Pretherapeutic gamma-glutamyltransferase is an independent prognostic factor for patients with renal cell carcinoma.

BACKGROUND: Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC). METHODS: Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months. RESULTS: Median pretherapeutic serum GGT level was 25 U l(-1). Gamma-glutamyltransferase levels increased with advancing T (P<0.001), N (P=0.006) and M stages (P<0.001), higher grades (P<0.001), and presence of tumour necrosis (P<0.001). An increase of GGT by 10 U l(-1) was associated with an increase in the risk of death from RCC by 4% (HR 1.04, P<0.001). Based on recursive partitioning-based survival tree analysis, we defined four prognostic categories of GGT: normal low (<17.5 U l(-1)), normal high (17.5 to <34.5 U l(-1)), elevated (34.5 to <181.5 U l(-1)), and highly elevated (⩾181.5 U l(-1)). In multivariable analyses that adjusted for the effect of standard features, both continuously and categorically coded GGT were independent prognostic factors. Adding GGT to a model that included standard features increased the discrimination by 0.9% to 1.8% and improved the clinical net benefit. CONCLUSIONS: Pretherapeutic serum GGT is a novel and independent prognostic factor for patients with RCC. Stratifying patients into prognostic subgroups according to GGT may be used for patient counselling, tailoring surveillance, individualised treatment planning, and clinical trial design.

Medical graphics to improve patient understanding and anxiety in elderly and cognitively impaired patients scheduled for transcatheter aortic valve implantation (TAVI).

BACKGROUND: Anxiety and limited patient comprehension may pose significant barriers when informing elderly patients about complex procedures such as transcatheter aortic valve implantation (TAVI). OBJECTIVES: We aimed to evaluate the utility of medical graphics to improve the patient informed consent (IC) before TAVI. METHODS: In this prospective, randomized dual center study, 301 patients were assigned to a patient brochure containing medical graphics (Comic group, n = 153) or sham information (Control group, n = 148) on top of usual IC. Primary outcomes were patient understanding of central IC-related aspects and periprocedural anxiety assessed by the validated Spielberger State Trait Anxiety Inventory (STAI), both analyzed by cognitive status according to the Montreal Cognitive Assessment (MoCA). RESULTS: Patient understanding was significantly higher in the Comic group [mean number of correct answers 12.8 (SD 1.2) vs. 11.3 (1.8); mean difference 1.5 (95% CI 1.2-1.8); p < 0.001]. This effect was more pronounced in the presence of cognitive dysfunction (MoCA < 26) [12.6 (1.2) in the Comic vs. 10.9 (1.6) in the Control group; mean difference 1.8 (1.4-2.2), p < 0.001]. Mean STAI score declined by 5.7 (95% CI 5.1-6.3; p < 0.001) in the Comic and 0.8 points (0.2-1.4; p = 0.015) in the Control group. Finally, mean STAI score decreased in the Comic group by 4.7 (3.8-5.6) in cognitively impaired patients and by 6.6 (95% CI 5.8 to 7.5) in patients with normal cognitive function (p < 0.001 each). CONCLUSIONS: Our results prove beneficial effects for using medical graphics to inform elderly patients about TAVI by improving patient understanding and reducing periprocedural anxiety (DRKS00021661; 23/Oct/2020). Medical graphics entailed significant beneficial effects on the primary endpoints, patient understanding and periprocedural anxiety, compared to the usual patient informed consent (IC) procedure. Patient understanding of IC-related aspects was significantly higher in the Comic group, with a more pronounced benefit in patients with cognitive impairment (p for IC method and cognitive status < 0.001, respectively; p for IC method x MoCA category interaction = 0.017). There further was a significant decline of periprocedural anxiety in patients with and without cognitive impairment (p for IC method x measuring time point < 0.001; p for IC method x MoCA category x measuring time point interaction = 0.018).

Informed Consent before coronary angiography and percutaneous coronary intervention from the patient's perspective: A picture is worth a thousand words.

Background: Patients scheduled for coronary angiography may feel insufficiently informed about the planned procedure. We aimed to evaluate the patient-rated quality of the Informed Consent (IC) process and to investigate the efficacy of medical graphics to assist and improve the IC procedure. Methods: A graphic-based information broschure illustrating central steps of the procedure was created in collaboration with scientific illustrators. In a randomized, controlled, prospective trial, 121 patients undergoing coronary angiography/PCI were randomized to a group obtaining the usual IC (Control group) or to a group that additionally obtained a graphic-based IC (Comic group). The perceived quality of the IC was compared between groups using single items of the Client Satisfaction Questionnaire-8 and self-designed single items. Results: Only 67.8% of patients stated to have completely read the standard written IC sheet. The quality of the IC was perceived to be very good in 45.0% of patients in the Comic group compared to 24.6% in the Control group (p =.023). 57.4% of the Control group compared to 76.7% of the Comic group stated that all of their questions were satisfactorily adressed (p =.015). 43.3% of the Comic group, in contrast to only 18.0% of the Control group, declared to feel "very satisfied" with the obtained IC procedure (p =.002). The acceptance of this new IC approach was very high: no patient expressed feelings of not being taken seriously when reading medical graphics. Conclusions: Our data confirm pronounced limitations of the usual IC practice. The use of medical graphics positively impacts on patient-evaluated endpoints and may significantly improve the IC procedure.

The German Transregional Collaborative Research Centre 'Inflammatory Cardiomyopathy--Molecular Pathogenesis and Therapy'. Methods and baseline results from a 3-centre clinical study.

OBJECTIVES: This report focuses on the design and methods of the 3-centre clinical study of the Transregional Collaborative Research Centre 'Inflammatory Cardiomyopathy--Molecular Pathogenesis and Therapy', which aims to establish a comprehensive research registry on the diagnostics, therapy and disease outcomes of patients with inflammatory cardiomyopathy (CMi). The study goals are to investigate specific disease sub-entities and to develop standardised strategies for diagnostics and treatment. METHODS: All consecutive patients with clinically suspected CMi, post-myocarditic cardiomyopathy and acute myocarditis are included in the research registry. Cardiopulmonary functional tests, clinical and patient data are obtained at baseline and subsequent readmission appointments and are linked to allow for prospective follow-up. Co-morbidities, quality of life, health- related behaviour and sociodemographic variables are ascertained using uniform self-administered questionnaires. PRESENT STATUS: By May 2008, 2,061 cases had been included in the research registry (1,300 data-sets completed). At registration, 335 patients were diagnosed with CMi. The mean age was 50 +/- 13 years and the mean ejection fraction was 39.9 +/- 15.8%. CONCLUSIONS: The broad range of the acquired molecular-biological, histological, immunohistological, clinical and patient data makes this the most comprehensive research registry on patients with CMi to date.

Erythroid progenitor renewal versus differentiation: genetic evidence for cell autonomous, essential functions of EpoR, Stat5 and the GR.

The balance between hematopoietic progenitor commitment and self-renewal versus differentiation is controlled by various transcriptional regulators cooperating with cytokine receptors. Disruption of this balance is increasingly recognized as important in the development of leukemia, by causing enhanced renewal and differentiation arrest. We studied regulation of renewal versus differentiation in primary murine erythroid progenitors that require cooperation of erythropoietin receptor (EpoR), the receptor tyrosine kinase c-Kit and a transcriptional regulator (glucocorticoid receptor; GR) for sustained renewal. However, mice defective for GR- (GR(dim/dim)), EpoR- (EpoR(H)) or STAT5ab function (Stat5ab(-/-)) show no severe erythropoiesis defects in vivo. Using primary erythroblast cultures from these mutants, we present genetic evidence that functional GR, EpoR, and Stat5 are essential for erythroblast renewal in vitro. Cells from GR(dim/dim), EpoR(H), and Stat5ab(-/-) mice showed enhanced differentiation instead of renewal, causing accumulation of mature cells and gradual proliferation arrest. Stat5ab was additionally required for Epo-induced terminal differentiation: differentiating Stat5ab(-/-) erythroblasts underwent apoptosis instead of erythrocyte maturation, due to absent induction of the antiapoptotic protein Bcl-X(L). This defect could be fully rescued by exogenous Bcl-X(L). These data suggest that signaling molecules driving leukemic proliferation may also be essential for prolonged self-renewal of normal erythroid progenitors.

[Rational use of catecholamines and inotropes]. / Rationaler Einsatz von Katecholaminen und Inotropika.

Acute heart failure syndromes (AHFS) are a growing health problem in Western Countries. Standard treatment includes vasodilators and diuretics, however, the subgroup of patients with AHFS and low cardiac output state represents a special therapeutic challenge that is complicated by high in-hospital and post-discharge mortality and by requiring additional i. v. inotropic support. The current inotropes in use are adrenoreceptor agonists (dopamine, dobutamine, norepinephrine, epinephrine), phosphodiesterase III inhibitors (milrinone, enoximone), and Ca2+ sensitizers (levosimendane). While most inotropes yield short-term haemodynamic improvements, they are associated with increased myocardial oxygen consumption, (supra-) ventricular arrhythmias and possibly increased post-discharge mortality. This review highlights current inotropes used in the treatment of AHFS and introduces new drug developments including myosin activators and Na+/K+ ATPase inhibitors.

Pulmonary release and coronary and peripheral consumption of big endothelin and endothelin-1 in severe heart failure: acute effects of vasodilator therapy.

BACKGROUND: We investigated plasma endothelin (ET) levels in patients with congestive heart failure (CHF) during treatment for acute decompensation; we also measured imbalances in ET peptides across the pulmonary, coronary, and peripheral circulation. Methods and Results-In patients with severe CHF (n=21; cardiac index [CI], 1.9+/-0.2 L. min(-1). m(-2); pulmonary capillary wedge pressure [PCWP], 31+/-1 mm Hg), vasodilation was achieved with the nitric oxide donor sodium nitroprusside (n=11) or with the alpha(1)-antagonist urapidil (nitric oxide-independent, n=10). ET concentrations were determined from arterial blood and blood from the pulmonary artery, coronary sinus, and antecubital vein. Depending on sites of measurement, baseline big ET and ET-1 levels were, respectively, 12 to 16 times and 5 to 11 times higher than in controls (n=11), and 4 to 6 times and 2 to 3 times higher than in patients with moderate CHF (n=10; CI, 2.7+/-0.3 L. min(-1). m(-2); PCWP, 14+/-2 mm Hg). Patients with severe CHF demonstrated pulmonary net release and coronary and peripheral net consumption of both peptides (ie, arterial levels [big ET, 7.3+/-1.3 pmol/L; ET-1, 1.8+/-0.1 pmol/L] were higher than levels in the pulmonary artery [6.7+/-1.2 pmol/L; 1. 3+/-0.1 pmol/L], coronary sinus [6.4+/-1.0 pmol/L; 1.4+/-0.1 pmol/L], and antecubital vein [6.6+/-1.1 pmol/L; 1.3+/-0.1 pmol/L]). In these patients, sodium nitroprusside (SNP) and urapidil resulted in comparable hemodynamic improvement after 6 hours (CI: SNP, 63+/-2%; urapidil, 72+/-3%; PCWP: SNP, -50+/-2%; urapidil, -47+/-2%) and a maximum decrease in ET peptides by >50%. After 3 hours, pulmonary net release and coronary and peripheral net consumption were no longer detectable. CONCLUSIONS: In patients with severe CHF, the lungs act as a producer and the heart and the periphery act as consumers of elevated circulating ETs. Short-term vasodilator therapy decreases ETs and restores their pulmonary, coronary, and peripheral balance.

Immunohistological changes in dilated cardiomyopathy induced by immunoadsorption therapy and subsequent immunoglobulin substitution.

BACKGROUND: Immunoadsorption (IA) and subsequent immunoglobulin (Ig) G substitution represent an additional therapeutic approach in dilated cardiomyopathy (DCM). It remains to be elucidated whether this treatment modulates myocardial inflammation, which is possibly a causal factor of ventricular dysfunction. METHODS AND RESULTS: From 25 DCM patients (EF <30%), 12 patients were randomized for IA therapy and subsequent IgG substitution at 1-month intervals until month 3. Before (<7 days) and after IA therapy, right ventricular biopsies were obtained from all patients. Biopsies were also obtained at intervals of 3 months from 13 patients without IA/IgG treatment (controls). IA/IgG treatment induced improvement in left ventricular ejection fraction from 21.3+/-1.7% (+/-SEM) to 27.0+/-1.3% (P<0.01 versus baseline/controls) and reduction of the beta-receptor autoantibody serum levels (P<0.01 versus baseline/controls). The number of CD3 cells decreased from 5.7+/-0.8 to 2.9+/-0.5 cells/mm(2) (P<0.01 versus baseline/controls). This decline was paralleled by a decrease in CD4 (P<0.01 versus baseline/controls) and CD8 (P<0.05 versus baseline/controls) lymphocytes. The number of leukocyte common antigen-positive cells (leukocytes) was reduced from 20.0+/-3.2 to 9.9+/-2.8 cells/mm(2) (P<0.01 versus baseline/P<0.05 versus controls). HLA class II expression decreased from 2.1+/-0.7% to 1.1+/-0.4% (P<0.05 versus controls/baseline). The number of immunopositive cells and the expression of HLA class II in controls remained stable. In both groups, the degree of fibrosis remained unchanged. CONCLUSIONS: IA and subsequent IgG substitution mitigate myocardial inflammation in DCM.

Arrhythmogenic effects induced by coronary conversion of pulmonary big endothelin to endothelin: aggravation of this phenomenon in heritable hyperlipidemia.

OBJECTIVES: We investigated whether endogenous pulmonary big endothelin has arrhythmogenic properties under normal conditions and in heritable hyperlipidemia. BACKGROUND: Endothelin (ET), one of the most potent vasoconstrictors, is known to induce ventricular arrhythmias. It is unclear, however, whether its precursor, big endothelin, released from the lung, contributes to arrhythmogenesis. METHODS: In a lung-heart model in which a Langendorff heart is serially perfused with the effluent from the isolated lung of the same animal, we evaluated arrhythmias in control and in Watanabe heritable hyperlipidemic (WHHL) rabbits. RESULTS: In both controls (n=12) and WHHL (n=8), serial perfusion evoked a decrease in coronary flow (controls, -11+/-3%; WHHL, -25+/-6%) and a fourfold increase of ventricular extrasystoles (VES) (controls, 40.7+/-8; WHHL, 40.2+/-5 VES/40 min, p < 0.05). However, WHHL developed more and longer nonsustained ventricular tachycardias (VT) compared with controls (incidence, 1.38+/-1.1 vs. 0.33+/-0.5 VT/40 min, p < 0.05; length, 14.36+/-3.1 vs. 7.25+/-1.5 beats/VT, p < 0.05). Arrhythmias were not ischemia-induced because corresponding mechanical flow reduction had no arrhythmogenic effect (n=6 in controls and WHHL). Although vasoconstriction disappeared entirely, arrhythmias were only partly suppressed by ET(A) antagonists (BQ-123, 2 micromol/liter; A-127722, 20 micromol/liter). The ET-converting enzyme inhibitor phosphoramidon (50 micromol/liter) completely suppressed arrhythmias and vasoconstriction. The ET(B) antagonists (IRL-1038, 4 micromol/liter; IRL-1025, 5 micromol/liter) had no effect (n=6). CONCLUSIONS: Endogenous pulmonary big ET produces arrhythmogenic effects that are aggravated in heritable hyperlipidemia. These effects, requiring coronary conversion of big ET into ET, are partly ET(A)-mediated and ET(B)-independent.

Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: The primary objective of the present study was to assess the efficacy of metoprolol CR/XL to reduce the risk of relapse after cardioversion of persistent atrial fibrillation to sinus rhythm. BACKGROUND: Indirect data from studies with d,l sotalol provide evidence that the beta-blocking effects of the compound are important in maintaining sinus rhythm after cardioversion of atrial fibrillation. METHODS: After successful conversion to sinus rhythm, 394 patients with a history of persistent atrial fibrillation were randomly assigned to treatment with metoprolol CR/XL or placebo. The two treatment groups were similar with respect to all pretreatment characteristics. Patients were seen on an outpatient basis for recording of resting electrocardiogram (ECG) after one week, one, three and six months of follow-up or whenever they felt that they had a relapse into atrial fibrillation or experienced an adverse event. RESULTS: In the metoprolol CR/XL group, 96 patients (48.7%) had a relapse into atrial fibrillation compared with 118 patients (59.9%) in the placebo group (p = 0.005). Heart rate in patients after a relapse into atrial fibrillation was significantly lower in the metoprolol group (98 +/- 23 beats/min) than in the placebo group (107 +/- 27 beats/min). The rate of adverse events reported was similar in both groups when the difference in follow-up time was taken into account. CONCLUSIONS: The results of this double-blind, placebo-controlled study in patients after cardioversion of persistent atrial fibrillation showed that metoprolol CR/XL was effective in preventing relapse into atrial fibrillation or flutter.

Reduced procedural risk for coronary catheter interventions in carriers of the coagulation factor VII-Gln353 gene.

OBJECTIVES: We have focused on the role of coagulation factor VII (FVII) Arg353Gln polymorphism as a risk predictor of complications following percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy (DCA), and stenting. BACKGROUND: The FVII Arg353Gln mutation decreases FVII activity, and presence of the Gln353 allele could be protective against thrombus formation during catheter interventions. METHODS: A total of 666 consecutive patients with coronary artery disease who had undergone PTCA (n = 280), DCA (n = 104), or stenting (n = 282) were followed up for a 30-day composite end point, which included need for target vessel revascularization, myocardial infarction, and death. The Arg353Gln polymorphism of FVII was determined by PCR/RFLP assay. RESULTS: Carriers of the Gln353 allele had significantly lower levels of total FVII activity (FVIIc, -20.7%, p < 0.001) and of activated circulating FVII (FVIIa, -32.7%, p = 0.03) compared with Arg353/Arg353. The composite end point occurred in 43 patients: 4 were heterozygous Arg353/Gln353, and 39 were homozygous Arg353/Arg353. The incidence of the composite end point was 2.5% in carriers of the Gln353 allele and 7.7% in Arg353/Arg353 homozygotes (p = 0.013). This corresponds to a 72% risk reduction in carriers of the Gln353 allele (relative risk: 0.28; 95% confidence interval: 0.09-0.81; p = 0.02). CONCLUSIONS: The Gln353 allele of FVII is associated with substantial risk reduction in adverse events that complicate coronary catheter interventions. With the perspective of active site-blocked activated FVII (FVIIai) as conjunctive medication, the results suggest that the FVII genotype should be taken into due consideration in assessment of FVIIai medication and of its dosage.

Role of Kozak sequence polymorphism of platelet glycoprotein Ibalpha as a risk factor for coronary artery disease and catheter interventions.

OBJECTIVES: We sought to determine the role of the -5T/C polymorphism of the platelet glycoprotein (GP) Ibalpha as a potential risk factor for coronary artery disease (CAD) and adverse events complicating a coronary catheter intervention. BACKGROUND: The platelet GP Ib-IX-V receptor complex plays a crucial role in arterial thrombus formation. The -5T/C polymorphism of GP Ibalpha is associated with increased receptor density. METHODS: We genotyped 1,000 patients with angiographically confirmed CAD, as well as 1,000 age- and gender-matched control subjects, for this polymorphism by polymerase chain reaction/restriction fragment length polymorphism. Among the patients with CAD, 269 underwent percutaneous transluminal coronary angioplasty (PTCA), 103 underwent directional coronary atherectomy and 278 underwent stenting. This intervention group was followed for a 30-day composite end point of target vessel revascularization, myocardial infarction or death. RESULTS: Carriers of the -5C allele were significantly over-represented in the group of patients developing acute coronary syndromes (relative risk [RR] 1.43, 95% confidence interval [CI] 1.05 to 1.95, p = 0.02). The -5C allele furthermore predicted an increased risk for developing complications after PTCA (RR 3.75, 95% CI 1.15 to 12.27, p = 0.029). CONCLUSIONS: The -5C allele of the GP Ibalpha Kozak polymorphism may represent a risk factor in clinical conditions in which thrombosis plays an important role, such as in acute coronary syndromes and in complications after PTCA.

Hemodynamic effects of immunoadsorption and subsequent immunoglobulin substitution in dilated cardiomyopathy: three-month results from a randomized study.

OBJECTIVES: The objective of our study was to assess the hemodynamic effects of immunoadsorption (IA) and subsequent immunoglobulin G (IgG) substitution in comparison with the effects of conventional medical treatment in patients with dilated cardiomyopathy (DCM). BACKGROUND: Various circulating cardiac autoantibodies have been detected among patients suffering from DCM. These antibodies are extractable by IA. METHODS: Patients with DCM (n = 18, New York Heart Association III-IV, left ventricular ejection fraction <30%) and who were on stable medication participated in the study. Hemodynamic measurements were performed using a Swan-Ganz thermodilution catheter. The patients were randomly assigned either to the treatment group with IA and subsequent IgG substitution (IA/IgG group, n = 9) or to the control group without IA/IgG (n = 9). In the IA/IgG group, the patients were initially treated in one IA session daily on three consecutive days. After the final IA session, 0.5 g/kg of polyclonal IgG was substituted. At one-month intervals, IA was then repeated for three further courses with one IA session daily on two consecutive days, until the third month. RESULTS: After the first IA course and IgG substitution, cardiac index (CI) increased from 2.1 (+/-0.1) to 2.8 (+/-0.1) L/min/m2 (p < 0.01) and stroke volume index (SVI) increased from 27.8 (+/-2.3) to 36.2 (+/-2.5) ml/m2 (p < 0.01). Systemic vascular resistance (SVR) decreased from 1,428 (+/-74) to 997 (+/-55) dyne x s x cm(-5) (p < 0.01). The improvement in CI, SVI and SVR persisted after three months. In contrast, hemodynamics did not change throughout the three months in the control group. CONCLUSIONS: Immunoadsorption and subsequent IgG substitution improves cardiovascular function in DCM.

The pregnancy hormone relaxin is a player in human heart failure.

Human congestive heart failure is characterized by complex neurohumoral activation associated with the up-regulation of vasoconstricting and salt-retaining mediators and the compensatory rise of counter-regulatory hormones. In the present study, we provide the first evidence that relaxin (RLX), known as a pregnancy hormone, represents a potential compensatory mediator in human heart failure: plasma concentrations of RLX and myocardial expression of the two RLX genes (H1 and H2) correlate with the severity of disease and RLX responds to therapy. The failing human heart is a relevant source of circulating RLX peptides, and myocytes as well as interstitial cells produce RLX. Elevation of ventricular filling pressure up-regulates RLX expression and the hormone acts as a potent inhibitor of endothelin 1, the most powerful vasoconstrictor in heart failure. Furthermore, RLX modulates effects of angiotensin II, another crucial mediator. Our data identify RLX as a new player in human heart failure with potential diagnostic and therapeutic relevance.

High CA repeat numbers in intron 13 of the endothelial nitric oxide synthase gene and increased risk of coronary artery disease.

Endothelial nitric oxide synthase (eNOS) plays a key role in vascular homeostasis. Because its product, nitric oxide, possesses vasodilatory and antiatherogenic properties, an altered eNOS function might promote atherosclerosis. We investigated the association between variations in CA repeat copy number [(CA), polymorphism] in intron 13 of the eNOS gene and the risk of coronary artery disease. (CA), polymorphism was investigated in 1000 consecutive patients with angiographically confirmed coronary artery disease and 1000 age- and gender-matched control subjects by a PCR-based fragment length calculation. Twenty-eight different alleles were identified containing 17-44 CA repeats. The presence of one allele containing > or = 38 repeats was associated with an excess risk of coronary artery disease (odds ratio 1.94, 95% confidence interval 1.31-2.86, P = 0.001). Carriers of alleles containing > or = 38 CA repeats were, in particular, overrepresented in the subgroup without common cardiovascular risk factors (odds ratio 3.39, 95% confidence interval 1.30-8.86, P = 0.009). Logistic regression analysis revealed that the (CA), polymorphism proved to be an independent risk factor (relative risk 2.17, 95% confidence interval 1.44-3.27, P = 0.0002). Our findings indicate that high numbers of CA repeats in intron 13 of the eNOS gene are associated with an excess risk of coronary artery disease.

Mutations in the human paraoxonase 1 gene: frequencies, allelic linkages, and association with coronary artery disease.

Oxidative damage is a major cause of atherosclerosis. Since human paraoxonase has been postulated as a factor which plays a role in protection from low density lipoprotein oxidation, recent studies have dealt with the impact of hereditary PON1 gene polymorphisms as risk factors for coronary artery disease (CAD). The results from these studies are conflicting. In a case-control study, 1000 Caucasian patients with angiographically confirmed CAD were recruited and matched by age and gender to 1000 control individuals. PON1 mutations in codons 55 and 192 were evaluated by polymerase chain reaction-restriction fragment length polymorphism and allocated to defined haplotypes *1 (55L/192Q), *2 (55L/192R), and *3 (55M/192Q). Frequency of PON1 genotypes without any mutation (PON1*1/*1, wild-type) in CAD cases was 16.9% versus 17.1% in control individuals. PON1*2/*2 showed a frequency of 6.6% versus 7.3% (P = 0.68 compared to wild-type), and PON1*3/3 occurred in 11.8% in CAD cases versus 10.3% among control individuals (P = 0.40). There was also no difference in the distribution of carriers heterozygous for *2 or *3 among cases and control individuals. A haplotype containing both mutations 55M and 192R was not observed. None of the investigated genotypes demonstrated association with early manifestation, severity of disease, acute coronary syndromes, or myocardial infarction. Logistic regression analysis with adjustment for age, gender, diabetes, hypertension, hypercholesterolemia and smoking revealed no evidence of increased coronary risk associated with PON1 genotypes. These results suggest that PON1 polymorphisms are not major genetic determinants of CAD.

Body fat distribution in men with angiographically confirmed coronary artery disease.

Body fat distribution and its relationship to coronary artery disease and established cardiovascular risk factors have been studied in a cohort of 286 men aged between 30 and 74 years undergoing coronary angiography. 207 (72.4%) patients showed stenosis (greater than 30%) or occlusion of one or more coronary arteries. whereas the remaining 79 (27.6%) men were free of coronary lesions and served as a control group. 112 men with angiographically defined coronary artery disease had an additional history of myocardial infarction. Body fat distribution was assessed by determining the waist-to-hip circumference ratio. A stepwise logistic regression analysis revealed that in addition to LDL-cholesterol (P = 0.0001) and age (P = 0.0005) an abdominal type of body fat distribution (P = 0.0129) is also a significant risk indicator for the occurrence of coronary artery disease (CAD) independent of body weight and other factors such as total cholesterol, HDL-cholesterol, triglycerides, insulin, systolic and diastolic blood pressure. The results of this study suggest that an abdominal type of fat distribution is associated with an increased risk of coronary artery disease.

Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms: impact on plasma homocysteine levels and development of coronary artery disease.

Although three common MTHFR polymorphisms (C677T, A1298C, T1317C) have been reported, only polymorphism C677T has been investigated intensively as a risk factor for coronary artery disease (CAD). We investigated polymorphism frequencies, allelic associations and the effect of the resulting MTHFR genotypes on total plasma homocysteine (tHcy) levels and on coronary risk in a case-control study with 1000 angiographically confirmed Middle-European CAD patients and 1000 matched controls. Three out of four theoretically possible MTHFR haplotypes were detected: *1 (677C, 1298A), *2 (677T, 1298A), and *3 (677C, 1298C). The frequencies were *1: 36.4 and 34.4%; *2: 30.8 and 32.3%; and *3: 32.8 and 33.3%, in cases and controls, respectively. Only one patient was heterozygous for 1317C. None of the six resulting genotypes showed significant influence on tHcy levels. Moreover, there was no significant association with CAD risk or with disease severity or early disease manifestation. In the subgroup presenting with acute coronary syndromes, MTHFR genotypes *2/*3 and *3/*3 were surprisingly underrepresented (relative risk of *3/*3, 0.40; 95% confidence interval 0.20-0.79, P=0.009). We conclude from our genotype-based analysis that, in this well-fed Middle-European population, the observed common allelic variants of the MTHFR gene have no significant influence on tHcy levels or on the chronic process of CAD development.

Fibrinogen breakdown, long-lasting systemic fibrinolysis, and procoagulant activation during alteplase double-bolus regimen in acute myocardial infarction.

Recent clinical studies comparing accelerated versus bolus administration of alteplase tissue plasminogen activator (t-PA) suggest similar thrombolytic efficacy, but reveal higher bleeding complications among older patients during the double-bolus regimen. The objective of the present study was to characterize the hemostatic profile of t-PA administered as double-bolus doses of 50 mg, at intervals of 30 minutes. Among 50 patients with acute myocardial infarction treated by double-bolus t-PA thrombolysis, coagulation and fibrinolysis parameters, as well as t-PA levels, were monitored. Monitored t-PA levels peaked at 5 and 35 minutes and were detectable within the therapeutic range even after 90 minutes. Marked systemic fibrinolytic activation was indicated by 75% depletion of both plasminogen and fibrinogen, as well as by 19-fold and 300-fold increases of fibrin degradation and fibrinogen degradation products. Plasminogen-activator inhibitor activity was completely suppressed. Pronounced procoagulant activation was reflected by a 3.4-fold increase of both factor XIIa and prothrombin fragment 1+2, and by a threefold increase of thrombin-antithrombin complex. Independent of t-PA weight dosage, fibrinolytic activation was more pronounced among older patients (> or = 63 years). We conclude that t-PA after bolus administration has a long half-life. Double-bolus regimen leads to a long-lasting systemic fibrinolytic state, which is even more remarkable among older patients--a fact that may explain the higher bleeding complications reported for this age group.

Dexamethasone inhibits stimulation of pulmonary endothelins by proinflammatory cytokines: possible involvement of a nuclear factor kappa B dependent mechanism.

OBJECTIVES: Recent studies have indicated effectiveness of glucocorticoid (GC) treatment in late, fibroproliferative adult respiratory distress syndrome. There is furthermore growing evidence for a role of endothelin-1 (ET-1) in lung fibroproliferation, but the impact of GC on stimulated pulmonary ET-1 is not well defined. DESIGN AND SETTING: Prospective study in an experimental laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Isolated lungs were perfused over 120 min in recirculatory mode in presence of vehicle, interleukin-1 beta (IL-1 beta; 5 ng/ml) plus tumor necrosis factor-alpha (TNF-alpha; 5 ng/ml), dexamethasone (Dx; 1 nmol/l), Dx (10 nmol/l), IL-1 beta plus TNF alpha plus Dx 1, or IL-1 beta plus TNF alpha plus Dx 10 (n = 6 each). Pulmonary artery endothelial cells were stimulated over 30 min using a similar protocol. MEASUREMENTS AND RESULTS: Control lungs released 15.2 +/- 0.6 pg/ml big ET-1 and 0.46 +/- 0.06 pg/ml ET-1, and contained 0.73 +/- 0.05 ng/g wet weight (ww) big ET-1 and 3.06 +/- 0.22 ng/g ww ET-1. IL-1 beta plus TNF-alpha increased release of big ET-1 and ET-1, to 220% and 217%, and lung content of peptides, to 236% and 230%. Dx dose-dependently inhibited the cytokine-induced rise in peptide release and lung content and completely suppressed these effects at 10 nmol/l. Electrophoretic mobility shift assays with nuclear extracts of pulmonary artery endothelial cells demonstrated nuclear binding of the transcription factor nuclear factor kappa B in response to IL-1 beta plus TNF-alpha, which was decreased in presence of Dx 1 and Dx 10. CONCLUSIONS: GC inhibit the cytokine-induced upregulation of pulmonary vascular and tissue endothelins, possibly via nuclear factor kappa B dependent mechanisms. This finding may reinforce the therapeutic employment of GC in late ARDS.