Risk factors and myocardial infarction in patients with obstructive sleep apnea: impact of β2-adrenergic receptor polymorphisms

BACKGROUND: The increased sympathetic nervous activity in patients with obstructive sleep apnea (OSA) is largely responsible for the high prevalence of arterial hypertension, and it is suggested to adversely affect triglyceride and high-density lipoprotein (HDL) cholesterol levels in these patients. The functionally relevant polymorphisms of the β2-adrenergic receptor (Arg-47Cys/Arg16Gly and Gln27Glu) have been shown to exert modifying effects on these risk factors in previous studies, but results are inconsistent. METHODS: We investigated a group of 429 patients (55 ± 10.7 years; 361 men, 68 women) with moderate to severe obstructive sleep apnea (apnea/hypopnea index (AHI) 29.1 ± 23.1/h) and, on average, a high cardiovascular risk profile (body mass index 31.1 ± 5.6, with hypertension in 60.1%, dyslipidemia in 49.2%, and diabetes in 17.2% of patients). We typed the β2-adrenergic receptor polymorphisms and investigated the five most frequent haplotypes for their modifying effects on OSA-induced changes in blood pressure, heart rate, and lipid levels. The prevalence of cardiovascular risk factors and coronary heart disease (n = 55, 12.8%) and survived myocardial infarction (n = 27, 6.3%) were compared between the genotypes and haplotypes. RESULTS: Multivariate linear/logistic regressions revealed a significant and independent (from BMI, age, sex, presence of diabetes, use of antidiabetic, lipid-lowering, and antihypertensive medication) influence of AHI on daytime systolic and diastolic blood pressure, heart rate, prevalence of hypertension, and triglyceride and HDL levels. The β2-adrenergic receptor genotypes and haplotypes showed no modifying effects on these relationships or on the prevalence of dyslipidemia, diabetes, and coronary heart disease, yet, for all three polymorphisms, heterozygous carriers had a significantly lower relative risk for myocardial infarction (Arg-47Cys: n = 195, odds ratio (OR) = 0.32, P = 0.012; Arg16Gly: n = 197, OR = 0.39, P = 0.031; Gln27Glu: OR = 0.37, P = 0.023). Carriers of the most frequent haplotype (n = 113) (haplotype 1; heterozygous for all three polymorphisms) showed a five-fold lower prevalence of survived myocardial infarction (OR = 0.21, P = 0.023). CONCLUSION: Our study showed no significant modifying effect of the functionally relevant β2-adrenergic receptor polymorphisms on OSA-induced blood pressure, heart rate, or lipid changes. Nevertheless, heterozygosity of these polymorphisms is associated with a lower prevalence of survived myocardial infarction in this group with, on average, a high cardiovascular risk profile

Analyse der Tätigkeiten kardiovaskulärer Gewebebanken in Deutschland in den Jahren 2007 bis 2010

__Background:__ Especially in complicated aortic valve endocarditis, infections of the aorta by mycotic aortic aneurysms and prosthetic infections, or as part of the Ross procedure, the use of allogeneic heart valve transplants remains important. The production of such allografts in Germany is the task of cardiovascular tissue banks (CVTB). __Materials and methods:__ During an analysis of the years 2007-2010, basic data on donor numbers, production, and distribution as well as the technical conditions of not only the four participating CVTB (Bad Oeynhausen, Berlin, Kiel, Munich) but also data from the CVTB Rotterdam as an external reference were recorded. __Results:__ The German CVTB delivered an average of 44 aortic and 95 pulmonary allografts per year to clinical users. By incorporating the annually imported valve allografts, the demand in Germany approximately averages 220 heart valve allografts per year. The heart tissue was harvested from approximately 100 multiorgan donors, 45 cardiovascular deaths, and 80 domino donors annually. __Discussion:__ The participating cardiovascular tissue banks have comparable technical and administrative requirements and are able to produce tissue preparations according to the rules of Good Professional Practice in accordance with § 3 (3) AMWHV to assess their quality, whereby harmonization of microbiological monitoring and antibiotic treatment is still necessary

Optimization of the metabolic stability of a fluorinated cannabinoid receptor subtype 2 (CB2) ligand designed for PET studies

The central CB2 receptor represents a promising target for the treatment of neuroinflammatory diseases as CB2 activation mediates anti-inflammatory effects. Recently, the F-18 labeled PET radiotracer [F-18]7a was reported, which shows high CB2 affinity and high selectivity over the CB1 subtype but low metabolic stability due to hydrolysis of the amide group. Based on these findings twelve bioisosteres of 7a were synthesized containing a non-hydrolysable functional group instead of the amide group. The secondary amine 23a (K-i = 7.9 nM) and the ketone 26a (K-i = 8.6 nM) displayed high CB2 affinity and CB2:CB1 selectivity in in vitro radioligand binding studies. Incubation of 7a, 23a and 26a with mouse liver microsomes and LC-quadrupole-MS analysis revealed a slightly higher metabolic stability of secondary amine 23a, but a remarkably higher stability of ketone 26a in comparison to amide 7a. Furthermore, a logD(7.4) value of 5.56 +/- 0.08 was determined for ketone 26a by micro shake-flask method and LC-MS quantification. (C) 2018 Elsevier Masson SAS. All rights reserved.Medicinal Chemistr

The CYP2J2 G-50T polymorphism and myocardial infarction in patients with cardiovascular risk profile

<p>Abstract</p> <p>Background</p> <p>Cytochrome P450 (CYP) enzyme 2J2, an epoxygenase predominantly expressed in the heart, metabolises arachidonic acid to biologically active eicosanoids. One of the CYP2J2 products, 11, 12-epoxyeicosatrienoic acid, has several vasoprotective effects. The CYP2J2-G-50T-promotor polymorphism decreases gene expression and is associated with coronary artery disease. This association supports the vascular protective role of CYP-derived eicosanoids in cardiovascular disease. In the present study, we investigated the influence of this polymorphism on survived myocardial infarction in two study groups of patients with on average high cardiovascular risk profile.</p> <p>Methods</p> <p>The CYP2J2 polymorphism was genotyped in two groups of patients that were collected with the same method of clinical data collection. Data from 512 patients with sleep apnoea (group: OSA) and on average high cardiovascular risk profile and from another 488 patients who were admitted for coronary angiography (CAR-group) were evaluated for a potential correlation of the CYP2J2 polymorphism G-50T and a history of myocardial infarction. The G-50T polymorphism of the CYP2J2 gene was genotyped by allele specific restriction and light cycler analysis.</p> <p>Results</p> <p>The T-allele of the polymorphism was found in 111 (11.1%; CAR-group: N = 65, 13.3%; OSA: N = 46, 9.0%). 146 patients had a history of myocardial infarction (CAR: N = 120, 24.6%; OSA: N = 26, 5.1%). Cardiovascular risk factors were equally distributed between the different genotypes of the CYP2J2 G-50T polymorphism. In the total group of 1000 individuals, carriers of the T-allele had significantly more myocardial infarctions compared to carriers of the wild type (T/T or G/T: 21.6%; G/G: 13.7%; p = 0.026, odds ratio 1.73, 95%-CI [1.06–2.83]). In the multivariate logistic regression analysis the odds ratio for a history of myocardial infarction in carriers of the T-allele was 1.611, 95%-CI [0.957–2.731] but this trend was not significant (p = 0.073).</p> <p>Conclusion</p> <p>In presence of other risk factors, the CYP2J2 G-50T failed to show a significant role in the development of myocardial infarction. However, since our result is close to the border of significance, this question should be clarified in larger, prospective studies in the future.</p

Climate Change in the Baltic Sea Region: A Summary

Based on the Baltic Earth Assessment Reports of this thematic issue in Earth System Dynamics and recent peer-reviewed literature, current knowledge about the effects of global warming on past and future changes in climate of the Baltic Sea region is summarized and assessed. The study is an update of the Second Assessment of Climate Change (BACC II) published in 2015 and focusses on the atmosphere, land, cryosphere, ocean, sediments and the terrestrial and marine biosphere. Based on the summaries of the recent knowledge gained in paleo-, historical and future regional climate research, we find that the main conclusions from earlier assessments remain still valid. However, new long-term, homogenous observational records, e.g. for Scandinavian glacier inventories, sea-level driven saltwater inflows, so-called Major Baltic Inflows, and phytoplankton species distribution and new scenario simulations with improved models, e.g. for glaciers, lake ice and marine food web, have become available. In many cases, uncertainties can now be better estimated than before, because more models can be included in the ensembles, especially for the Baltic Sea. With the help of coupled models, feedbacks between several components of the Earth System have been studied and multiple driver studies were performed, e.g. projections of the food web that include fisheries, eutrophication and climate change. New data sets and projections have led to a revised understanding of changes in some variables such as salinity. Furthermore, it has become evident that natural variability, in particular for the ocean on multidecadal time scales, is greater than previously estimated, challenging our ability to detect observed and projected changes in climate. In this context, the first paleoclimate simulations regionalized for the Baltic Sea region are instructive. Hence, estimated uncertainties for the projections of many variables increased. In addition to the well-known influence of the North Atlantic Oscillation, it was found that also other low-frequency modes of internal variability, such as the Atlantic Multidecadal Variability, have profound effects on the climate of the Baltic Sea region. Challenges were also identified, such as the systematic discrepancy between future cloudiness trends in global and regional models and the difficulty of confidently attributing large observed changes in marine ecosystems to climate change. Finally, we compare our results with other coastal sea assessments, such as the North Sea Region Climate Change Assessment (NOSCCA) and find that the effects of climate change on the Baltic Sea differ from those on the North Sea, since Baltic Sea oceanography and ecosystems are very different from other coastal seas such as the North Sea. While the North Sea dynamics is dominated by tides, the Baltic Sea is characterized by brackish water, a perennial vertical stratification in the southern sub-basins and a seasonal sea ice cover in the northern sub-basins</p

Climate change in the Baltic Sea region: a summary

Based on the Baltic Earth Assessment Reports of this thematic issue in Earth System Dynamics and recent peer-reviewed literature, current knowledge of the effects of global warming on past and future changes in climate of the Baltic Sea region is summarised and assessed. The study is an update of the Second Assessment of Climate Change (BACC II) published in 2015 and focuses on the atmosphere, land, cryosphere, ocean, sediments, and the terrestrial and marine biosphere. Based on the summaries of the recent knowledge gained in palaeo-, historical, and future regional climate research, we find that the main conclusions from earlier assessments still remain valid. However, new long-term, homogenous observational records, for example, for Scandinavian glacier inventories, sea-level-driven saltwater inflows, so-called Major Baltic Inflows, and phytoplankton species distribution, and new scenario simulations with improved models, for example, for glaciers, lake ice, and marine food web, have become available. In many cases, uncertainties can now be better estimated than before because more models were included in the ensembles, especially for the Baltic Sea. With the help of coupled models, feedbacks between several components of the Earth system have been studied, and multiple driver studies were performed, e.g. projections of the food web that include fisheries, eutrophication, and climate change. New datasets and projections have led to a revised understanding of changes in some variables such as salinity. Furthermore, it has become evident that natural variability, in particular for the ocean on multidecadal timescales, is greater than previously estimated, challenging our ability to detect observed and projected changes in climate. In this context, the first palaeoclimate simulations regionalised for the Baltic Sea region are instructive. Hence, estimated uncertainties for the projections of many variables increased. In addition to the well-known influence of the North Atlantic Oscillation, it was found that also other low-frequency modes of internal variability, such as the Atlantic Multidecadal Variability, have profound effects on the climate of the Baltic Sea region. Challenges were also identified, such as the systematic discrepancy between future cloudiness trends in global and regional models and the difficulty of confidently attributing large observed changes in marine ecosystems to climate change. Finally, we compare our results with other coastal sea assessments, such as the North Sea Region Climate Change Assessment (NOSCCA), and find that the effects of climate change on the Baltic Sea differ from those on the North Sea, since Baltic Sea oceanography and ecosystems are very different from other coastal seas such as the North Sea. While the North Sea dynamics are dominated by tides, the Baltic Sea is characterised by brackish water, a perennial vertical stratification in the southern subbasins, and a seasonal sea ice cover in the northern subbasins