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  1. 1. Workshop 5: Arteriosclerosis: basic mechanisms and clinical consequences 122 The gap between evidence based medicine and clinical practice in ACS - the Swedish experience U. Stenestrand Department of Cardiology, University Hospital Linköping, Sweden Sweden has since 1995 had a national quality assurance registry that records all patients with suspicion of ischemic heart disease admitted to coronary care units at participating hospitals. Since the year 2002 the Register of Information and Knowledge about Swedish Heart Intensive care Admissions has covered over 90% of all ACS patients in Sweden. Data is recorded prospectively by attending doctors and nurses over the internet. The register includes background data regarding concomitant diseases and risk factors. During hospital stay interventions, medications and test results are recorded in the registry. Every year about 60.000 new hospitalisations are entered into the registry. Today 73 of 75 Swedish hospital participates. This gives us an unique opportunity to investigate how different hospitals adhere to European and national guidelines regarding evidence based medicine within a whole country. Due to the use of personal identification numbers in Sweden, complete follow up regarding new hospitalisations and death is possible in all Swedish citizens. Initially there were very large differences between hospitals in adherence to guidelines, ranging from 10% to 90% at different hospitals. Variations could be seen in all evidence based therapies including antiplatelet therapy, beta-blockers, ACE-inhibitors, statins, reperfusion therapy, and use of coronary angiography. To make hospitals aware of this was not enough initiative for the low achievers to improve. Several measures have been taken and in recent years adherence to guidelines has improved substantially. We have also been able to correlate better adherence to guidelines within a hospital to improved outcome in patients with acute myocardial infarction. Our experience is that quality registries are needed to assure that patients receive evidence based medicine. Further supportive systems and engaging activities are needed to involve attending physicians in the improvement of quality of care. 122a The gap between evidence based medicine and clinical practice in ACS - the European experience A.K. Gitt Institut für Herzinfarktforschung, Universität Heidelberg, Germany Cardiovascular diseases continue to be the main cause of death, and a major cause of morbidity and loss of quality of life in Europe. New options for the treatment of cardiovascular diseases have resulted in an increasing number of patients who survive a cardiovascular event, and who require subsequent medical or interventional therapy. Due to strict inclusion criteria especially the elderly, an increasing patient population in clinical practice, are not represented by randomised controlled trials. The European Society of Cardiology takes responsibility for the development of clinical practice guidelines to translate the findings of mainly randomised trials into treatment recommendations for clinical practice. The Euro Heart Survey Programme of the ESC monitors to which extent clinical practice corresponds with these guidelines. It was developed to achieve three main goals: 1. To assess the adherence of guidelines for the prevention, diagnosis and management of cardiovascular disease in clinical practice in the ESC member countries. 2. To evaluate to what extent patients who are seen in the daily clinical practice of cardiology and vascular medicine are
  2. 2. appropriately represented in clinical trials, which are the main source for guideline development. 3. To assess the relation between the adherence to clinical practice guidelines and patient outcome. Within the Euro Heart Survey Programme two ACS-surveys were conducted in 2000 and in 2004 to document presentation of ACS and its treatment and outcome in clinical practice throughout Europe. The data of both ACS-surveys provide answers to the main questions of the programme: 1. There is a wide variation in practice among hospitals in Europe, as well as among hospitals in individual countries. Adherence to guidelines is variable and there is still space for improvement. Comparing both survey periods, in ACS-II, ACS-patients with and without ST-elevation did receive recommended medical treatment more often during hospitalization and at discharge, suggesting an improvement in adherence to guidelines as compared to ACS-I. Especially the use of coronary interventions such as coronary angiography and PCI was more frequent in both ACS with and without ST-elevation in 2004 as compared to 2000. Although the time from symptom onset to acute reperfusion therapy was shortened in the second survey, there were still delays beyond the recommended time for reperfusion therapy. Although acute reperfusion for STEMI went up from 56% in 2000 to 64% in 2004 with a significant shift from fibrinolytic therapy to primary PCI, one third of the STEMI patients did not receive any reperfusion treatment, partly due to late arrival. 2. Patients seen in routine clinical practice differ significantly from those selected for participation in clinical trials as they are older, more often female, have a more severe cardiac condition and more often suffer from concomitant diseases. Evidence based medicine described by guidelines does not cover this specific patient population. 3. Patients managed according to guidelines have overall best patient outcomes. A total of 34 centres participated in both surveys in 2000 and in 2004. The documented increases in the use of evidence-based therapies and interventions were accompanied by a reduction in mortality for ACS-II as compared to ACS-I. The relative risks of hospital and 30-day mortality were 42% and 34% lower in ACS-II in comparison with ACS-I. National ongoing registries enrolling consecutive ACS patients such as the Swedish RIKS-HIA- Registry or the German MITRAplus-Registry were able to document the influence of improved guideline adherence on acute and long-term outcome of ACS patients. By documenting daily practice and benchmarking each hospital against the overall rest of the participating centres, gaps between guidelines and current real practice in the treatment of ACS patients became visible and treatable. Based on these experiences the Euro Heart Survey Programme started two ongoing registries in ACS and PCI in 2006 which will offer “quality assurance” through benchmarking to the participating hospitals to improve quality of care in Europe. 123 How to close the gap B. Lindahl Department of Cardiology and Uppsala Clinical Research Center, Uppsala, Sweden Background: The Swedish National Register of coronary care (RIKS-HIA) and other national and international registries have repeatedly shown a considerable gap between optimal treatment of acute myocardial infarction (AMI) according to current guidelines and what is actually given. Even in the best performing hospitals, it is common that no more than two thirds of the patients receive a recommended treatment. Much of the effort to improve the quality of care has so far been focused on the development and dissemination of evidence-based guidelines. However, mere publications of guidelines and other forms of passive diffusion of information have been ineffective in changing physician’s behaviour, and more successful interventions have instead relied on a multifaceted approach. In the AMI area, a handful of studies have used various quality improvement (QI) strategies such as the collaborative approach. A weakness in these studies has been the lack of properly selected control groups, which has been an important impediment when interpreting the results. We therefore designed a prospective controlled study with the primary
  3. 3. objective of examining the extent to which a multicentre quality improvement collaborative, in combination with continuous local feedback by a web-based registry, could increase adherence to national AMI guidelines. Methods: Multidisciplinary teams from 19 hospitals participating in RIKS-HIA, ranging from small to large hospitals, were trained in continuous quality improvement methodology, 19 matched hospitals also participating in RIKS-HIA served as controls. The work was focused on finding and applying tools and methods suited to the local situation in order to increase adherence to the national guidelines for 5 different treatments in AMI. The base line level of treatment was determined during the year prior to start of the project. The initial 6 months were a training and implementation phase. After this phase the effects were measured for 12 months and compared with the “spontaneous” changes in the control hospitals. Results: In the control and QI intervention hospitals, the mean absolute increase of patients receiving ACE-inhibitors was 1.4% vs 12.6% (p=.002); lipid lowering therapy 2.3% vs 7.2% (p=.065); clopidogrel 26.3% vs 41.2% (p=.010); heparin/l.m.w.heparin 5.3% vs 16.3% (p=.010) and coronary angiography 6.2% vs 16.8% (p=.027), respectively. The number of QI intervention hospitals reaching a treatment level of at least 70% in ≥4 of the 5 indicators stated above was 15 vs. no hospital in the control group. Conclusions: By combining a systematic and multidisciplinary quality improvement collaborative with continuous compilations of performance feedback from a web-based quality registry, major improvements in the adherence to national AMI guidelines were achieved. This combined model is widely applicable for quality improvement initiatives in cardiac care. 124 Old and new markers – what does every doctor need to know? J. Ravkilde Department of Cardiology, Aarhus University Hospital (Skejby), Aarhus, Denmark The diagnosis of acute coronary syndrome (ACS) i.e., acute myocardial infarction, unstable angina pectoris and sudden cardiac death has changed significantly within the recent years. The background for this is based on the interest in risk stratification of patients with ACS due to improved knowledge of pathology, progress in immunoassays of already existing biochemical markers, the introduction of new biochemical markers, especially cardiac troponin I (cTnI) and T (cTnT)], and new methods of treatments. This lecture at the 41st Annual Meeting of the ESCI is concentrating on the new definition of acute MI of 2007, the potential difference of cardiac troponin I and T in diagnosing ACS, and that old markers is - old. The use of troponins in guidelines from the cardiology community i.e, European Society of Cardiology, American College of Cardiology/American Heart Association as well as from the clinical biochemist community i.e, American Association of Clinical Chemistry, National Academy of Clinical Biochemistry and International Federation of Clinical Chemistry is aimed clarified as well as the conditions one has to bear in mind regarding the choice of biomarker including the specific biomarker (s), immunoassay (which generation), the cut-off value of each biomarker keeping in mind the diagnostic window and the site of implication (general practitioner, emergency room, chest pain unit, coronary care unit). The above will be seen from a clinical/cardiologist point of view with the purpose to be employed in everyday use of diagnosing ACS patients. 125 Associations between genetic variations and levels of biochemical markers and outcome in acute coronary syndromes A. Siegbahn Clinical Coagulation Science, Uppsala University, Uppsala, Sweden
  4. 4. The underlying cause of acute coronary syndromes (ACS) is the chronic degenerative inflammatory process of atherosclerosis. The vessel wall injury at the site of plaque rupture exposes collagen and induces rapid activation of platelets. Rupture of lipid-rich coronary plaques exposes the highly thrombogenic core with an abundance of tissue factor (TF) to the circulating blood, thus setting off the coagulation cascade. In ACS, we and others have demonstrated an activation of coagulation and inflammation that coinsides with an increased activation of platelets and leukocytes. CD40L is largely expressed by CD4+ T-cells and activated platelets. Coupling of CD40L to CD40 mediates various proatherogenic processes including expression of TF. IL-6, a pleiotropic, proinflammatory cytokine, plays an important role in the development and progression of ACS and plasma levels are independent markers for future events. The antiinflammatory cytokine IL-10 in vitro inhibits the monocyte/macrophage production of TF and proinflammatory cytokines. However, in ACS the role of IL-10 is unresolved. The interindividual variations of phenotypes, including clinical and biochemical risk factors for ACS, mostly have a genetic cause. Well established classical riskfactors, such as smoking, diabetes, blood pressure, and genetic factors act in cooperation in the development and progression of atherothrombosis in these syndromes. We investigated the importance of a number of single nucleotide polymorphisms (SNPs) in four candidate genes, i.e TF, CD40L, IL-6 and IL-10, for atherothrombosis and prognosis of ACS using the well-characterised material from the Fast Revascularisation in InStability in Coronary disease trial (FRISC-II) including patients with unstable angina or non-ST elevation MI. Plasma samples and DNA were obtained on admission from 3489 patients in the FRISC-II study. Five hundred healthy individuals similar in age and gender as the patients served as controls. Ten to fifthteen SNPs in each gene were analysed in relation to intermediate phenotypes and environmental factors. A novel SNP in the TF gene was identified; the 5466A>G SNP was associated with significantly higher risk of death/MI in ACS. The cardiovascular risk was explained by a high TF procoagulant activity in monocytes. In contrast to these results, plasma soluble(s)CD40L concentrations were associated with increased risk of future MI, but not with death, in the FRISC-II patients. Elevated sCD40L concentrations also identified patients that benefit from a prolonged treatment strategy. The novel -3459 A>G SNP in the CD40LG gene was associated with plasma concentrations of sCD40L. The -572 CG genotype in the IL-6 gene predicted IL-6 concentrations in patients with a subsequent cardiovascular event. One SNP in the IL-10 gene was associated with IL-10 levels and also with other inflammatory markers. High Il-10 concentrations were not protective in the context of cardiovascular events, but rather indicated an increased systemic inflammatory activity. The genotype/phenotype variants discussed have the potential effects to modify risk, progression and outcome in ACS and exemplify the interplay of coagulation and inflammation in these syndromes. 126 Diabetes and cardiovascular disease A. Norhammar Physiology clinic and Cardiology Unit, Institution of Medicine, Karolinska University Hospital, Stockholm, Sweden Despite improvement in the treatment of cardiovascular disease there is evidence that individuals with diabetes have not gained the same benefit as their non-diabetic counterparts. In fact the relative impact of diabetes on cardiovascular mortality is steadily increasing. Cardiologists seem more focused on measures directed towards the manifestation of the cardiac condition and do not fully appreciate the need for simultaneous interactions directed towards the underlying metabolic disorder to reach full effect of the therapy for the cardiac disorders. Diabetologists have succeeded in improving treatment for insulin dependent diabetes mellitus. As regards non-insulin dependent diabetes there increased attention has lately been devoted to therapeutic measures that
  5. 5. may decrease the risk for cardiovascular complications, but there is still a need for considerable improvement. Enhanced co-operation between diabetologists and cardiologists is a key success in this respect. The prevalence of type 2 diabetes, about 90% of the diabetic population, increases rapidly due to an ageing population in combination with increasing over weight and decreased physical activity. The increasing prevalence suggests a considerable rise in diabetes related cardiovascular disease in the near future. It is not only overt diabetes that relates to an enhanced risk for cardiovascular disease. This risk increases continuously throughout a wide spectrum of glycaemia starting already at levels that, according to present definitions, are considered as normal. The proportion of patient with known diabetes is around 20-25% among people with acute of stable manifestations of coronary artery disease. The actual proportion of impaired glucose tolerance or previously undetected diabetes is, however, considerable higher amounting to around 60%. Screening for diabetes and hyperglycemia, by means of oral glucose tolerance testing, is therefore recommended in such patients. In the present coronary care setting it seems that evidence-based treatment of acute coronary disease in patients with concomitant diabetes is under utilised. Moreover there is a considerable discrepancy between recommended treatment targets and actual management of traditional risk factors in particular hypertension and hyperlipidaemia among diabetic high risk patients. It may be assumed that an improved application of established treatment modalities would improve the outcome for the diabetic patients, however, only to a certain extent. Diabetes specific disturbances, including hyperglycemia and a decreased thrombolytic capacity, are certainly important contributors to the high morbidity and mortality that follows diabetes and impaired glucose tolerance. The potential for interaction with theses disturbances by means of metabolically directed treatment will be reviewed. A limitation when issuing preventive and /or therapeutic recommendations is lack of data from trials on accurately characterised diabetes. Prospective stratification of diabetic patients in large clinical trials and documentation of their glucose lowering treatment and metabolic characteristics or, even better, studies on pure diabetic population are sparse. This is astonishing in the light of the increasing commonness of diabetes mellitus and the high prevalence of diabetic patients among those with manifestation of coronary artery disease. It should encourage to further research in this field. 127 Reperfusion treatment of STEMI in 2007 O. Hlinomaz Clinic of Cardioangiology, St. Anne University Hospital, Brno, Czech Republic Primary percutaneous coronary intervention (PCI) is a method of choice for treatment of patients with acute myocardial infarction with ST segment elevation (STEMI) in Czech Republic. The PRAGUE-1 study proved that transferring patients from community hospitals to a tertiary angioplasty centre is feasible and safe. Facilitation with streptokinasis before transport for primary PCI did not show benefit for the patients with STEMI in PRAGUE-1 study. This data were confirmed by ASSENT-4 trial which was published recently. So, there is no evidence for the recommendation of thrombolysis-facilitated PCI at present time. The PRAGUE-2 and DANAMI-2 studies confirmed, that long distance transport from a community hospital to tertiary PCI centre in the acute phase of STEMI was not only safe, but also markedly decreased mortality in patients presenting >3 hrs after symptom onset. For patients presenting within 3 hrs of symptoms, thrombolysis results were similar to those with long distance transport for primary PCI. CAPTIM trial proved, that prehospital thrombolysis can be effective especially in patients presenting in first hours of STEMI. Transport to the PCI centre directly from the home of the patient is essential to shortcut the treatment delay.
  6. 6. Treatment of STEMI in 2007 depends on the national specifications very much. In Central European countries, where distances are small, quality of roads is good and so the time delay can be minimized, primary PCI is the method of choice. In countries with not sufficient network of myocardial infarction centers thrombolysis remains a useful therapy for many STEMI patients. 128 CVD and renal dysfunction: Scope of the problem A.G. Jardine BHF Glasgow CRC, University of Glasgow, United Kingdom Preventative cardiovascular disease is increased in patients with chronic kidney disease (CKD). The magnitude of the increase in CVD is increased as GFR declines. However, it remains unclear what the underlying mechanisms for the increased CVD are. In the absence of specific studies in patients with early CKD we are reliant on sup group analyses of population studies on interventional trials in other patient groups together with data from patients with end-stage renal failure. From these data it appears that: 1) CVD in CKD differs from the general population – although there is an increase in sudden arrhythmic death; 2). There is clustering of conventional CV risk factors with CKD and 3) CKD is associated with additional risk factors specifically for arrhythmias and sudden death. Improved understanding of the pathophysiology of CVD in CKD has important implications for its treatment. 129 Inflammation in end-stage renal disease – a fire that burns within P. Stenvinkel Dept. of Renal Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden Cardiovascular disease (CVD) remains the major cause of morbidity and mortality in end-stage renal disease (ESRD) patients. As traditional risk factors alone cannot alone explain the high prevalence and incidence of CVD in this high-risk population, inflammation, which is interrelated to insulin resistance, dyslipidemia, oxidative stress, wasting and endothelial dysfunction, has been suggested to be a significant contributor. Indeed, several different inflammatory biomarkers, such as high sensitivity C-reactive protein (hs-CRP), interleukin-6 and white blood cell count, are independent predictors of mortality in ESRD patients. As CRP is strongly associated with CVD it has been suggested that this hepatic-derived protein is not only a marker, but also a mediator, of vascular disease. Although in vitro data from studies on endothelial cells, smooth muscle cells and monocytes-macrophages support a direct causative role for CRP in atherogenesis data from studies using the Mendelian randomization approach does not suggest a direct causative role. There are multiple causes of inflammation in ESRD, including inflammatory signals associated with the dialysis procedure, decreased renal function, volume overload, co-morbidity and intercurrent clinical events. The fact that the prevalence of inflammation varies considerable between continents and races suggests that dietary and/or genetic factors may have an impact on the pattern of inflammation in ESRD. As interventions directed towards traditional risk factors has so far not proven to be very effective in controlling vascular disease, randomized controlled studies are needed to evaluate if various nutritional as well as pharmacological anti-inflammatory treatment strategies, alone or in combination, may affect the unacceptable high cardiovascular mortality rate in this patient group. 130 Vascular calcification in uremia – when men turn to stone M. Ketteler Department of Nephrology, Klinikum Coburg, Germany
  7. 7. Tissue calcification is a complex and coordinated process in bone, teeth as well as at extraosseous sites. However, the most threatening localization of unwanted calcification is at vascular sites, where it manifests as both medial and intimal calcification of arteries. Atherosclerotic plaque calcification is associated with cardiovascular events such as myocardial infarction and stroke. Medial calcification causes arterial stiffness, increased pulse pressure and increased pulse wave velocity, and contributes to left ventricular dysfunction. Vascular calcifications are usually progressive, while their severity is highest in patients with chronic kidney disease (CKD) and associated with increased mortality in this population. Age, duration of dialysis, inflammation and diabetes mellitus are major predictors of progressive calcification. Additionally, hyperphosphatemia and hypercalcemia contribute to extraosseous calcifications. Both trigger osteogenic differentiation of vascular smooth muscle cell (VSMC) into osteoblast-like cells, while high phosphate may be a master switch towards unwanted calcification processes. Newly discovered calcium(Ca)-regulatory factors with calcification-inhibitory properties include the negative acute-phase protein fetuin-A, the vitamin K-dependent protein matrix Gla protein (MGP), osteoprotegerin (OPG) and pyrophosphates (PP). In cohorts of dialysis patients, low serum fetuin-A and high OPG levels were found to be associated with increased extraosseous calcification as well as mortality, and further clinical data currently emerge for additional Ca- regulatory factors. Anti-inflammatory drugs, vitamin K and bisphosphonates may have preventive and therapeutic potential in selected patients in the future. 131 Renal impairment as prognostic marker in acute coronary syndromes B. Lindahl Department of Cardiology and Uppsala Clinical Research Center, Uppsala, Sweden Patients presenting with symptoms suggestive of an acute coronary syndrome (ACS), constitute a diagnostic, prognostic and therapeutic challenge. These patients encompass a broad spectrum of diagnoses with different prognosis, from relatively large MI over minor MI or UA to chest pain of noncardiac causes, but must be considered to have an ACS until otherwise is proven. Hence, early prognostic evaluation is essential for the application of appropriate treatment and further management. Many clinical variables and biochemical markers have been shown to be predictive of future events in this group of patients. It has been known for a long time that severe renal impairment is associated with a strongly increased risk of cardiovascular events. However, recently it has been shown in several papers, including some from our group, that even a subtle impairment in renal function is associated with an adverse prognosis after an episode of ACS. Renal function can be assessed by several different methods. Among them, Cystatin C has been shown to be at least an accurate marker of renal function as calculated creatinine clearance, and has in some papers been shown to be superior to creatinine and calculated creatinine clearance as prognostic marker in patients with ACS. Although markers of renal dysfunction have been shown to be useful for determining prognosis, they have not so far been shown to be useful for selection of treatment in ACS. In this workshop the literature will be reviewed and the practical use of markers of renal dysfunction will be discussed. 132 Vascular function in renal dysfunction L. Lind Dept. of Medicine, Uppsala University Hospital, Uppsala, Sweden Background: Renal dysfunction is a condition known to be associated with an increased risk for atherosclerosis-related cardiovascular disorders. Methods: The present presentation will review studies that have investigated endothelium- dependent vasodilation and arterial compliance in subjects with renal dysfunction. Also the
  8. 8. pathophysiological links between a reduced kidney function and impairments in endothelium- dependent vasodilation and arterial compliance will be discussed. Conclusion: Existing data clearly indicate that renal dysfunction has a deleterious effect on endothelium-dependent vasodilation and arterial compliance, two main characteristics of arterial function. 133 Lipoprotein abnormalities and cardiovascular disease in chronic renal disease O. Samuelsson Dept. of Nephrology, Sahlgrenska Hospital, Göteborg, Sweden Chronic renal insufficiency is associated with several metabolic abnormalities. Already at mildly reduced renal function the patients are insulin resistant, and have lipoprotein alterations. With more advanced renal functional impairment this, so called, renal dyslipidemia becomes more pronounced. It is characterized by an accumulation of triglyceride-rich lipoproteins, whereas cholesterol-rich lipoproteins are in the normal range or only slightly increased. In contrast to the epidemiological evidence in the general population the relation between lipoprotein abnormalities and cardiovascular disease (CVD) still remains to be clarified in patients with chronic renal disease. In patients with end-stage renal disease neither increased cholesterol nor increased triglyceride levels have been shown to correlate with CVD mortality and morbidity. Post-hoc, subgroup analyses from the CARE and VA-HIT trials suggest that both statin and fibrate therapy have beneficial effects on CVD in patients with mild renal insufficiency. However, in patients on renal replacement therapy both the 4D- and the ALERT study, which both used statins, were disappointingly negative in this regard. Since statins primarily reduce cholesterol-rich lipoproteins, and the majority of patients with such advanced renal insufficiency have normal levels of these lipoproteins this poor outcome may not be surprising. Treatment with a PPAR agonist with dual actions on both PPARα and PPARγ seems to be superior to both statin and fibrate therapy in normalizing the lipoprotein abnormalities of renal failure. However, there is presently no such drug in development for clinical use. Thus, the appropriate way to handle renal dyslipidemia is far from being established. Therefore, the widespread recommendations from various national boards and nephrology societies to prescribe statins to all patients with chronic renal disease must be questioned. 134 Ischemia-modified albumin does not detect acute coronary syndrome S. C. Martin, S. C. Pallant & D. Stuart-Thompson West Suffolk Hospital, Bury St. Edmunds, UK. Background: Ischemia-modified albumin (IMA) has been proposed as an early marker of acute coronary syndrome allowing early risk stratification in the Emergency Room. Materials and methods: Every patient attending the hospital’s Emergency Room with “Chest pain” over a 3 week period had an IMA analysis (Inverness Medical) performed on the first blood sample using a Roche Modular analyser (in accordance with the manufacturer’s instructions). Results: There was no relationship between IMA levels and troponin I, CRP, albumin, d-dimer or white cell counts. The closest relationship was a negative one between IMA and CRP with an R 2 value of 0.021. Conclusions: IMA is not a useful test for acute coronary syndrome. 135 Impact of posttransplant weight gain on cardiac allograft vasculopathy G. Höfle1,2,3, C.H. Saely2, M. Martinelli1,, R. Hullin1, B. Meier1, T. Carrel4, M. Seitz3, P.M. Villiger3 & P. Mohacsi1
  9. 9. 1 Dept. of Cardiology, Swiss Cardiovascular Center Bern, University Hospital, Bern, Switzerland; 2 Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT) and Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 3Dept. of Rheumatology and Clinical Immunology/Allergology, University Hospital, Bern, Switzerland; 4Dept. of Cardiovascular Surgery, University Hospital, Bern, Switzerland Background: Excessive weight gain and obesity are commonly reported after heart transplantation (HTx). Currently, it is not clear whether weight gain is a risk factor of cardiac allograft vasculopathy (CAV) in heart transplant recipients. Materials and methods: We studied all patients (n = 95; mean age 50 ± 13 years) who underwent orthotopic cardiac transplantation at the Swiss Cardiovascular Center Bern since 1994 and survived for ≥1 year. Vascular risk factors were registered before transplantation and at regular follow-up visits. Coronary angiography was performed yearly for the evaluation of CAV. The follow-up period was 6 ± 3 years. Results: Baseline body mass index (BMI) was 24 ± 3 kg/m² and increased to 28 ± 4 kg/m² at follow-up year 10 (+4; p<0.001). Weight gain proved inversely associated with incident CAV (hazard ratio 0.78, 95% confidence interval (CI) 0.64 – 0.94; p=0.01) in Cox regression analysis adjusting for type 2 diabetes, BMI preHTx, hypertension, recipient ischemic heart disease preHTx, number of cardiac allograft rejection episodes, lipids, statin use, recipient age and gender. In contrast, recipient preHTx ischemic heart disease was positively predictive of the incidence of CAV (hazard ratio 7.22; 95% CI 1.70 – 30.61; p<0.01). No significant associations between hypertension, lipid parameters, gender, type 2 diabetes, or recipient age at the time of HTx with CAV were observed. Conclusions: Weight gain after heart transplantation is common but does not necessarily reflect a risk factor for CAV in heart transplant recipients. Recipient preHTx ischemic heart disease is positively predictive of the incidence of CAV. 136 Healthy postmenopausal women with higher index of androgenicity exhibit a pro- atherogenic risk profile I. Lambrinoudaki(1), G. Christodoulakos(1), S. Vlachou(1), D. Rizos(2), E. Economou(2), J. Argeitis(1), M. Creatsa(1), E. Kouskouni(2), A. Augoulea(1) & D. Botsis(1) (1) 2nd Department of Obstetrics and Gynecology, University of Athens, Aretaieion Hospital, Athens, Greece; (2) Hormonal and biochemical Laboratory, University of Athens, Aretaieion Hospital, Athens, Greece Background: Cross-sectional study in order to assess the association between endogenous sex hormones and risk factors for atherosclerosis in healthy postmenopausal women. Material and methods: Serum sex hormones and lipid-lipoprotein profile, arterial pressure, homocysteine and insulin resistance by the HOMA-IR model were assessed in 626 healthy postmenopausal women not on hormone therapy. Results: Testosterone showed a strong positive association with total and LDL-cholesterol, triglycerides, AIP, apoB and HOMA-IR and a negative association with HDL-cholesterol and apoA. Compared to women in the lowest testosterone quartile, women in the highest testosterone quartile had higher total cholesterol (Q1:226.4 +/- 41.0 vs Q4:245.8+/-38.1 mg/dL, p<0.001), LDL-cholesterol (Q1:148.5 +/- 37.8 vs Q4:170.0 +/- 35.3 mg/dL, p<0.001), Atherogenic Index of Plasma (AIP Q1:-0.231 +/- 0.235 vs Q4:-0.058+/-0.263, p<0.001), apolipoprotein B (ApoBQ1:226.4 +/- 41 vs Q4:245.8+/-38.1 mg/dL, p<0.001) and higher HDL-cholesterol (Q1:60.7 +/- 14.4 vs Q4:52.3+/-13.2 mg/dL, p<0.001). Free Androgen Index (FAI) exhibited the same associations as total testosterone and moreover it associated positively with both systolic and diastolic arterial pressure. Women in the highest FAI quartile had higher AIP (Q1:-0.242 +/- 0.252 vs Q4:-0.068+/-.263, p<0.001) and ApoB (Q1:102.4 +/- 25.4 vs Q4:114.4+/-25.6 mg/dL, p<0.001) and lower HDL-cholesterol (Q1: 62.1 +/- 15.6 vs Q4: 52.0+/-12.1 mg/dL, p<0.001) and
  10. 10. apolipoprotein A (Q1:158.8 +/- 24.8 vs Q4:148.6+/-24.1mg/dL, p<0.001) compared to women in the lowest FAI quartile. These differences remained significant after adjustment for age, BMI, insulin resistance and social habits. Estradiol showed a negative association only with Lp(a), while Free Estrogen Index (FEI) exhibited similar associations as FAI, which, however, were rendered non-significant in multivariate analysis. HOMA-IR showed an independent positive association with total testosterone (Q1:1.98+/-1.33 vs Q4:2.68+/-1.59, p<0.001), FAI (Q1:1.64+/-1.10 vs Q4:2.94+/-1.63, p<0.001) and FEI (Q1:1.76+/-0.92 vs Q4:2.92+/-1.38, p<0.001). Conclusions: Increased androgenicity in healthy postmenopausal women, indicated by higher total testosterone, higher FAI and lower SHBG, is associated with an unfavourable cardiovascular risk profile. On the contrary, estradiol and FEI is not associated significantly with most of the cardiovascular risk factors assessed. The association of endogenous estradiol with lipids, lipoproteins, blood pressure or insulin resistance seems to be mediated primarily by body mass index. 137 Platelet activation is associated with generation of microparticles of different origin in patients with acute myocardial infarction E.Stankiewicz, E. Stepien, A. Undas, J. Zalewski, J. Godlewski & K. Zmudka Institute of Cardiology, Krakow, Poland Background: Increased amounts of endothelial, platelets, monocytes and neutrophils microparticles (MP), accompanied by platelet activation and enhanced inflammation were reported in patients with myocardial infarction (AMI) and stable angina. Materials and methods: Microparticle counts were determined in 12 patients with documented ST-elevation AMI, 10 patients with stable angina, and 9 healthy controls. MP were assayed by flow cytometry. Platelet activation was determined by the expression of surface and soluble P- selectin, along with monocyte- and neutrophil-platelet aggregates. Interleukin 6 (IL-6) and CD40 ligand (CD40L) levels were measured by ELISAs. Results: Patients with AMI displayed higher levels of all microparticles than patients with stable angina, however the only statistical difference was observed in CD31 MP levels (p=0.03). Expression of surface P-selectin was raised in both patient groups as compared to healthy controls. Soluble P-selectin levels and monocyte-platelets aggregates were increased in patients with AMI. Significant elevations of IL-6 (p=0.05) and CD40L (p=0.0001) were observed in AMI patients as compared to patients with stable angina. In patients with AMI were significant correlations between both the total number as well as the level of CD34, CD51, CD142, CD42 MP and expression of surface P-selectin. Similarly CD40L levels correlated with surface P- selectin expression. Conclusions: We conclude that in AMI, platelet activation is associated with increased generation of MP from not only platelets, but also monocytes and endothelial cells. It suggests that interactions between platelets, monocytes and endothelial cells play an important role in the pathogenesis of myocardial ischemia. 138 Adhesive molecules, cytokines and uric acid in patients with stable coronary artery disease D. Drobniak-Hełdak 1, R. Rajtar 1, W. Kolasińska-Kloch 1, A. Furgała 3, M. Kloch 2, B. Kieć-Wilk 2 & A. Dembińska-Kieć 2 1) 2nd Dept. of Cardiology, 2) Dept. of Clinical Biochemistry, 3) Dept. of Pathophysiology, Medical College of Jagiellonian University, Cracow, Poland Background: Chronic inflammatory reaction initiates systemic inflammatory response and leads to an increase of adhesive molecules and cytokines. In some studies also elevated levels of uric acid have been shown in patients with stable coronary artery disease (CAD).
  11. 11. Materials and methods: 71 men aged 37-53 years: 40 men (mean age 47.07 ± 4.23) with stable CAD confirmed by coronary angiography (26 men with CCS I and 14 men with CCS II) and 31 healthy, non-smoking men (mean age 44.96± 5.37), with normal lipid levels, blood pressure and body mass. Subjects with active inflammatory process, hypertension, diabetes mellitus, autoimmunological disorders and neoplasms were not included. Levels of ICAM-1, VCAM-1, TNFα, thrombomodulin, von Willebrand factor, IL-6, fibrinogen, hsCRP, uric acid and leucocytes were measured in all subjects. Results: The study confirmed: 1. Significantly higher levels of ICAM-1 (267,5±68,61ng/ml vs 203,13±36,92ng/ml; p<0,0001), IL-6 (1,72±1,04pg/ml vs 1,04±0,65pg/ml; p=0,02), fibrinogen(3,96±0,99g/l vs 3,1±0,35g/l; p=0,0003), hs-CRP (2,72±2,33ng/ml vs 1,37±1,4ng/ml; p=0,0027), leucocytes (6,88 x103±1,38 vs 5,19x103±0,85; p<0,0001) in patients with stable CAD as compared with healthy subjects. 2. Significantly lower level of thrombomodulin (32,31±8,13ng/ml vs 40,25±8,71ng/ml; p=0,0002) in patients with stable CAD. 3. The elevated levels of VCAM-1, TNFα, von Willebrand factor and uric acid were not detected in patients with stable CAD as compared with healthy subjects. Conclusions: 1. Concentrations of the inflammatory markers (fibrinogen, hsCRP, IL-6, ICAM-1, leucocytes) are significantly elevated whereas thrombomodulin is decreased in patients with stable CAD as compared with healthy subjects. 2. Role of uric acid in the pathogenesis in atherosclerosis needs further investigations. 139 Serum high total cholesterol level in postmenopausal women is associated with high Tumor Necrosis Factor - alpha and Vascular Cell Adhesion Molecule - 1 levels during standard exercise test 2 D. Drobniak-Hełdak, 1T. Milewicz, 2R. Rajtar, 3D. Fedak, 2W. Kolasinska-Kloch, 4A. Furgała, 1 J. Krzysiek & 4P. Thor 1) Department of Gynecological Endocrinology, 2) 2nd Department of Cardiology, 3) Department of Clinical Biochemistry, 4) Department of Pathophysiology, Medical College of Jagiellonian University, Cracow, Poland Background: The evaluation of serum ICAM-1, VCAM-1, endothelin-1 (Et-1), TNF-alpha and its soluble receptor levels and the secretion of nitric oxide in postmenopausal women with hypercholesterolemia. Materials and methods: 26 postmenopausal patients who neither received replacement hormonal therapy nor cholesterol lowering treatment. Group A consisted of 16 women with high serum total cholesterol and group B of 10 women with normal cholesterol level. Basic fasting serum FSH, 17b-estradiol, as well as total cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride levels were measured. Standard exercise test was performed according to Bruce protocol. Blood samples were taken thrice (prior to, at peak exercise, 15th min of recovery) during the test to evaluate the serum levels of ICAM-1, VCAM-1, ET-1, TNF-alpha and its soluble receptors as well as secretion of nitric oxide. Results: In group A VCAM-1 (660.0 ± 106.4 mg/l vs 518.6 ± 65.4 mg/l; p<0.05) and TNF-alpha serum levels (2.2 ±1.0 ng/l versus 1.2 ± 0.4 ng/l; p<0.05) at peak exercise were higher as compared with group B. There was a tendency (p>0.05) towards higher ET-1 plasma levels in group A. Conclusions: Serum levels of adhesion molecules and inflammatory mediators were higher during physical exercise in postmenopausal women with atherosclerosis risk factors. 140 Polymorphism of AGT and ATPA2 genes, essential hypertension and left ventricular hypertrophy
  12. 12. B. Kieć-Wilk, 1A. Olszanecka, 1K. Stolarz, 1K. Kawecka-Jaszcz & A. Dembińska-Kieć Dept. of Clinical Biochemistry and 1Ist Cardiac Dept. Jagiellonian University Medical College, Krakow, Poland Introduction: Angiotensinogen gene (AGT) polymorphism as well as SERCA2a reticular endoplasmic Ca channel gene (ATP2A2) polymorphisms may be responsible for, hypertension and left ventricular hypertrophy (LVH). Methods: Hypertensive participants were divided into groups with LVH(+) (n=52) and without LVH(-) (n=55). Control group (n=50) consisted of healthy volunteers. The 24-hour ambulatory blood pressure monitoring, ABPM and echocardiography were done. The M235T polymorphism of AGT gene was analysed with real-time PCR and TaqMan. The genotyping of ATP2A2 was performed by dHPLC and sequencing analysis. Results: The frequency of homozygotes CC of M235T AGT polymorphism was the highest in LVH(+) group in comparison with LVH(-) (p=0.679) and controls (p=0.645). The allel T carriers of M235T polymorphism had higher value of office blood pressure (p=0.878 SBP, p=0.319 DBP), and mean systolic blood pressure in ABPM analysis. In ATP2A2 gene the new c.2171G>A polymorphism was detected. The G to A substitution was present in 18% of control, 6% of LVH(+) and in 5,2% of LVH(-) group. The allele A frequency was significantly higher in control group vs. the hypertensive group (p=0,017). The GA carriers demonstrated lower blood pressure level than GG homozygotes (p=0.367 SBP, p=0.439 DBP). The LVM and LVMI were lower in GA than in GG carriers (p=0.107 LVM, p=0.154 LVMI). Conclusions: The M235T (c.704 C>T) polymorphism of AGT does not play an essential role in hypertension and LVH. However the G724A (c.2171G>A) ATP2A2 polymorphism, protects against hypertension and the LVH development in hypertensives. 141 Proangiogenic activity of progenitor cells isolated from human adipose tissue A. Balwierz1, A. Dembińska-Kieć1, A. Polus1, L. Kaczmarek2 & J. Pryjma3 1. Dept. Clinical Biochemistry Collegium Medicum, Jagiellonian University, Krakow, 2. Dept. Molecular and Cellular Neurobiology, Laboratory of Molecular Neurobiology, Nencki Institute, Warsaw; 3. Dept. Immunology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland; Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland Introduction: Adipose tissue contains a population stromal vascular fraction (SVF), cells, which differentiate to several lineages. Development of a microvascular network precedes the adipogenesis. Aim of the study was to confirm the proangiogenic properties of the human subcutaneous adipose tissue SVF cells. Methods: SVF cells isolated according to Hauner`s were cultured in proangiogenic (EBM with 2% FCS), or proadipogenic (DMEM plus hydrocortisone, insulin, transferrin, triiodothronine after stimulation with dexamethasone, IBMX, insulin) medium. Phenotype were characterized by flow cytometry or expression of genes characteristic for endothelial progenitors (CD34, CD31, vWF, eNOS, CXCR4, CXCR12, Jagged, Notch4) as well as for preadipocytes (PPARγ1, PPARγ2, CEBPα, CD36, LPL, ap2, adiponectin, leptin) (real-time PCR). Assay of proliferation and migration was performed. Tubulogenesis of co-cultured the GFP transfected SVF with HUVEC, was measured in 3D matrigel model. Differentiation to adipocyte was confirmed by the red-Oil staining. Results: Growing of SVF cells in serum-free hormone-supplemented medium or incubation of cells in serum-containing medium changes the cell from adipogenic to proangiogenic phenotype. Such SVF cells proliferate, migrate and form the tube-like structure in in vitro 3D model of angiogenesis.
  13. 13. Conclusions: The differentiation of SVF cells towards endothelium is stimulated by the presence of human serum and argues for the deep influence of the environment on the differentiation of progenitors towards adipose versus proangiogenic cells. Sponsored by MNiI grant PBZ-MIN-005/P04/2002/5 142 Evaluation of genetic predisposition to insulin resistance by nutrient-induced insulin output ratio (NIOR) I. Wybranska, M. Malczewska-Malec, L. Partyka, B. Kiec-Wilk, I. Leszczyńska-Gołąbek & A. Dembinska-Kiec Department of Clinical Biochemistry, Jagiellonian University, Medical College, Krakow, Poland Background: There is a necessity to implement the new tools to identify the genotype-phenotype interactions. The aim of this study was to find the correlation between risk originating from gene variation and diet-dependent development of insulin resistance. Methods: Estimation of the 18 common of “obesity risk-genes” polymorphisms and standard phenotyping was performed within the 322 patients with familiar obesity. The insulin output as area under insulin curve after glucose tolerance test (AUCIns OGTT) and lipid tolerance test (AUCIns OLTT) were measured within 165 members of the study group. Results: Insulin output during oral glucose tolerance test (AUCIns OGTT) correlated strongly with insulin output after standard high fat meal (AUCIns OLTT) in the whole group. However, within the genotypic sub-groups the correlation was lower or even does not exist. The implemented AUCIns OLTT/AUCIns OGTT output ratio (NIOR) was implemented. Its value ranged from 0,42 to 5,83 and significantly correlated with BMI and leptin, but not with age, gender, WHR, HOMA or adiponectin level. The high NIOR value was found in the subgroup of carriers of rare allelic variants of genes characteristic for the worse tolerance to lipids in the diet, when the low NIOR value was found for the sub-group of the rare genetic variants regulating carbohydrate metabolism. Thus the new insulin index NIOR segregated the gene variant carriers into the groups of the glucose, or the lipid content sensitive phenotypes. Conclusion: We suggest that the OLTT/OGTT insulin output ratio (NIOR) may have the predictive value for discrimination between the phenotype of insulin resistance susceptible to fat or carbohydrate containing diet. Granted by Polish MNiI: Nr 3PO5D08424 and Nr 501/NKL/49/L