Genpolymorphismus bei der verkalkten Aortenklappenstenose

In the Caucasian world calcified and stenosed aortic valves are a common disease. Due to increasing life expectancy prevalence of aortic valve disease will increase dramatically. In order to establish alternative therapeutic approaches to valve replacement, we have to get a better understanding of the pathophysiological process and genetic determinations leading to calcified and stenotic valve disease. Exploring these genetic determinations will open new specific fields of therapeutic modulations of the disease process. In the literature, different gene polymorphisms have been characterized to develop calcifications and further stenosis of the aortic valves.Here, congestive polyvalent aortic valve abnormalities without specific genetic determinations (i. e., DiGeorge syndrome or fragile x syndrome), autosomal inherited alterations leading to congestive aortic valve disease (i. e., Williams-Beuren syndrome, Gaucher's disease, tetralogy of Fallot, genetic aberrations of chromosomes 2 and 4 as well as trisomy 18), X- and Y-chromosomal specific alterations (i. e., Turner syndrome), congestive structure-based aortic valve disease (i. e., bicuspid aortic valve with regard to hand-heart syndromes, tetracuspid aortic valve associated with DiGeorge syndrome) and genetic mutations of specific target genes (i. e., epidermal growth factor receptor, NOTCH-1, elastin, angiotensin I conversion enzyme, beta-glucocerebrosidase, interleukin-10, chemokine receptor 5, connective tissue growth factor, transforming growth factor beta1, vitamin D receptor, estrogen receptor-alpha, apolipoproteins A1, B, and E) are summarized.The roles of gene polymorphism in the development of calcified and stenosed aortic valve appear slowly in the understanding of the process leading to the valve disease and are mainly based on studies of supravalvular and bicuspid aortic valve stenoses. New molecular biological methods enabling broad gene expression analyses demonstrate the similarity in the pathophysiology of atherosclerotic vessel inflammation, bone formation/fibrosis, with the processes leading to stenosed and calcified aortic valves. Based on to-date knowledge, further analyses have to be done and will improve understanding of the pathophysiological processes with regard to the development of new therapeutic drug targets.     

Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents.

OBJECTIVES: We sought to define the incidence of late clinical events and late stent thrombosis in patients treated with drug-eluting (DES) versus bare-metal stents (BMS) after the discontinuation of clopidogrel as well as their timing and outcome. BACKGROUND: There is growing concern that delayed endothelialization after DES implantation may lead to late stent thrombosis and related myocardial infarction (MI) or death. However, event rates and outcomes after clopidogrel discontinuation versus BMS are unknown. METHODS: A consecutive series of 746 nonselected patients with 1,133 stented lesions surviving 6 months without major events were followed for 1 year after the discontinuation of clopidogrel. Patients were assigned randomly 2:1 to DES versus BMS in BASKET (Basel Stent Kosten Effektivit?ts Trial). The primary focus of this observation was cardiac death/MI. RESULTS: Rates of 18-month cardiac death/MI were not different between DES and BMS patients. However, after the discontinuation of clopidogrel (between months 7 and 18), these events occurred in 4.9% after DES versus 1.3% after BMS implantation. Target vessel revascularization remained lower after DES, resulting in similar rates of all clinical events for this time period (DES 9.3%, BMS 7.9%). Documented late stent thrombosis and related death/target vessel MI were twice as frequent after DES versus BMS (2.6% vs. 1.3%). Thrombosis-related events occurred between 15 and 362 days after the discontinuation of clopidogrel, presenting as MI or death in 88%. CONCLUSIONS: After the discontinuation of clopidogrel, the benefit of DES in reducing target vessel revascularization is maintained but has to be balanced against an increase in late cardiac death or nonfatal MI, possibly related to late stent thrombosis.     

Prognostic value of lipoproteins and their relation to inflammatory markers among patients with coronary artery disease

BACKGROUND: Lipoproteins and their subfractions are associated with the incidence of atherosclerotic diseases. In patients with coronary artery disease (CAD), low serum concentrations of high density lipoprotein (HDL) and high low-density lipoproteins (LDL) are correlated to myocardial infarction and cardiovascular death. There is growing evidence indicating that those lipoprotein factors are related to the inflammatory process in atherogenesis. METHODS: We investigated in a median follow up of 3.9 years the association of HDL, apolipoprotein A-I (apoA-I), LDL, apolipoprotein B (apoB), and triglycerides with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and their relation to markers of inflammation in 1298 patients with angiographically documented CAD. RESULTS: In univariate analysis, serum concentrations of apoA-I were significantly and inversely related to the combined endpoint, whereas serum concentrations of LDL, apoB, and triglycerides were not. HDL was not significantly related to the endpoint in univariate analyses (p=0.057). Multivariate analyses showed that only apoA-I is an independent predictor. ApoA-I (and HDL) was significantly related to markers of inflammation. CONCLUSION: Serum apoA-I levels were an independent predictor for fatal and non-fatal cardiovascular events in patients with CAD. This may be related to its anti-inflammatory effect.     

Aspirin, but not clopidogrel, reduces collateral conductance in a rabbit model of femoral artery occlusion.

OBJECTIVES: The objective of this study was to test the potential of aspirin and clopidogrel to influence collateral artery growth (arteriogenesis). BACKGROUND: Aspirin and clopidogrel are antiplatelet agents commonly used in the treatment of ischemic cardiovascular disease. Both inhibit platelet aggregation; however, they differ mechanistically because aspirin acts via cyclooxygenase (COX) inhibition, while clopidogrel noncompetitively antagonizes the P2Y12 adenosine diphosphate receptor. We hypothesized that aspirin, due to its anti-inflammatory effects through inhibition of COX activity could inhibit arteriogenesis. Given that clopidogrel does not affect COX activity, it would be less likely to interfere with collateral artery growth. METHODS: Fifty-four New Zealand White rabbits received either saline, aspirin (10 mg/kg), or clopidogrel (10 mg/kg) for seven days after femoral artery ligation. Maximal collateral conductance was assessed with fluorescent microspheres under maximal vasodilation; cellular migration and proliferation (Ki-67) was evaluated by quantitative immunohistology. RESULTS: Collateral conductance was significantly reduced by aspirin treatment, whereas clopidogrel had a neutral effect (saline: 0.94 +/- 0.04; clopidogrel: 0.94 +/- 0.05; aspirin: 0.64 +/- 0.03 ml x min(-1) x 100 mm Hg(-1) x g(-1); p < 0.001). Ki-67 proliferation indexes were consistent with these results (saline: 23.1 +/- 2.9%; clopidogrel: 23.5 +/- 1.1%; aspirin: 19.2 +/- 1.1% Ki-67-positive cells). Immunohistochemistry showed COX expression in collateral arteries and a significantly decreased monocyte/macrophage accumulation in the perivascular tissue after aspirin treatment. Cell adhesion molecule expression on monocytes after activation was significantly reduced by aspirin, which might explain the reduced migratory ability. CONCLUSIONS: In summary, clopidogrel had a neutral effect on natural arteriogenesis. Aspirin significantly inhibited collateral artery growth, probably due to its anti-inflammatory effect. Additional studies are needed to substantiate these results before translation into clinical practice.     

Idiopathic hemochromatosis presenting as amenorrhea and arthritis

Idiopathic hemochromatosis in young adults has been increasingly recognized over the last three decades. Younger patients with hemochromatosis frequently have presenting problems other than diabetes, cirrhosis, and hyperpigmentation. A young woman with idiopathic hemochromatosis is described. Arthritis and secondary amenorrhea developed at age 20, and liver biopsy showed hemochromatosis at age 29. Further work-up revealed that the amenorrhea was due to underproduction of pituitary gonadotropins. The patient was treated with phlebotomy. Estrogen and progesterone replacement was begun because of severe osteoporosis. Serum iron studies may be useful in young patients with unexplained amenorrhea and/or arthropathy.     

Circulating 5-hydroxytryptamine concentrations in preterm newborns

Alterations in circulating 5-hydroxytryptamine (5-HT) concentrations play a role in the pathophysiology of respiratory failure in adults. We undertook a study to develop a micromethod and measure circulating free 5-HT concentrations in preterm newborns with and without respiratory distress. Forty-six samples of platelet-poor plasma were obtained from 29 preterm newborns with varying degrees of respiratory distress. Samples were taken on days 2-3 and 6-7 of life. For measuring 5-HT concentrations we used a precolumn sample enhancement technique followed by ion exchange HPLC with electrochemical detection. The assay allowed detection of extremely small (50 pg) amounts of 5-HT from small (0.2 ml) amounts of blood. The mean 5-HT concentration on days 2-3 was 1.77 +/-0.74 ng/ml (mean +/- 95% confidence limits) and on days 6-7 was 0.69 +/- 0.23 ng/ml. This represented a significant fall in 5-HT concentrations (P = 0.01). All of 16 paired serial samples fell with time (P = 0.006). We conclude that platelet-poor plasma 5-HT concentrations in premature newborns are low, that there is a significant decline in these values over the first week of life, and that, in contrast with adults, the presence of respiratory failure is not associated with increased free 5-HT concentrations. The low 5-HT concentrations seen in newborns may reflect the ability to increase pulmonary uptake.     

Mortality and morbidity in relation to changes in albuminuria,glucose status and systolic blood pressure: an analysis of the ONTARGET and TRANSCEND studies

Aims/hypothesis

Urinary albumin excretion is a strong predictor of cardiovascular disease. It is uncertain whether improvement from microalbuminuria or deterioration from normoalbuminuria over time in patients with differing changes in glucose and BP change their cardiovascular risk.

Methods

Data on mortality, cardiovascular and renal outcomes were analysed in 22,984 patients from two large parallel randomised clinical trials followed for 56 months. A central laboratory analysed first morning spot urine samples at baseline and after 24 months, and events were recorded over the subsequent 32 months. Patients were stratified by changes in albuminuria, glucose status and mean systolic BP over 2 years.

Results

There was a strong association between albuminuria status and all-cause and cardiovascular mortality and combined cardiovascular and renal endpoints (all p?p?=?0.0004).

Conclusions/interpretation

Patients who showed improvement to normoalbuminuria over 2 years were at lower risk of all-cause and cardiovascular mortality and of cardiovascular and renal events than those who deteriorated to microalbuminuria over time. Albuminuria over time was significantly better than glucose status and BP control in predicting mortality and both cardiovascular and renal outcomes in patients at a high cardiovascular risk.