Douwe J. Mulder

Skin autofluorescence is elevated in acute myocardial infarction and is associated with the one-year incidence of major adverse cardiac events

Background.ST-elevation myocardial infarction (STEMI) is associated with increased inflammation and oxidative stress, enhancing the formation of advanced glycation endproducts (AGEs). These encompass a characteristic fluorescence pattern, which can be non-invasively measured as skin autofluorescence (AF). In this study we investigate whether skin AF is elevated in STEMI, its association with inflammatory and glycaemic stress and its predictive value for future events.Methods.Skin AF was measured in 88 STEMI patients (mean age 64±13 years) within 72 hours and around six months after discharge, in 81 stable coronary artery disease (sCAD) patients (64±10 years), and in 32 healthy controls (63±11 years). The cumulative one-year incidence of all-cause mortality and hospitalisation for myocardial infarction or heart failure was documented.Results.Skin AF was significantly higher in STEMI compared with sCAD and controls, irrespective of confounders, and was associated with HbA1c and C-reactive protein. Skin AF decreased significantly in STEMI patients, when measured >200 days after discharge. In STEMI patients, skin AF above the median was predictive of future events (hazard ratio 11.6, 95% CI 1.5 to 90.8, p=0.019).Conclusion.Skin AF is elevated in STEMI, is associated with inflammation and glycaemic stress, and predicts future major adverse cardiac events. (Neth Heart J 2009;17:162–8.)

Skin Autofluorescence as a Measure of Advanced Glycation End Products Deposition Is Elevated in Peripheral Artery Disease

Objective—Evidence for an important role of advanced glycation end products (AGEs) in the development of atherosclerosis and cardiovascular disease beyond diabetes mellitus and renal disease is growing. Skin autofluorescence (SAF) is a validated noninvasive measure of tissue AGEs. We hypothesized that SAF is elevated in peripheral artery disease (PAD). Methods and Results—A case–control study was performed in 492 patients with PAD and 164 controls, matched for age (mean 66±10 years) and presence of diabetes mellitus. Cardiovascular risk factors and comorbidity (coronary artery disease, cerebrovascular disease, abdominal aortic aneurysm) were assessed. SAF was measured with the AGE Reader. SAF was higher in patients compared with controls: geometric mean 2.77 (95% confidence interval [CI], 2.71–2.83) versus 2.44 (95% CI, 2.35–2.53) arbitrary units, P=0.4×10−8. In logistic regression, the adjusted odds ratio for the presence of PAD was 2.47 (95% CI, 1.66–3.69) per 1 unit increase of SAF. PAD patients with cardiovascular comorbidity had a higher SAF compared with those without: geometric mean 2.93 (95% CI, 2.85–3.02) versus 2.63 (95% CI, 2.55–2.71) arbitrary units, P=0.4×10−6, also after correction for confounders. Regression analysis showed that age, smoking, diabetes mellitus, chronic kidney disease, and a history of cerebrovascular disease or abdominal aortic aneurysm were independently associated with SAF in the patients with PAD. Conclusion—Accumulation of tissue AGEs is increased in patients with PAD, independent of cardiovascular risk factors and comorbidity, although these conditions are associated with a further increase. These findings underscore the importance of AGEs in PAD, irrespective of the presence of diabetes mellitus and renal insufficiency.

Skin Autofluorescence Is Associated With 5-Year Mortality and Cardiovascular Events in Patients With Peripheral Artery Disease

Objective—Advanced glycation end products play a pivotal role in atherosclerosis. Recently, we showed that tissue advanced glycation end products deposition, noninvasively assessed by skin autofluorescence (SAF), is increased in patients with peripheral artery disease. The aim of the present study was to establish whether SAF is associated with all-cause mortality and with fatal or nonfatal major adverse cardiovascular events (MACE) in patients with peripheral artery disease. Approach and Results—We performed a single-center prospective cohort study of 252 patients with peripheral artery disease (mean age, 66±11 years), recruited from the outpatient clinic (October 2007 to June 2008) who were followed until June 2013. SAF was measured with the AGE Reader. The primary end point was all-cause mortality, and the secondary end point was fatal or nonfatal MACE, defined as cardiovascular death and nonfatal myocardial infarction or stroke. During a median follow-up of 5.1 (interquartile range, 5.0–5.3) years, 62 (25%) patients died. Fatal or nonfatal MACE occurred in 62 (25%) patients. A higher SAF was associated with increased risk for all-cause mortality (hazard ratio per unit increase, 2.01; 95% confidence interval, 1.40–2.88; P=0.0002) and fatal or nonfatal MACE (hazard ratio, 1.82; 95% confidence interval, 1.28–2.60; P=0.001), also after adjustment for cardiovascular risk factors and the use of lipid-lowering drugs (hazard ratio, 1.63; 95% confidence interval, 1.13–2.34; P=0.009 and hazard ratio, 1.50; 95% confidence interval, 1.04–2.17; P=0.03, for all-cause mortality and fatal and nonfatal MACE, respectively). Conclusions—SAF as a measure of advanced glycation end products deposition is independently associated with all-cause mortality and fatal or nonfatal MACE in patients with peripheral artery disease after a 5-year follow-up.

Skin autofluorescence and risk of micro- and macrovascular complications in patients with Type 2 diabetes mellitus-a multi-centre study

Diabet. Med. 29, 1556–1561 (2012)

Advanced glycation end products and the absence of premature atherosclerosis in glycogen storage disease Ia

SummaryIntroductionDespite their unfavourable cardiovascular risk profile, patients with glycogen storage disease type Ia (GSD Ia) do not develop premature atherosclerosis. We hypothesized that this paradox might be related to a decreased formation of advanced glycation end products (AGEs) resulting from lifetime low plasma glucose levels and decreased oxidative stress.MethodsIn 8 GSD Ia patients (age 20–24 years) and 30 matched controls we measured carotid intima-media thickness (IMT), skin autofluorescence (AF; a non-invasive index for AGEs), and specific AGEs (pentosidine, N-(carboxymethyl)lysine (CML), N-(carboxyethyl)lysine (CEL)) and collagen linked fluorescence (CLF, measured at excitation/emission wavelength combinations of 328/378 and 370/440 nm) in skin samples.ResultsCarotid IMT was significantly lower in GSD Ia patients. Skin AF did not differ between patients and controls. The skin samples showed higher CEL levels in the patient group (p=0.008), but similar levels of pentosidine, CML, and CLF. In the total group, skin AF correlated with CML (r=0.39, p=0.031), CLF 328/378 nm (r=0.53; p=0.002) and CLF 370/440 nm (r=0.60; p=0.001). In the control group, AF also correlated with the maximum carotid IMT (r=0.6; p=0.004).ConclusionAlthough our data confirm that GSD Ia patients present with a reduced burden of atherosclerosis, this phenomenon cannot be explained by differences in AGE accumulation as measured in the skin.

Coronary artery calcification score and carotid intima-media thickness in patients with hemophilia

See also Makris M, van Veen JJ. Reduced cardiovascular mortality in hemophilia despite normal atherosclerotic load. This issue, pp 20–2; Biere‐Rafi S, Tuinenburg A, Haak BW, Peters M, Huijgen R, de Groot E, Verhamme P, Peerlinck K, Visseren FLJ, Kruip MJHA, Laros‐van Gorkom BAP, Gerdes VEA, Buller HR, Schutgens REG, Kamphuisen PW. Factor VIII deficiency does not protect against atherosclerosis. This issue, pp 30–7.

Skin Autofluorescence, a Non-Invasive Marker for AGE Accumulation, Is Associated with the Degree of Atherosclerosis

Introduction Advanced glycation endproducts (AGEs) may be involved in the development of atherosclerosis, beyond diabetes and renal disease. Skin autofluorescence (AF) is a non-invasive marker for AGEs. We examined whether skin AF is increased in (subclinical) atherosclerosis and associated with the degree of atherosclerosis independent of diabetes and renal function. Methods A cross-sectional study of 223 patients referred for primary (n = 163) or secondary (n = 60) prevention between 2006 and 2012 was performed. Skin AF was measured using the AGE-Reader. Ultrasonography was used to assess plaques in carotid and femoral arteries and computed tomography for the calculation of the coronary artery calcium score (CACS; in primary prevention only). Primary prevention patients were divided into a group with subclinical atherosclerosis defined as >1 plaque or CACS>100 (n = 67; age 53 year [interquartile range 48–56]; 49% male) and without (controls; 96; 43 [38–51]; 55%). Secondary prevention were patients with peripheral arterial disease (60; 64 [58–70]; 73%). Results Skin AF was higher in subclinical and clinical atherosclerosis compared with controls (skin AF 2.11 [interquartile range 1.83–2.46] and 2.71 [2.15–3.27] vs. 1.87 [1.68–2.12] respectively; P = 0.005 and <0.001). In a multivariate analysis, the association of skin AF with the atherosclerosis categories was independent of age, sex, diabetes, presence of the metabolic syndrome, Framingham Risk Score, and renal function. Skin AF correlated with most cardiovascular risk factors, Framingham risk score, and IMT and CACS. Conclusions Skin AF is increased in documented subclinical and clinical atherosclerosis, independent of known risk factors such as diabetes and renal disease. These data suggest that AGEs may be associated with the burden of atherosclerosis and warrant a prospective study to investigate its clinical usability as a risk assessment tool for primary prevention.

Skin Autofluorescence Based Decision Tree in Detection of Impaired Glucose Tolerance and Diabetes

Aim Diabetes (DM) and impaired glucose tolerance (IGT) detection are conventionally based on glycemic criteria. Skin autofluorescence (SAF) is a noninvasive proxy of tissue accumulation of advanced glycation endproducts (AGE) which are considered to be a carrier of glycometabolic memory. We compared SAF and a SAF-based decision tree (SAF-DM) with fasting plasma glucose (FPG) and HbA1c, and additionally with the Finnish Diabetes Risk Score (FINDRISC) questionnaire±FPG for detection of oral glucose tolerance test (OGTT)- or HbA1c-defined IGT and diabetes in intermediate risk persons. Methods Participants had ≥1 metabolic syndrome criteria. They underwent an OGTT, HbA1c, SAF and FINDRISC, in adition to SAF-DM which includes SAF, age, BMI, and conditional questions on DM family history, antihypertensives, renal or cardiovascular disease events (CVE). Results 218 persons, age 56 yr, 128M/90F, 97 with previous CVE, participated. With OGTT 28 had DM, 46 IGT, 41 impaired fasting glucose, 103 normal glucose tolerance. SAF alone revealed 23 false positives (FP), 34 false negatives (FN) (sensitivity (S) 68%; specificity (SP) 86%). With SAF-DM, FP were reduced to 18, FN to 16 (5 with DM) (S 82%; SP 89%). HbA1c scored 48 FP, 18 FN (S 80%; SP 75%). Using HbA1c-defined DM-IGT/suspicion ≥6%/42 mmol/mol, SAF-DM scored 33 FP, 24 FN (4 DM) (S76%; SP72%), FPG 29 FP, 41 FN (S71%; SP80%). FINDRISC≥10 points as detection of HbA1c-based diabetes/suspicion scored 79 FP, 23 FN (S 69%; SP 45%). Conclusion SAF-DM is superior to FPG and non-inferior to HbA1c to detect diabetes/IGT in intermediate-risk persons. SAF-DM’s value for diabetes/IGT screening is further supported by its established performance in predicting diabetic complications.

Skin autofluorescence is inversely related to HDL anti-oxidative capacity in type 2 diabetes mellitus

OBJECTIVE High density lipoprotein (HDL) particles protect apolipoprotein B-containing lipoproteins from oxidative modification. An impaired anti-oxidative functionality of HDL in type 2 diabetes mellitus (T2DM) may contribute to enhanced formation of oxidative stress products, such as Advanced Glycation Endproducts (AGEs). We tested whether in T2DM the HDL anti-oxidative capacity is related to the accumulation of AGEs in the skin. METHODS Skin autofluorescence (AF), a non-invasive read-out for AGEs, and HDL anti-oxidative capacity, i.e. the ability of HDL to protect against LDL oxidation in vitro, were assessed in 67 non-smoking T2DM patients without complications (median age: 60 (53-65), 60% males, 6.5 (5.2-8.5) years of diabetes duration). RESULTS In univariate analysis, skin AF correlated inversely with HDL anti-oxidative capacity (r=-0.305, P<0.02), but not with HDL cholesterol or apolipoprotein A-I. HDL anti-oxidative capacity correlated inversely with glucose, HbA(1c), triglycerides, and insulin resistance (homeostasis model assessment) (P<0.05 to P ≤ 0.001). Multiple linear regression showed that skin AF remained inversely related to HDL anti-oxidative capacity (partial r=-0.314, P=0.015) taking account of age, plasma glucose, non-HDL cholesterol, triglycerides, HOMA(ir), and CRP. CONCLUSION These findings suggest that skin AF is inversely related to the HDL anti-oxidative capacity rather than to the HDL cholesterol concentration in T2DM. Impaired anti-oxidative functionality of HDL could contribute to tissue accumulation of AGEs.

Skin Autofluorescence as a Measure of Advanced Glycation End Products Deposition Predicts 5-Year Amputation in Patients With Peripheral Artery Disease

Objective—Patients with peripheral artery disease are at risk for critical limb ischemia and amputation. Accumulation of advanced glycation end products is increased and predictive for coronary and cerebrovascular events in several high cardiovascular risk groups. We hypothesized that accumulation of tissue advanced glycation end products, measured by skin autofluorescence (SAF), predicts amputation in patients with peripheral artery disease. Approach and Results—Between October 2007 and June 2008, 252 patients with peripheral artery disease were included at the outpatient clinic. During a 5-year follow-up, 22 (9%) had an amputation because of critical limb ischemia. Competing risks regression analysis showed a subproportional hazard ratio of 3.05 (95% confidence interval [CI], 1.87–4.96); P<0.0001 for amputation per unit incease of SAF. After correction for diabetes mellitus and Fontaine stage, subproportional hazard ratio was 2.72 (95% CI, 1.38–5.39); P=0.004. In patients with Fontaine stage I and II only (n=215), SAF was the only predictor for amputation, subproportional hazard ratio 4.05 (95% CI, 2.09–7.83); P<0.0001. Fontaine stage multiplied by SAF resulted in a significant increase of the area under the curve for prediction of amputation when compared with Fontaine stage only: area under the curve increased from 0.74 (95% CI, 0.63–0.86) to 0.83 (95% CI, 0.74–0.92); P=0.003. Conclusions—Skin autofluorescence, as a measure of tissue advanced glycation end products deposition, predicts amputation in patients with peripheral artery disease during a 5-year follow-up, independent from the presence of diabetes mellitus and Fontaine stage. Even at lower Fontaine stage (I or II), SAF is a strong predictor of amputation. The multiplication of Fontaine stage by SAF results in a good prediction model of amputation.