[Pseudoaneurysm in the subclavian artery as a long-term complication to clavicula fracture].

Post-traumatic pseudoaneurysm in the subclavian artery is a rare complication to clavicula fracture, but it seldom requires intervention, and therefore screening for pseudoaneurysms is not recommended after a relevant trauma. This case report confirms that a pseudoaneurysm can develop slowly and can manifest even several years after the primary trauma. A 79-year-old patient presented herself with a 20 × 20 cm large pulsating tumour on the left side of her neck, and a pseudoaneurysm on the subclavian artery had been diagnosed as a late complication to a clavicula fracture nine years before. This case was rare because of the late-onset aneurysm, manifesting itself by the large size and neurological symptoms. The patient was treated with stent grafting without further surgical intervention, resulting in relief from neurological symptoms and a decreasing size of the pseudoaneurysm. Antithrombotic treatment after the endovascular procedure was not recommended.

Endothelial progenitor cells in long-standing asymptomatic type 1 diabetic patients with or without diabetic nephropathy.

UNLABELLED: A decrease in the number and dysfunction of endothelial progenitor cells (EPC) may increase the risk for progression of cardiovascular disease (CVD) in type 1 diabetic patients with diabetic nephropathy (DN). Our aim was to evaluate EPC numbers in asymptomatic CVD type 1 diabetic patients with or without DN and to study the effect of CVD and medication on EPC numbers. METHODS: We examined EPC numbers in 37 type 1 diabetic patients with DN and 35 type 1 diabetic patients with long-standing normoalbuminuria. Patients were without symptoms of CVD and the prevalence of CVD was previously shown to be very low. EPC number was assessed in in vitro cultures by fluorescent staining of attached cells. RESULTS: There was no difference in EPC numbers between patients with DN (mean ± SD 120 ± 49 cells/field) and normoalbuminuria (108 ± 41 cells/field; p = 0.25). Furthermore, EPC number was not associated with CVD (p > 0.05). Conventional risk factors were significantly higher in patients with DN and they received more CVD-preventive treatment. All patients receiving simvastatin or calcium-channel blockers had higher numbers of EPC compared to patients not treated with these drugs. CONCLUSIONS: Asymptomatic patients with DN had EPC numbers similar to normoalbuminuric patients, which was related to aggressive CVD intervention therapy. This may have contributed to the low prevalence of CVD.

Tubular and glomerular injury in diabetes and the impact of ACE inhibition.

OBJECTIVE: We studied tubular and glomerular damage in type 1 diabetic patients by measuring urinary-liver fatty acid binding protein (U-LFABP) and albuminuria. Subsequently, we evaluated the effect of ACE inhibition on U-LFABP in patients with diabetic nephropathy. RESEARCH DESIGN AND METHODS: We studied Caucasians with type 1 diabetes: 58 with normoalbuminuria (urinary albumin <30 mg/24 h), 45 with persistent microalbuminuria (30-300 mg/24 h), and 45 with persistent macroalbuminuria (> or =300 mg/24 h). A control group consisted of 57 healthy individuals. The groups were matched by sex and duration of diabetes. In addition, U-LFABP was measured in 48 type 1 diabetic patients with diabetic nephropathy in a randomized crossover trial consisting of 2 months of treatment with 20, 40, and 60 mg lisinopril once daily in random order. RESULTS: In the cross-sectional study, levels of U-LFABP were significantly higher in normoalbuminuric patients versus those in the control group (median 2.6 [interquartile range 1.3-4.1] vs. 19 [0.8-3.0] microg/g creatinine, P = 0.02) and increased with increasing levels of albuminuria (microalbuminuric group 4.2 [1.8-8.3] microg/g creatinine and nephropathy group 71.2 [8.1-123.4], P < 0.05 for all comparisons). U-LFABP correlates with the urinary albumin-to-creatinine ratio (R(2) = 0.54, P < 0.001). In the intervention study, all doses of lisinopril significantly reduced urinary albumin excretion rate and U-LFABP from baseline. The reductions in U-LFABP were 43, 46, and 40% with increasing doses of lisinopril (NS). CONCLUSIONS: An early and progressive increase in tubulointerstitial damage as reflected by increased U-LFABP levels occurs in type 1 diabetic patients and is associated with albuminuria. Furthermore, ACE inhibition reduces the tubular and glomerular damage and dysfunction.

Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study.

BACKGROUND: Despite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment with metformin versus placebo in patients with T1DM and persistent poor glycaemic control. METHODOLOGY/PRINCIPAL FINDINGS: One hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA(1c) (HbA(1c)) > or = 8.5% during the year before enrolment entered a one-month run-in on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA(1c) after one year of treatment. At enrolment, mean (standard deviation) HbA(1c) was 9.48% (0.99) for the metformin group (n = 49) and 9.60% (0.86) for the placebo group (n = 51). Mean (95% confidence interval) baseline-adjusted differences after 12 months with metformin (n = 48) versus placebo (n = 50) were: HbA(1c), 0.13% (-0.19; 0.44), p = 0.422; Total daily insulin dose, -5.7 U/day (-8.6; -2.9), p<0.001; body weight, -1.74 kg (-3.32; -0.17), p = 0.030. Minor and overall major hypoglycaemia was not significantly different between treatments. Treatments were well tolerated. CONCLUSIONS/SIGNIFICANCE: In patients with poorly controlled T1DM, adjunct metformin therapy did not provide any improvement of glycaemic control after one year. Nevertheless, adjunct metformin treatment was associated with sustained reductions of insulin dose and body weight. Further investigations into the potential cardiovascular-protective effects of metformin therapy in patients with T1DM are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT00118937.

Markers of endothelial dysfunction and inflammation in type 1 diabetic patients with or without diabetic nephropathy followed for 10 years: association with mortality and decline of glomerular filtration rate.

OBJECTIVE: We evaluated the association of biomarkers of endothelial dysfunction and inflammation with all-cause mortality and cardiovascular mortality and morbidity and decline in glomerular filtration rate (GFR) in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with persistent normoalbuminuria. Biomarkers were measured at baseline. RESULTS: We constructed two Z scores: the mean inflammatory Z score combined C-reactive protein, interleukin-6, soluble intercellular adhesion molecule (sICAM-1), and secreted phospholipase A2 and the mean Z score for endothelial dysfunction combined soluble vascular cell adhesion molecule 1, plasminogen activator inhibitor-1, and sICAM-1. The mean Z score of inflammatory biomarkers was associated with mortality and the combined end point in patients with diabetic nephropathy after multivariate adjustment (hazard ratio 1.7 [95% CI 1.1-2.6]; P = 0.025 and 1.5 [1.1-2.2]; P = 0.017). The mean Z score for endothelial dysfunction biomarkers was associated with mortality in a model adjusting for age and sex in patients with diabetic nephropathy (1.6 [1.0-2.3]; P = 0.031). The mean Z score for endothelial dysfunction correlated with decline in GFR (r = -0.243; P = 0.001); the correlation persisted after multivariate adjustment (coefficient -1.38 [95% CI -2.27 to -0.50]; P = 0.002). CONCLUSIONS: Mean Z scores of inflammatory biomarkers are significantly associated with all-cause mortality and cardiovascular morbidity and mortality in patients with nephropathy after multivariate adjustment. These data suggest that the high risk of cardiovascular disease in type 1 diabetes may be explained in part by inflammatory activity. Mean Z score of endothelial dysfunction correlated after multivariate adjustment with the rate of decline in GFR.

Relation of left ventricular function, mass, and volume to NT-proBNP in type 1 diabetic patients.

OBJECTIVES: To measure left ventricular mass (LVM), left ventricular volumes, and left ventricular function (LVF) in a cohort of type 1 diabetic patients and to correlate measures of imaging to NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP). RESEARCH DESIGN AND METHODS: In a cross-sectional study, all patients with type 1 diabetes underwent cardiovascular magnetic resonance imaging. We included 63 patients with diabetic nephropathy and 73 patients with normoalbuminuria. RESULTS: All patients had normal global LVF. LVM was increased in patients with diabetic nephropathy compared with patients with persistent normoalbuminuria. Patients with nephropathy had smaller left ventricular volumes and increased levels of NT-proBNP. Linear regression analysis in patients with diabetic nephropathy showed that NT-proBNP and creatinine were associated with LVM. CONCLUSIONS: Increased LVM is identified in asymptomatic type 1 diabetic patients with nephropathy compared with normoalbuminuric patients. Elevated levels of NT-proBNP were associated with increased LVM, which are both markers of increased cardiovascular risk.

Plasma alpha-defensin is associated with cardiovascular morbidity and mortality in type 1 diabetic patients.

CONTEXT: alpha-Defensins are antimicrobial peptides of the innate immune system. In addition, experimental evidence suggests that alpha-defensins are proatherogenic. OBJECTIVE: The objective of the study was to examine the predictive value of plasma alpha-defensin as a clinical marker of cardiovascular disease (CVD) in patients with type 1 diabetes. METHODS: In an observational, prospective design, 389 patients with long-lasting type 1 diabetes were examined for CVD at study start (1993; baseline) and followed up through the Danish National Register for a median of 10.1 yr (range 0.2-10.4 yr). Plasma was collected in 1993 and stored at -80 C until analysis of plasma alpha-defensin using an in-house RIA. RESULTS: At baseline, plasma alpha-defensin was significantly higher in patients with than without nephropathy [median and interquartile ranges: 305 (205-321) vs. 223 (182-263) mug/liter; P < 0.0001]. During follow-up, 98 patients reached the primary end point (fatal and nonfatal events of CVD). Prospectively a baseline alpha-defensin within the upper vs. the lower tertile significantly increased the covariate-adjusted risk for CVD-related morbidity and mortality to a hazard ratio of 2.8 (1.3-5.9) (median and 95% confidence intervals, P = 0.006). CONCLUSION: This study suggests that plasma alpha-defensin may serve as a clinical risk marker for CVD-related morbidity and mortality in type 1 diabetes. However, future studies are needed to clarify whether plasma alpha-defensin is causally linked to the development of CVD or an innocent bystander.

Predictors of mortality in patients with type 2 diabetes with or without diabetic nephropathy: a follow-up study.

OBJECTIVE: To evaluate the prognostic significance of cardiovascular risk factors including 24-h ambulatory blood pressure level and rhythm for all-cause mortality in type 2 diabetic patients. METHODS: In a prospective observational study, 104 patients with type 2 diabetes were followed: 51 patients with diabetic nephropathy and 53 patients with persistent normoalbuminuria. At baseline, 24-h ambulatory blood pressure, left ventricular hypertrophy, glomerular filtration rate and cardiac autonomic neuropathy were measured. Blood samples were taken and patients answered a World Health Organization questionnaire. Dipping was calculated as the average nocturnal reduction in systolic and diastolic blood pressure. RESULTS: Mean follow-up was 9.2 years (range 0.5-12.9). During follow-up, 54 of 104 patients died. Sixteen patients (15%) had higher blood pressure at night than during the day (reversed pattern); 14 of these patients died (88%), compared to 40 of 88 patients (45%) with reduced dipping or normal dipping; log rank P = 0.001. In a Cox regression analysis, predictors of all-cause mortality were: age, male sex, presence of left ventricular hypertrophy, glycated haemoglobin A1c (HbA1c), daytime systolic blood pressure, cardiac autonomic neuropathy, glomerular filtration rate and dipping (1% increase; hazard ratio 0.97, 95% confidence interval 0.94-0.998, P = 0.033). CONCLUSION: Type 2 diabetes patients with non-dipping of night blood pressure were at higher risk of death as compared to dippers, independent of known cardiovascular risk factors. Since non-dipping has a high prevalence in patients with diabetic nephropathy, 24-h ambulatory blood pressure should be used to assess a full risk profile and blood pressure-lowering therapy in these patients.

Subclinical coronary and aortic atherosclerosis detected by magnetic resonance imaging in type 1 diabetes with and without diabetic nephropathy.

BACKGROUND: Patients with type 1 diabetes and nephropathy maintain an excess cardiovascular mortality compared with diabetic patients with normoalbuminuria. We sought to evaluate coronary and aortic atherosclerosis in a cohort of asymptomatic type 1 diabetic patients with and without diabetic nephropathy using cardiovascular magnetic resonance imaging. METHODS AND RESULTS: In a cross-sectional study, 136 subjects with long-standing type 1 diabetes without symptoms or history of cardiovascular disease, including 63 patients (46%) with nephropathy and 73 patients with normoalbuminuria, underwent cardiovascular magnetic resonance imaging. All subjects underwent cardiac exercise testing and noninvasive tests for peripheral artery disease and autonomic neuropathy. Coronary artery stenoses were identified in 10% of subjects with nephropathy (versus 0% with normoalbuminuria; P=0.007). Coronary plaque burden, expressed as right coronary artery mean wall thickness (1.7+/-0.3 versus 1.3+/-0.2 mm; P<0.001) and maximum right coronary artery wall thickness (2.2+/-0.5 versus 1.6+/-0.3 mm; P<0.001), was greater in subjects with nephropathy. The prevalence of thoracic (3% versus 0%; P=0.28) and abdominal aortic plaque (22% versus 16%; P=0.7) was similar in both groups. Subjects with and without abdominal aortic plaques had similar coronary plaque burden. CONCLUSIONS: In asymptomatic type 1 diabetes, cardiovascular magnetic resonance imaging reveals greater coronary plaque burden in subjects with nephropathy compared with those with normoalbuminuria.

Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.

OBJECTIVE: Cardiac autonomic neuropathy (CAN) has been associated with a poor prognosis in patients with diabetes. Because CAN is common in patients with diabetic nephropathy, we evaluated the predictive value of CAN in type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy and a matched group of 191 patients with long-standing type 1 diabetes and normoalbuminuria were followed for 10.1 years (range 0.0-10.3 years). At baseline, CAN was assessed by heart rate variation (HRV) during deep breathing. HRV was evaluated as a predictor of the primary end point: cardiovascular morbidity and mortality. As secondary end points, all-cause mortality and the influence of HRV on progression of diabetic nephropathy (decline in glomerular filtration rate [GFR]) was evaluated. RESULTS: During the follow-up, 79 patients (40%) with nephropathy reached the combined primary end point vs. 19 patients (10%) with normoalbuminuria (log-rank test, P < 0.0001). The unadjusted hazard ratio (HR) for reaching the primary end point when having an abnormal HRV (< or =10 bpm) measured at baseline compared with a normal HRV was 7.7 (range 1.9-31.5; P = 0.004) in patients with nephropathy. Similarly in the normoalbuminuric patients, the unadjusted HR was 4.4 (1.4-13.6; P = 0.009). In patients with nephropathy, abnormal HRV was significantly associated with fatal and nonfatal cardiovascular disease after adjustment for cardiovascular risk factors. The adjusted HR for reaching the primary end point in a patient with nephropathy and an abnormal HRV was 6.4 (1.5-26.3, P = 0.010), as compared with a normal HRV. The unadjusted HR for dying when having an abnormal HRV compared with a normal HRV was 3.3 (95% CI 1.0-10.7; P = 0.043) in patients with diabetic nephropathy. After adjustment for confounding factors, the impact of HRV on all-cause mortality in patients with nephropathy was no longer significant (P = 0.293). There was no relationship between abnormal HRV and rate of decline in GFR. CONCLUSIONS: HRV is an independent risk factor for cardiovascular morbidity and mortality in type 1 diabetic patients with nephropathy.

Improved prognosis in type 1 diabetic patients with nephropathy: a prospective follow-up study.

BACKGROUND: In early studies, a median survival time of 5 to 7 years from onset of diabetic nephropathy was observed. Furthermore, end-stage renal disease (ESRD) was the main cause of death. We prospectively assessed the impact of reno- and cardiovascular protective treatment on prognosis in type 1 diabetic patients with diabetic nephropathy. METHODS: We prospectively followed 199 type 1 diabetic patients with diabetic nephropathy and 192 patients with normoalbuminuria for 10 years. Aggressive antihypertensive treatment was initiated in patients with diabetic nephropathy in mid 1980s, whereas statins and aspirin were not prescribed routinely until April 2002. The primary end point was cardiovascular mortality and morbidity. Secondary end points were all-cause mortality and ESRD. RESULTS: During follow-up, 79 patients (40%) with nephropathy reached the primary end point versus 19 (10%) of normoalbuminuric patients, log rank test P < 0.0001. Predictors of the primary end point were: nephropathy (hazard ratio 3.26; 95% confidence interval 1.89 to 5.62), previous event (3.19; 2.04 to 4.97), age (1.27; 1.04 to 1.55), and systolic blood pressure (1.13; 1.03 to 1.24). In the nephropathy group, 60 patients (30%) died; hereof, 25 deaths (42%) were ascribed to cardiovascular causes while 30 patients (50%) with nephropathy died with ESRD. The estimate of median survival time from onset of diabetic nephropathy was 21.7 years, SE 3.3 years. CONCLUSION: The survival of patients with diabetic nephropathy has improved most likely due to aggressive antihypertensive treatment and improved glycaemic control.

Elevated placental growth factor (PlGF) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.

BACKGROUND AND AIM: Placental growth factor (PlGF) is up-regulated in early and advanced atherosclerotic lesions, acts as a primary inflammatory instigator of atherosclerotic plaque instability, and may be an independent biomarker of adverse outcome in patients with acute coronary syndromes. In diabetic nephropathy the relative cardiovascular mortality and morbidity is increased and therefore, this study investigated the prognostic value of PlGF in a large cohort of type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: In a prospective, observational follow-up study 190 type 1 diabetic patients with overt diabetic nephropathy (116 men, age (mean (SD)) 41+/-10 years, duration of diabetes 28+/-8 years, glomerular filtration rate (GFR) 76+/-33 mL/min/1.73 m2) and a matched control group of 174 patients with normoalbuminuria (104 men, age 43+/-10 years, duration of diabetes 27+/-9) were followed for 10 years (range: 0-10.3). The primary endpoint was a composite endpoint of cardiovascular death, hospitalization for myocardial infarction or stroke, coronary artery bypass grafting or percutanous coronary intervention, ischaemic amputation or peripheral bypass-surgery. Plasma PlGF was determined by an enzyme linked immunosorbent assay at baseline. RESULTS: During 10 years of follow-up 74 patients (39%) with diabetic nephropathy reached the primary endpoint versus only 18 (10%) of normoalbuminuric patients, log rank test; p<0.001. During follow-up 16 (25%) patients in the lowest, 24 (39%) in the middle and 34 (52%) patients in the upper tertile reached the primary cardiovascular endpoint, p=0.007. Hazard ratios in the second and third tertile as compared with the first tertile were 1.76 (0.92-3.38) and 2.64 (1.41-4.91) (p=0.009). Cox regression analyses including PlGF concentration as a continuous variable revealed an unadjusted hazard ratio of the primary endpoint for each 1 ng/L increase in PlGF of 1.10 (1.03-1.16), p=0.002; covariate adjusted hazard ratio 1.07 (1.00-1.14), p=0.03. CONCLUSIONS: Increased PlGF is a new independent predictor of cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.