Heavy metal pollutants and angiogenesis-factors in patients with coronary artery disease

Hintergrund: Die Erforschung bereits bekannter kardiovaskulärer Risikofaktoren wie Hypertension, Dyslipidämie, Diabetes mellitus, physische Inaktivität oder schlechter sozioökonomischer Status läuft auf Hochtouren. Schwermetalle wie cadmium, Quecksilber und Blei werden bei weiten nicht so intensiv beforscht obwohl bereits seit Jahrzehnten ein negativer Einfluss auf das kardiovaskuläre System vermutet wird; einerseits durch die Beeinflussung zirkulatorischer Komponenten per se, andererseits durch Verursachung von Risikofaktoren. Angiogenese und Angiostase sind Prozesse, die in der Genese von Herz-Kreislauf-Erkrankungen eine wichtige Rolle spielen. Die Ballance zwischen angiostatischen Faktoren wie Endostatin und Angiostatin sowie von Faktoren mit angiogenen Eigenschaften wie VEGF und osteopontin ist essentiell für die Homeostase des Zirkulationssystems. Ziel: Diese Studie untersucht Schwermetallgehalte und Spiegel angogener/statischer Faktoren bei PatientInnen mit koronarer Herzkrankheit (KHK) und deren Beziehung zu kardiovaskulären Risikofaktoren innerhalb der Studienpopulation. Material und Methoden: Insgesamt wurden 191 PatientInnen, 65 weibliche (mittleres Alter: 67,66 7,89 Jahre) und 128 männliche (mittleres Alter: 60,27 11,33 Jahre) mit KHK rekrutiert. Daten bzgl. Anamnese, Life-Style, Bildungsgrad, Ernährung wurden ebenso gesammelt wie aus Routinelabor-Befunden, EKG, Echokardiographie und Herzkatheter. Der Schweregrad der Koronarstenose wurde berechnet, indem 1 Punkt pro Segment mit leichter Stenose (<30 %), 2 Punkte pro Segment mit mittlerer Stenose und 3 Punkte pro Segment mit Schwerer Stenose vergeben wurden. Cadmium wurde im Harn, Quecksilber, Blei und Zink im Vollblut analysiert. Endostatin, Angiostatin und VEGF wurden im Serum, Osteopontin im Plasma analysiert. Resultate: Hypertension war present in 91,1 % der Fälle, Hyperlipidämie in 90,1 %, Übergewicht/Adipositas in 66 % und Diabetes in 27,2 %. Von 86, % der PatientInnen waren aktuelle Herzkatheterbefunde verfügbar. Die am häufigsten betroffenen Gefäßabschnitte waren die proximale und mediale LAD und RCA (49,1 %, 54,5 %, 47,3 %, 44,8 %). Der Schweregrad der Koronarstenosen korrelierte positiv mit Kreatinin (p=0,010), BUN (p=0,022), Harnsäure (p=0,035), Triglyzeriden (p=0,019) CRP (p=0,001), Leukozyten (p=0,007), systolischem Blutdruck (p=0,009) und BMI und negativ mit HDL (p=0,014). Obwohl Patienten höhere Werte bei Cadmium (1,05 vs. 0,90 myg/l), Quecksilber (0,60 vs. 0,41 myg/l), Blei (21 vs. 18 myg/l) und Zink (6370 vs. 5979 myg/l) aufwiesen, war der Unterschied nur bei Quecksilber signifikant (p=0,031). Es zeigte sich keine Korrelation zwischen den Metallspiegeln und dem Schweregrad der Stenosen oder der Präsenz/Absenz von Diabetes und Hypertension. Ex-RaucherInnen hatten jedoch höhere Cadmiumspiegel verglichen mit Nie-RaucherInnen (1,20 vs. 0,86 myg/l; p=0,033). Endostatin korrelierte negativ mit Quecksilber im Blut (p=0,014) und Angiostatin negativ mit Blei und Zink (p=0,049 bzw. 0,030). Angiostatin korrelierte jedoch positiv mit dem Schweregrad der Koronarstenosen (p=0,023). Der Ex-RaucherInnen-Status und Hypertension hatten keinen Einfluss auf die angiogenen/statischen Faktoren aber sowohl Osteopontin- als auch Endostatin-Level waren höher bei DiabetikerInnen und korrelierten mit HbA1c (p=0,044 bzw. 0,011). Zusammenfassung: In der untersuchten Studienpopulation, die hauptsächlich aus Ost-ÖsterreicherInnen bestand, scheint es unwahrschienlich, dass Quecksilber und Blei bedeutend zur Genese der KHK beitragen, da sie eher geringe Level auswiesen. Betreffend Cadmium wären jedoch weitere Studien und vor allem Überwachung ratsam. Angiostatin dürfte durch die Korrelation mit dem Stenose-Schweregrad von besonderem Interesse sein und auch der Zusammenhand von Endostatin/Osteopontin mit Diabetes muss näher erforscht werden.Background: Research effort in investigating well-known cardiovascular risk factors such as hypertension, dyslipidaemia, diabetes mellitus, physical inactivity and poor socioeconomic status is huge. However, heavy metal pollutant such as cadmium, mercury and plumbum are by far less often subject of cardiovascular research although they were suspected for decades to have a negative impact on cardiovascular diseases by either influencing components of the circulatory system per se or causing and worsening atherosclerosis. Both angiogenesis and angiostasis are processes that are involved in the genesis of coronary artery disease. The balance between angiostatic factors such as endostatin and angiostatin and factors with angiogenic potential like VEGF and osteopontin is essential for the homeostasis of the circulatory system. Aim: This thesis aims to investigate heavy metal pollutant amounts and levels of angiogenesis/stasis factors in patients with coronary artery disease (CAD) and their relationship to cardiovascular risk factors within the study population. Material and methods: In total 191 patients, 65 females (mean age: 67,66 7,89 years) and 128 males (mean age: 60,27 11,33 years) with coronary artery disease were recruited. Anamnestic data, information about lifestyle, education and nutrition and data from routine laboratory analysis, ECG, echocardiography and angiography were collected. Severity of coronary artery stenosis was calculated by giving one point per mild stenosis per segment (70 %). Cadmium amounts were analysed in urine; mercury, lead and zinc in full blood. Endostatin, angiostatin and VEGF levels were analysed in serum; osteopontin levels in plasma. Results: Hypertension was present in 91,1 %, hyperlipidaemia in 90,1 %, overweight/adipositas in 66 % and diabetes in 27,2 %. In 86 % results from recently performed angiography were available. Most commonly concerned coronary artery segments were the proximal and medial LAD and RCA (49,1 %, 54,5 %, 47,3 %, 44,8 %). Severity of coronary artery stenosis correlated positively with creatinine (p=0,010), BUN (p=0,022), uric acid (p=0,035), triglycerides (p=0,019) CRP (p=0,001), leucocytes (p=0,007), systolic blood pressure (p=0,009) and BMI and negatively with HDL (p=0,014). Although male patients showed higher levels for cadmium (1,05 vs. 0,90 myg/l), mercury (0,60 vs. 0,41 myg/l), lead (21 vs. 18 myg/l) and zinc (6370 vs. 5979 myg/l), significant difference was only found for mercury (p=0,031). There was no correlation between the metals and severity of stenosis and presence/absence of diabetes and hypertension. However, ex-smoking patients showed significantly higher levels for cadmium compared to never-smokers (1,20 vs. 0,86 myg/l; p=0,033). Endostatin levels correlated negatively with mercury amounts in blood (p=0,014) and angiostatin correlated negatively with both lead and zinc levels (p=0,049 and 0,030 resp.). Angiostatin correlated positively with severity of stenosis (p=0,023). Ex-smoking and hypertension had no influence on the angiogenesis-factors, however, both osteopontin and endostatin were higher in patients suffering diabetes and correlated with HbA1c (p=0,044 and 0,011 resp.). Conclusion: In this study population which mostly consisted of patients living in East-Austria, is seems improbably that mercury and lead contribute seriously to the genesis of CAD because the levels they reached were quite low. However, concerning cadmium amounts further studies and observation would be advisable. With regard to angiogenesis and angiostasis in particular angiostatin seems to be of interest because of its correlation with severity of stenosis and the role of osteopontin and endostatin in diabetes should also be investigated more deeply.submitted by Michael SponderAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersZsfassung in dt. SpracheWien, Med. Univ., Diss., 2014OeBB(VLID)171533

Endostatin and osteopontin are elevated in patients with both coronary artery disease and aortic valve calcification

Background: The angiostatic factor endostatin (ES) plays an important role as mediator of angiogenesis. Elevated osteopontin (OPN) was associated with valve calcification in healthy individuals. The present study aimed to investigate ES and OPN levels in patients with both coronary artery disease (CAD) and aortic valve calcification (AVC). Methods and results: In total 224 non- or ex-smoking patients (161 male, mean age: 61.09 ± 11.02 years; 63 female: mean age: 67.49 ± 7.87 years) with angiographically verified and quantified CAD were recruited. Serum ES and plasma OPN levels were measured by ELISA and AVC was evaluated by a parasternal short axis view and quantified as non-, mild or moderate/severe. There was a stepwise increase of ES measurable with increasing severity of AVC, independent from age, BMI and CAD-severity (p = 0.018; F = 4.09). OPN also increased significantly with the grade of AVC severity (p = 0.029; F = 3.61) but was no longer significant when the co-variables (p = 0.31; F = 1.18) were inserted. Conclusions: This is the first study showing an association of ES with AVC in CAD-patients independent from age, BMI and CAD-severity which seems to be of distinct interest when trying to understand the process of heart valve calcification. OPN also correlates with AVC-severity but is mostly dependent on the age of the patients

Heart and Vessels / Prevalence of early repolarization syndrome and long-term clinical outcome in patients with the diagnosis of idiopathic ventricular fibrillation

Idiopathic ventricular fibrillation (IVF) is diagnosed in up to 14% of sudden cardiac death (SCD) survivors. Early repolarization syndrome (ERS) in patients with ventricular tachyarrhythmia is characterized by an elevated J-point in inferior and/or antero-lateral leads. Our objectives were to determine the prevalence of ERS in IVF patients, and to evaluate potential differences in clinical outcome. Out of 3,552 implantable cardioverter defibrillator (ICD) carriers, 758 SCD survivors were retrospectively identified from the databases of the Medical Universities of Vienna and Innsbruck within the last three decades. Early repolarization pattern (ERP) was classified either as "notching" or "slurring". Endpoints were defined as appropriate ICD therapies for ventricular tachyarrhythmia, either anti-tachycardia pacing or shock, and all-cause mortality. After exclusion of recognized reasons for SCD, 50 patients were assigned to the diagnosis of IVF (6.6%). An ERP was identified in 10 patients, most of them with notching (n=8). After a mean follow-up of 11.26.7 years (539.3 patient years), appropriate ICD therapies were found in 50% of ERS and 43% of IVF patients without ERP (p=0.732). In ERS patients, all ICD therapies were found in patients with notching pattern. Similarly, incidence of inappropriate ICD therapies, and all-cause mortality was comparable (30% vs. 23%, p=0.707; 10% vs. 5%, p=0.496, respectively). In 758 SCD survivors, we found a low prevalence of IVF and ERS. Similar event rates were reported concerning all-cause mortality and ICD therapies for ventricular tachyarrhythmia after long-term follow-up in this cohort.(VLID)364364

Heart and Vessels / Long-term physical activity leads to a significant increase in serum sRAGE levels : a sign of decreased AGE-mediated inflammation due to physical activity?

There is growing evidence that low levels of the circulating soluble receptor of advanced glycation end products (sRAGE) are a valuable predictor of cardiovascular disease (CVD). The aim of this prospective study was to investigate the influence of long-term physical activity on serum sRAGE levels. 109 subjects were recruited, and 98 completed the study. Participants were asked to perform exercise within the calculated training pulse for 8 months. The performance gain was measured/quantified by bicycle stress tests at the beginning and end of the observation period. sRAGE was measured at baseline and after 2/6/8 months by ELISA. Backwards, multiple linear regression analysis was performed to investigate the association of co-variables age, sex, BMI, and performance at baseline, HbA1c, and lipoprotein a with baseline sRAGE levels. We identified BMI and lipoprotein a as significant predictors for baseline sRAGE levels. Compared to subjects with a performance gain 4.9% subjects with a gain > 5% showed a significant increase in sRAGE levels up to 22%. sRAGE serum levels correlate negatively with lipoprotein a levels and BMI and long-term physical activity leads to a significant increase in serum sRAGE levels (922%), whereby the sRAGE increase is most pronounced in subjects with initially low-performance levels, suggesting that in particular, these subject profit the most from increased physical activity. The sport-mediated increase of sRAGE might be a sign of decreased AGE-mediated inflammation and highlight the protective effect of sports on CVD and other disease which are at least partly mediated by an increased inflammation status. Clinical trials registration NCT02097199.(VLID)359103

Endurance training significantly increases serum endocan but not osteoprotegerin levels: a prospective observational study

Background Endocan (EN) was suggested a potential inflammatory and cardiovascular disease (CVD) marker which might also be involved in renal failure and/or renal failure-associated vascular events. It is not clear whether osteoprotegerin (OPG) is a pro- or anti-atherogenic factor, however, it is agreed upon that OPG is elevated in subjects with increased calcification status. The aim of the study was to investigate the influence of long-term physical activity on serum endocan (EN) and osteoprotegerin-levels. Methods One hundred nine subjects were told to increase their amount of physical activity for 8 months by performing 150min/week moderate or 75min/week vigorous exercise. Incremental cycle ergometer tests were performed at the beginning and the end of the study to prove and quantify the performance gain. Blood samples were drawn at baseline and every 2 months for the determination of EN and OPG. To investigate the difference between baseline and 8 months levels of EN and OPG we used a paired sample t-test. To investigate the significance of the tendency of the progression (baseline/2 months/4 months/6 months/8 months) we used a Friedman test. Results Thirty-eight female and 60 male subjects completed the study. In the group of 61 subjects who had a performance gain by >4,9% EN-levels increased from 146 110 to 196 238 pg/ml (p = 0,036) equivalent to an increase of 33,5% but there was no significant change in OPG (4,4 2,4 pmol/l vs. 4,3 2,1 pmol/l; p = 0,668). Conclusions Physical activity increases significantly EN-levels relativizing the status of EN as proinflammatory factor. EN should rather be considered as a mediator which is involved in several physiological (e.g., angiogenesis) but also pathological processes (e.g., CVD, tumour progression or endothelium-dependent inflammation) and whose expression can be significantly influenced by long term endurance training.(VLID)484340

Journal of Clinical Medicine / New Cardiovascular Biomarkers in Ischemic Heart DiseaseGDF-15, A Probable Predictor for Ejection Fraction

Background: Various biomarkers have been associated with coronary artery disease (CAD) and ischemic heart failure. The aim of this study was to investigate the correlation of serum levels of soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor 15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), and soluble suppression of tumorigenicity 2 (sST2) with left ventricular ejection fraction (EF) in CAD patients and controls. Methods and Results: CAD patients were divided into three groups according to their EF as measured by the biplane Simpson method (5384%, 3152%, 30%). Overall, 361 subjects were analyzed. In total, 155 CAD patients had an EF of 5384%, 71 patients had an EF of 3152%, and 23 patients had an EF of 30% as compared to 112 healthy controls (age 51.3 9.0 years, 44.6% female). Mean ages according to EF were 62.1 10.9, 65.2 10.1, and 66.6 8.2 years, respectively, with females representing 29.0, 29.6, and 13.0%. suPAR, GDF-15, H-FABP, and sST2 values were significantly higher in CAD patients and showed an exponential increase with decreasing EF. In a multiple logistic regression model, GDF-15 (p = 0.009), and NT-brain natriuretic peptide (p = 0.003) were independently associated with EF. Conclusion: Biomarkers such as suPAR, GDF-15, H-FABP, and sST2 are increased in CAD patients, especially in highly impaired EF. Besides NT-proBNP as a well-known marker for risk prediction, GDF-15 may be an additional tool for diagnosis and clinical follow-up.(VLID)491673

Irish Journal of Medical Science (1971 -) / Long-term endurance training increases serum cathepsin S levels in healthy female subjects

Background Circulating cathepsin S (CS) has been associated with a lower risk for breast cancer in a large Swedish cohort. Long-term physical activity has been shown to have beneficial effects on the development of various cancer subtypes, in particular breast and colorectal cancers. The aim of this study was to investigate the effect of long-term endurance sport on CS levels in females. Material and methods Thirty-six of 40 subjects completed the study. Subjects were told to increase their activity pensum for 8 months reaching 150 min/week moderate or 75 min/week intense exercise. Ergometries were performed at the beginning and the end of the study to prove/quantify the performance gain. Blood samples were drawn at baseline and every 2 months. Serum CS levels were measured by ELISA. To analyse the change and the progression of CS, Wilcoxon rank sum and Friedman tests were used. Results The sportive group (performance gain by > 4.9%) showed a significant increase of CS levels from 3.32/2.73/4.09 to 4.00/3.09/5.04 ng/ml (p = 0.008) corresponding to an increase of 20.5%. Conclusions We could show a significant increase of circulating CS levels in healthy female subjects induced by long-term physical activity. CS, occurring in the tumour microenvironment, is well-known to promote tumour growth, e.g. by ameliorating angiogenesis. However, the role of circulating CS in cancer growth is not clear. As physical activity is known as preventive intervention, in particular concerning breast and colorectal cancers, and long-term physical activity leads to an increase of CS levels in female subjects, circulating CS might even be involved in this protective effect. Trial registration Clinical trial registration: NCT02097199(VLID)366407