independent risk factor for atherothrombotic disease, have recently been found to be associated with the presence of (micro)albuminuria. However, it is unknown whether increased homocysteine levels precede the occurrence of (micro)albuminuria. Normoalbuminuric subjects (n=316, 66 with non–insulin-dependent diabetes mellitus [NIDDM]) of an age-stratified, sex-stratified, and glucose tolerance–stratified sample of a population-based cohort study were investigated at baseline and after a mean follow-up duration of 6.1 years. Development of (micro)albuminuria was defined as a mean albumin-to-creatinine ratio >2.0 mg/mmol at the follow-up examination. The cumulative incidence of (micro)albuminuria was 14.0% (9.7 % to 18.3%) among nondiabetic subjects and 22.7% (12.9% to 32.5%) among NIDDM patients. Age-adjusted, sex-adjusted, and glucose tolerance status–adjusted logistic regression analyses showed development of (micro)albuminuria to be significantly associated with baseline homocysteine levels >19.0 &mgr;mol/L compared with homocysteine levels <9.1 &mgr;mol/L (odds ratio [OR] 5.1, 95% CI 1.1 to 23.0). For homocysteine levels of 9.1 to 14.0 &mgr;mol/L and 14.1 to 19.0 &mgr;mol/L, the values were OR 1.2 (95% CI 0.5 to 3.0) and OR 1.8 (95% CI 0.6 to 5.3), respectively. Additional adjustment for baseline insulin resistance, blood pressure, body mass index, presence of cardiovascular disease and retinopathy, current smoking, or estimates of glomerular filtration rate did not materially affect the results. Substituting homocysteine levels as a continuous variable for categories of homocysteine levels showed that a 5-&mgr;mol/L increase of the homocysteine level was associated with an increased risk of developing (micro)albuminuria (OR 1.38, 95% CI 0.97 to 1.95) . Analyses performed in nondiabetic and diabetic subjects separately gave similar results among nondiabetic subjects. Among diabetic subjects, the association between homocysteine level and (micro)albuminuria could not be estimated, because there was an insufficient number of diabetic subjects with high homocysteine levels. Hyperhomocysteinemia is an independent determinant of the development of (micro)albuminuria among nondiabetic subjects, even after adjustment for estimates of glomerular filtration rate. We could neither confirm nor reject an association between homocysteine levels and the development of (micro)albuminuria among NIDDM subjects. These data suggest that homocysteine may play a pathophysiological role in the development of (micro)albuminuria.

Why is soluble intercellular adhesion molecule-1 related to cardiovascular mortality?

Increased plasma levels of soluble adhesion molecules are associated with an increased risk of atherothrombosis. The pathophysiological mechanisms responsible for these associations are not known. The aim of the present study was to investigate the association of soluble intercellular adhesion molecule‐1 (sICAM‐1) concentration and risk of cardiovascular and all‐cause mortality among individuals with and without type 2 diabetes. In addition, we assessed potential pathophysiological mechanisms by which sICAM‐1 may promote mortality.

Impact of diabetes duration and cardiovascular risk factors on mortality in type 2 diabetes: the Hoorn Study.

Background Several studies have reported differences in the mortality risk between diabetic subjects detected by screening and known diabetic patients. We studied mortality in relation to diabetes duration, and the contribution of other cardiovascular risk factors to the elevated risk.