Plasma matrix metalloproteinases are associated with incident cardiovascular disease and all-cause mortality in patients with type 1 diabetes: a 12-year follow-up study.

BACKGROUND: Altered regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular events and all-cause mortality in type 1 diabetic patients. METHODS: We prospectively followed 337 type 1 diabetic patients [mean age 41.4 years (9.6), 39% female], 170 with and 167 without diabetic nephropathy, with median follow-up of 12.3 years. Survival analyses were applied to investigate differences in plasma MMP-1, -2, -3, -9, -10, and TIMP-1-levels in patients with and without a cardiovascular event and in those who died vs survivors. All analyses were adjusted for age, sex, duration of diabetes, HbA1c, nephropathy and for other conventional cardiovascular risk factors. RESULTS: After adjustment for potential confounders, higher MMP-2 plasma levels were significantly associated with higher incidence of cardiovascular events [HR 1.49 (95% CI 1.11; 1.99)], and higher plasma levels of MMP-1 [1.38 (1.07; 1.78)], MMP-2 [1.60 (1.19; 2.15)] and MMP-3 [1.39 (1.05; 1.85)] were associated with all-cause mortality. All associations were independent of low-grade inflammation and endothelial dysfunction as estimated by plasma markers. Associations between MMP-2 and cardiovascular events and between MMP-3 and mortality were attenuated after further adjustment for eGFR and changes in eGFR. CONCLUSIONS: Higher levels of MMP-2 are associated with CVD and higher MMP-1, -2 and -3 with all-cause mortality. In addition, associations between MMP-2 and CVD, and MMP-3 and mortality were attenuated after adjustment for eGFR while both MMPs were associated with eGFR decline, indicating a possible mediating role of eGFR.

Higher plasma high-mobility group box 1 levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12 year follow-up study.

AIMS/HYPOTHESIS: This study aimed to investigate the associations of plasma levels of the pro-inflammatory cytokine high-mobility group box 1 (HMGB1) with incident cardiovascular disease (CVD) and all-cause mortality in patients with type 1 diabetes. METHODS: We prospectively followed 165 individuals with diabetic nephropathy and 168 individuals with persistent normoalbuminuria who were free of CVD at study entry and in whom levels of HMGB1 and other cardiovascular risk factors were measured at baseline. RESULTS: During the course of follow-up (median, 12.3 years [interquartile range, 7.8-12.5]), 80 patients died, 82 suffered a fatal (n = 46) and/or non-fatal (n = 53) CVD event. After adjustment for age, sex, case-control status and other risk factors, patients with higher levels of log(e) HMGB1 had a higher incidence of fatal and non-fatal CVD and all-cause mortality: HR 1.55 (95% CI 0.94, 2.48) and HR 1.86 (95% CI 1.18, 2.93), respectively. Further adjustments for differences in markers of low-grade inflammation, endothelial and renal dysfunction and arterial stiffness did not attenuate these associations because plasma levels of HMGB1 were not independently associated with these variables. CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes, higher levels of plasma HMGB1 are independently associated with a higher risk of all-cause mortality and, to a lesser extent, with a higher incidence of CVD. Larger studies are needed to ascertain more definitely the role of HMGB1 in the development of vascular complications in diabetes.

Arterial stiffness and endothelial dysfunction independently and synergistically predict cardiovascular and renal outcome in patients with type 1 diabetes.

AIMS: To evaluate whether pulse pressure alone or with placental growth factor as estimates of arterial stiffness and endothelial dysfunction, predicts mortality, cardiovascular disease and progression to end-stage renal disease in patients with Type 1 diabetes. METHODS: Prospective, observational study, median (range) follow-up 8 (0-13) years, 900 patients with Type 1 diabetes, 458 with diabetic nephropathy, mean ± SD age 44 ± 11 years. RESULTS: During follow-up, we recorded 178 (20%) all-cause deaths, 109 (12%) cardiovascular deaths, 213 (24%) cardiovascular events and 73 (16%) progressed to end-stage renal disease. Elevated pulse pressure predicted all-cause and cardiovascular mortality and cardiovascular events [Hazard Ratio (HR) (95% CI) per 10 mmHg increase]: HR 1.2 (1.1-1.3), 1.3 (1.2-1.5) and 1.2 (1.1-1.3), P<0.001 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, creatinine, smoking, previous cardiovascular disease and nephropathy status). Furthermore, pulse pressure predicted the development of end-stage renal disease in patients with diabetic nephropathy: HR 1.2 (1.1-1.4), P=0.011 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, previous cardiovascular disease and glomerular filtration rate). In a two-hit model, patients with pulse pressure and placental growth factor levels above the median vs. below the median had increased risk of all-cause and cardiovascular mortality, cardiovascular events and progression to end-stage renal disease: adjusted HRs 2.3 (1.2-4.2), 4.2 (1.6-11.0), 2.3 (1.3-4.1) and 3.5 (1.0-11.8),P<0.05. CONCLUSIONS: Elevated pulse pressure independently predicts mortality, cardiovascular events and progression to end-stage renal disease in patients with Type 1 diabetes. Placental growth factor adds to the predictive value of pulse pressure on cardiovascular and renal outcome.

Evaluation of placental growth factor and soluble Fms-like tyrosine kinase 1 as predictors of all-cause and cardiovascular mortality in patients with Type 1 diabetes with and without diabetic nephropathy.

AIMS: Placental growth factor is a vascular endothelial growth factor involved in angiogenesis, vascular inflammation and plaque formation. Soluble Fms-like tyrosine kinase 1 is a decoy receptor for placental growth factor, reducing its activity. The aim of this study is to evaluate the predictive value of placental growth factor and soluble Fms-like tyrosine kinase 1 in relation to all-cause and cardiovascular mortality and decline in kidney function in Type 1 diabetes. METHODS: This was a prospective, observational follow-up study with 8 (0-13) years [median (range)] of follow-up, including patients with Type 1 diabetes, of whom 458 had diabetic nephropathy [278 men; age 42 ± 11 years (mean ± sd), diabetes duration 28 ± 9 years, glomerular filtration rate 76 ± 33 ml min(-1) 1.73 m(-2) ] and 442 had long-standing normoalbuminuria (234 men; age 45 ± 12 years, diabetes duration 28 ± 10 years). RESULTS: Placental growth factor and soluble Fms-like tyrosine kinase 1 levels measured at baseline were higher in patients with diabetic nephropathy compared with patients with long-standing normoalbuminuria [median (range)] 15 (4-131) vs. 11 (7-64) ng/l, (P < 0.001) and 86 (42-3462) vs. 77 (43-1557) ng/l (P < 0.001), respectively. In patients with diabetic nephropathy, high levels of placental growth factor predicted all-cause and cardiovascular mortality [hazard ratio 1.94 (1.16-3.24) and hazard ratio 2.91 (1.45-5.85)] after adjustment for sex, age, smoking, systolic blood pressure, HbA(1c) , cholesterol, glomerular filtration rate and previous cardiovascular disease. High levels of placental growth factor predicted increased risk of end-stage renal disease [hazard ratio 2.77 (1.47-5.14)], but covariate adjustments attenuated the association [hazard ratio 1.89 (0.91-3.95)]. Among patients with long-standing normoalbuminuria, placental growth factor levels predicted fatal and non-fatal cardiovascular events [hazard ratio 1.97 (1.03-3.76)], but not all-cause mortality. Baseline soluble Fms-like tyrosine kinase 1 levels did not predict outcome in either group after adjustment. CONCLUSION: Placental growth factor is elevated in patients with Type 1 diabetes and diabetic nephropathy and predicts all-cause and cardiovascular mortality, but not deterioration of kidney function.

Telomere length predicts all-cause mortality in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Type 1 diabetic patients with diabetic nephropathy have increased mortality and morbidity compared with normoalbuminuric patients. Telomere length in proliferative cells is inversely related to the total number of cell divisions, and therefore to biological age. We aimed to evaluate differences in telomere length in patients with type 1 diabetes with or without diabetic nephropathy; we also evaluated the prognostic value of telomere length. METHODS: In a prospective follow-up study, 157 type 1 diabetic patients with diabetic nephropathy and a control group of 116 patients with type 1 diabetes and normoalbuminuria were followed for 11.1 years (range 0.2-12.9). Telomere length was measured from DNA samples extracted from white blood cells at baseline. RESULTS: The mean telomere length did not differ between patients with or without diabetic nephropathy, and was similar in men and women, but was inversely correlated with age and systolic blood pressure, p < 0.05. When dividing patients into tertiles after telomere length, 36 (37%) patients died in the tertile with the shortest telomere length, 24 (28%) died in the middle tertile, and 15 (17%) of patients in the tertile with the longest telomere length died, log rank test p = 0.017. After adjustment for traditional risk factors, telomere length was still predictive of all-cause mortality. CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes we found no differences in telomere length between patients with or without diabetic nephropathy. We also found that telomere length was associated with all-cause mortality; however, confirmative studies are needed to verify our findings.

The V16A polymorphism in SOD2 is associated with increased risk of diabetic nephropathy and cardiovascular disease in type 1 diabetes.

AIMS/HYPOTHESIS: Hyperglycaemia increases oxidative stress and may thereby increase the risk of diabetic complications, including diabetic nephropathy. Cells are protected from oxidative damage by, for example, the manganese superoxide dismutase enzyme (MnSOD), but the functional polymorphism V16A affects the localisation of MnSOD and therefore its ability to scavenge superoxide radicals. In a Danish cohort of type 1 diabetes patients, we sought to confirm previous findings of association between the V allele and the risk of diabetic nephropathy and to investigate the influence of this polymorphism on the development of cardiovascular disease. METHODS: Type 1 diabetes patients attending the Steno Diabetes Center, Gentofte, Denmark, between 1993 and 2001 were enrolled in this study. A total of 441 cases with diabetic nephropathy (albumin excretion > or =300 mg/24 h) and 314 controls with persistent normoalbuminuria (<30 mg/24 h), despite diabetes of duration > or =20 years, were identified. The median duration of diabetes was 35 years (range 12-73 years). RESULTS: We confirmed the significant association between carrier status of the V allele and diabetic nephropathy. The association was independent of age at diabetes onset, HbA(1c), sex, smoking and diabetes duration (OR 1.7, 95% CI 1.2-2.4). The VV and AV genotypes considered together also predicted the risk of cardiovascular disease, independently of age at follow-up, HbA(1c), sex, smoking, systolic blood pressure, cholesterol and nephropathy status. The hazard ratio was 1.6 (95% CI 1.0-2.5). CONCLUSIONS/INTERPRETATION: The MnSOD V16A polymorphism is involved in the development of nephropathy caused by type 1 diabetes and seems to predict cardiovascular disease during follow-up.

Plasma osteoprotegerin levels predict cardiovascular and all-cause mortality and deterioration of kidney function in type 1 diabetic patients with nephropathy.

AIMS/HYPOTHESIS: The bone-related peptide osteoprotegerin is produced by vascular cells and is involved in the process of vascular calcification. The aim of this study was to investigate the predictive value of plasma levels of osteoprotegerin in relation to mortality, cardiovascular events and deterioration in kidney function in patients with type 1 diabetes. METHODS: This prospective observational follow-up study included 397 type 1 diabetic patients with overt diabetic nephropathy (243 men; age [mean+/-SD] 42.1 +/- 10.6 years, duration of diabetes 28.3 +/- 9.9 years, GFR 67 +/- 28 ml min(-1) 1.73 m(2)) and a group of 176 patients with longstanding type 1 diabetes and persistent normoalbuminuria (105 men; age 42.6 +/- 9.7 years, duration of diabetes 27.6 +/- 8.3 years). RESULTS: The median (range) follow-up period was 11.3 (0.0-12.9) years. Among patients with diabetic nephropathy, individuals with high osteoprotegerin levels (fourth quartile) had significantly higher all-cause mortality than patients with low levels (first quartile) (covariate-adjusted hazard ratio [HR] 3.00 [1.24-7.27]). High osteoprotegerin levels also predicted cardiovascular mortality (covariate-adjusted HR 4.88 [1.57-15.14]). Furthermore, patients with high osteoprotegerin levels had significantly higher risk of progression to end-stage renal disease than patients with low levels (covariate-adjusted HR 4.32 [1.45-12.87]). In addition, patients with high levels of plasma osteoprotegerin had an elevated rate of decline in GFR. CONCLUSIONS/INTERPRETATION: High levels of osteoprotegerin predict all-cause and cardiovascular mortality in patients with diabetic nephropathy. Furthermore, high levels of osteoprotegerin predict deterioration of kidney function towards end-stage renal disease.

The PPAR gamma 2 Pro12Ala variant predicts ESRD and mortality in patients with type 1 diabetes and diabetic nephropathy.

UNLABELLED: The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma 2 gene is suggested to associate with diabetic nephropathy and cardiovascular disease in type 2 diabetes. The aim of this study was to investigate the polymorphism in relation to diabetic nephropathy, end-stage renal disease (ESRD), mortality and cardiovascular (CVD) events in type 1 diabetic patients. This prospective observational follow-up study included 415 type 1 diabetic patients with overt diabetic nephropathy (252 men; age 42.2+/-10.4 years [mean+/-SD], duration of diabetes 28.3+/-8.8 years, GFR 66+/-8.8 ml/min) and 428 patients with longstanding type 1 diabetes and persistent normoalbuminuria (230 men; age 45.4+/-11.6 years, duration of diabetes 27.8+/-10.1 years). FOLLOW-UP: 8.1 (0.0-12.8) years (median [range]). There where no significant differences between cases and controls in genotype (p=0.51) or allele frequencies (p=0.25). Cox regression analysis revealed a covariate-adjusted hazard ratio (HR) for all-cause mortality in patients with the Ala/Ala genotype of 2.44 (1.23-4.84). The Pro12Ala polymorphism did not predict CVD events. However, the Ala/Ala genotype predicts ESRD (covariate-adjusted HR 2.60 (1.11-6.07)). Furthermore, Carriers of the Ala-allele had a higher rate of decline in GFR (p=0.040). In conclusion, the Pro12Ala polymorphism is not associated with type 1 diabetic nephropathy. The Ala-allele is associated with enhanced decline in GFR and predicts ESRD and all-cause mortality in patients with nephropathy.