Association of Estimated Glomerular Filtration Rate and Proteinuria With Lipid-Rich Plaque in Coronary Artery Disease.

BACKGROUND: Estimated glomerular filtration rate (eGFR) and proteinuria are both important determinants of the risk of cardiovascular disease and mortality. The aim of the present study was to investigate the independent and combined effects of eGFR and proteinuria on tissue characterization of the coronary plaques of culprit lesions. METHODS AND RESULTS: Conventional intravascular ultrasound and 3-D integrated backscatter intravascular ultrasound (IB-IVUS) were performed in 555 patients undergoing elective percutaneous coronary intervention. They were divided into 2 groups according to the absence or presence of proteinuria (dipstick result ≥1+). Patients with proteinuria had coronary plaque with significantly greater percentage lipid volume compared with those without (43.6±14.8% vs. 48.6±16.1%, P=0.005). Combined analysis was done using eGFR and absence or presence of proteinuria. Subjects with eGFR 45-59 ml/min/1.73 m2 and proteinuria were significantly more likely to have higher percent lipid volume compared with those with eGFR >60 ml/min/1.73 m2 without proteinuria. After multivariate adjustment for confounders, the presence of proteinuria proved to be an independent predictor for lipid-rich plaque (OR, 1.85; 95% CI: 1.12-3.06, P=0.016). CONCLUSIONS: The addition of proteinuria to eGFR level may be of value in the risk stratification of patients with coronary artery disease.

Urine proteome analysis reflects atherosclerotic disease in an ApoE-/- mouse model and allows the discovery of new candidate biomarkers in mouse and human atherosclerosis.

Noninvasive diagnosis of atherosclerosis via single biomarkers has been attempted but remains elusive. However, a previous polymarker or pattern approach of urine polypeptides in humans reflected coronary artery disease with high accuracy. The aim of the current study is to use urine proteomics in ApoE(-/-) mice to discover proteins with pathophysiological roles in atherogenesis and to identify urinary polypeptide patterns reflecting early stages of atherosclerosis. Urine of ApoE(-/-) mice either on high fat diet (HFD) or chow diet was collected over 12 weeks; urine of wild type mice on HFD was used to exclude diet-related proteome changes. Capillary electrophoresis coupled to mass spectrometry (CE-MS) of samples identified 16 polypeptides specific for ApoE(-/-) mice on HFD. In a blinded test set, these polypeptides allowed identification of atherosclerosis at a sensitivity of 90% and specificity of 100%, as well as monitoring of disease progression. Sequencing of the discovered polypeptides identified fragments of α(1)-antitrypsin, epidermal growth factor (EGF), kidney androgen-regulated protein, and collagen. Using immunohistochemistry, α(1)-antitrypsin, EGF, and collagen type I were shown to be highly expressed in atherosclerotic plaques of ApoE(-/-) mice on HFD. Urinary excretion levels of collagen and α(1)-antitrypsin fragments also significantly correlated with intraplaque collagen and α(1)-antitrypsin content, mirroring plaque protein expression in the urine proteome. To provide further confirmation that the newly identified proteins are relevant in humans, the presence of collagen type I, α(1)-antitrypsin, and EGF was also confirmed in human atherosclerotic disease. Urine proteome analysis in mice exemplifies the potential of a novel multimarker approach for the noninvasive detection of atherosclerosis and monitoring of disease progression. Furthermore, this approach represents a novel discovery tool for the identification of proteins relevant in murine and human atherosclerosis and thus also defines potential novel therapeutic targets.

Urinary Phosphate and Subclinical Atherosclerosis: The AWHS Study.

(1) Background: Atherosclerosis is a leading cause of vascular death worldwide. High urinary phosphate has recently been identified as a cardiovascular risk factor, but its role has not been fully established. The aim of this study was to investigate the association between urinary phosphate and subclinical atherosclerosis in the carotid, femoral as well as coronary territories; (2) Methods: We performed a cross-sectional analysis of a sample of 1169 middle-aged men, aged 50.9 years (SD 3.7), without previous cardiovascular disease, belonging to the Aragon Workers Health Study (AWHS). Urinary phosphate was analyzed in urine samples using the Fiske-Subbarow method. The presence of carotid plaque and femoral plaque was assessed by ultrasound and coronary artery calcium score (CACS) by computed tomography. Demographic, anthropometric and clinical data were collected at annual medical examinations. Logistic regression models were used to estimate the prevalence of adjusted atherosclerosis in the different vascular arteries; (3) Results: A significant inverse association was observed between urinary phosphate and subclinical atherosclerosis in the carotid [OR 95% CI 0.69 (0.49-0.99)] and coronary (CACS > 200) [OR 95% CI 0.46 (0.23-0.88)] arteries; however, no statistically significant association was found between urinary phosphate and the presence of atheroma plaques in the femoral territory [OR 1.02 (0.72-1.45)]; (4) Conclusions: In middle-aged men, a higher urinary phosphate concentration is associated with a lower prevalence of subclinical carotid and coronary atherosclerosis compared with those with a lower urinary phosphate concentration.

Relationship between microalbuminuria and vulnerable plaque components in patients with acute coronary syndrome and with diabetes mellitus. Virtual histology-intravascular ultrasound.

BACKGROUND: The purpose of the present study was to use virtual histology-intravascular ultrasound (VH-IVUS) to evaluate the relationship between microalbuminuria and plaque components in 920 patients. METHODS AND RESULTS: Patients with albumin levels <30mg/g creatinine were defined as having normoalbuminuria (n=824), and those with albumin levels 30-300mg/g as having microalbuminuria (n=96). The microalbuminuria group contained more patients with acute coronary syndrome (ACS; 72% vs. 61%, P=0.018) and more patients with diabetes (53% vs. 26%, P<0.001). In ACS patients, %necrotic core (NC) volume was significantly greater in the microalbuminuria group compared with the normoalbuminuria group (19±10% vs. 15±9%, P=0.019), but not in patients with stable angina. In ACS patients, thin-cap fibroatheroma (TCFA) was observed more frequently in the microalbuminuria group (36% vs. 18%, P=0.008), and microalbuminuria was the independent predictor of TCFA (odds ratio [OR], 1.106; 95% confidence interval [CI]: 1.025-1.144, P=0.018). In diabetic patients, %NC volume was significantly greater in the microalbuminuria group compared with the normoalbuminuria group (20±9% vs. 16±10%, P=0.017), but not in non-diabetic patients. In diabetic patients, TCFA was observed more frequently in the microalbuminuria group (38% vs. 17%, P=0.002) and microalbuminuria was the independent predictor of TCFA (OR, 1.120; 95%CI: 1.038-1.204, P=0.012). CONCLUSIONS: Microalbuminuria was associated with a higher number of vulnerable plaque components in ACS and diabetic patients. More intensive medical therapy is needed to stabilize the vulnerable plaque if microalbuminuria is observed in diabetic ACS patients.

Urinary 8-iso-prostaglandin F2α as a risk marker for the vulnerability of culprit plaque in diabetic patients with stable coronary artery disease.

We evaluated the association of urinary excretion of 8-iso-prostaglandin F2α (8-iso-PGF2α) with the vulnerability of culprit lesions in 156 age- and sex-matched diabetic stable coronary artery disease (CAD) patients with or without thin-capped fibroatheroma (TCFA) identified by iMAP intravascular ultrasound. Fasting urinary 8-iso-PGF2α level was measured and corrected by creatinine clearance. Compared to non-TCFA group, patients with TCFA had higher urinary 8-iso-PGF2α levels [114.6 (71.1, 181.5) vs. 83.0 (63.2, 138.2) pmol/mmolCr, P = 0.012]. Urinary 8-iso-PGF2α level was positively correlated with percent necrotic volume of culprit lesion (r = 0.218, P = 0.006). High urinary 8-iso-PGF2α level (OR 2.941, P = 0.009) was independently associated with the presence of TCFA and displayed a significant value in predicting TCFA plaques in study patients. The current study indicated that urinary 8-iso-PGF2α may be an important surrogate marker for the vulnerability of culprit lesion in diabetic patients with CAD.

Development and validation of an enzyme-linked immunosorbent assay for the quantification of a specific MMP-9 mediated degradation fragment of type III collagen--A novel biomarker of atherosclerotic plaque remodeling.

OBJECTIVE: Degradation of collagen in the arterial wall by matrix metalloproteinases is the hallmark of atherosclerosis. We have developed an ELISA for the quantification of type III collagen degradation mediated by MMP-9 in urine. DESIGN AND METHODS: A monoclonal antibody targeting a specific MMP-9 generated fragment of collagen III was used in a competitive ELISA. The assay was validated in urine and arterial tissue of Apolipoprotein-E knockout (ApoE-KO) mice. RESULTS: The lower limit of detection was 0.5ng/mL, intra- and inter-assay coefficients of variation were below 10%. By the end of 20weeks of the study, urine levels of the novel CO3-610 biomarker in ApoE-KO mice increased by two-fold (p<0.0001) and were three-fold higher than in control mice. Western blots confirmed high expression of CO3-610 in arterial extracts of ApoE-KO mice. CONCLUSION: We have developed a novel competitive ELISA, capable of measuring a urine biomarker indicative of pathological extracellular matrix remodeling in a mouse model of atherosclerosis.