SummaryBackground Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest antiischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT).

Objective: Reduced numbers of regulatory T (T reg ) cells have been observed in visceral adipose tissue of obese mice and humans. However, it is unknown whether human obesity affects circulating Treg cells and whether their number is associated with markers of systemic inflammation or glucose intolerance. Design and Methods: Peripheral blood mononuclear cells were isolated from venous blood of obese (BMI ! 27 kg/m 2 ; n ¼ 30) and nonobese (BMI ! 27 kg/m 2 ; n ¼ 13) individuals and analyzed using flow cytometry for the expression of CD4, CD25, and Foxp3. Results: Reduced circulating T reg -cell numbers were detected in obese compared with nonobese study participants (P ¼ 0.038). Circulating CD4 þ CD25 þ CD127 À Foxp3 T reg cells inversely correlated with body weight (P ¼ 0.009), BMI (P ¼ 0.004) and plasma leptin levels (P ¼ 0.004) and were reduced in subjects with hsCRP ! 3.0 mg/L (P ¼ 0.034) or HbA1c ! 5.5% (P < 0.005). Receiver operating characteristic curve analysis revealed a cutoff of circulating Treg cells < 1.06% to be predictive for hsCRP levels ! 3.0 mg/L, and logistic regression showed that the risk of having hsCRP levels ! 3.0 mg/L was increased 9.6-fold (P ¼ 0.008), if T reg cells were below this threshold. The T reg cutoff for HbA1c levels ! 5.5% was 0.73%, and this cutoff also predicted an increased risk of having elevated levels of both hsCRP and HbA1c, if only obese subjects were examined. Conclusion: Our findings thus reveal an association between circulating T reg cells and measures of adiposity, inflammation, and glucose intolerance. Although further prospective studies are needed, we present data suggesting that the determination of T reg cells might be useful to identify obese subjects at increased risk of developing cardiovascular and/or metabolic complications.

Our findings suggest that locally elevated leptin levels may promote neointima formation, independent of obesity and systemic hyperleptinemia, but also underline the importance of perivascular inflammation in mediating the increased cardiovascular risk in obesity.

Abstract. Czepluch FS, Kuschicke H, Dellas C, Riggert J, Hasenfuss G, Sch€ afer K (University Medical Center G€ ottingen, G€ ottingen, Germany ++ cells, which differ in their functional properties. The aim of this study was to examine monocyte subset distribution, monocyte-platelet aggregate (MPA) formation and expression of CCR5, the receptor of the platelet-derived chemokine CCL5, and to determine whether these parameters are altered in individuals with coronary atherosclerosis.

Abstract-Sprouting and invasive migration of endothelial cells are important steps of the angiogenic cascade. Vascular endothelial growth factor (VEGF) induces angiogenesis by activating intracellular signal transduction cascades, which regulate endothelial cell morphology and function. BTB-kelch proteins are intracellular proteins that control cellular architecture and cellular functions. The BTB-kelch protein KLEIP has been characterized as an actin-binding protein that interacts with the nucleotide exchange factor ECT2. We report that KLEIP is preferentially expressed in endothelial cells, suggesting that it may play a critical role in controlling the functions of migrating, proliferating, and invading endothelial cells during angiogenesis. KLEIP mRNA level in endothelial cells is strongly regulated by hypoxia which is controlled by hypoxia-inducible factor-1␣. Functional analysis of KLEIP in endothelial cells revealed that it acts as an essential downstream regulator of VEGF-and basic fibroblast growth factor-induced migration and in-gel sprouting angiogenesis. Yet, it is not involved in controlling VEGF-or basic fibroblast growth factor-mediated proliferative responses. The depletion of KLEIP in endothelial cells blunted the VEGF-induced activation of the monomeric GTPase RhoA but did not alter the VEGF-stimulated activation of extracellular signal-regulated kinase 1/2. Moreover, VEGF induced a physical association of KLEIP with the guanine nucleotide-exchange factor ECT2, the depletion of which also blunted VEGF-induced sprouting. We conclude that the BTB-kelch protein KLEIP is a novel regulator of endothelial function during angiogenesis that controls the VEGF-induced activation of Rho GTPases. (Circ Res. 2007;100:1155-1163.)Key Words: BTB-kelch protein KLEIP Ⅲ angiogenesis Ⅲ migration Ⅲ hypoxia Ⅲ G proteins A ngiogenesis, the formation of blood vessels from preexisting ones, is a crucial process during embryonic development and in several pathological conditions. Vascular endothelial growth factor (VEGF) and its receptors are major regulators of endothelial cell (EC) function and angiogenesis. 1 VEGF is upregulated under hypoxic conditions and induces several angiogenesis-related functions in ECs, such as proliferation, migration, and NO release, which are mediated by cascades of intracellular signaling pathways. [2][3][4] Genetic experiments suggest that VEGF receptor Flk-1/KDR signaling is required for proper positioning of hemangioblastic cells from the posterior primitive streak in the yolk sac. 5 Furthermore, cells lacking Flk1/KDR are unable to coalesce to form blood islands, suggesting that Flk1/KDR signaling controls the migration of ECs. 5 The signaling pathways regulating EC migration involve the phosphorylation of p38 mitogen-activated protein kinase and focal adhesion kinase, 6 activation of phosphatidylinositol 3-kinase, 7 as well as the phosphorylation of protein kinase Akt/protein kinase B, 8,9 with subsequent formation of NO by endothelial NO synthase (eNOS). 10 Yet, mechanistically, V...

The relevance of gene mutations leading to heart diseases and hence heart failure has become evident. The risk for and the course of heart failure depends on genomic variants and mutations underlying the so‐called genetic predisposition. Genetic contribution to heart failure is highly heterogenous and complex. For any patient with a likely inherited heart failure syndrome, genetic counselling is recommended and important. In the last few years, novel sequencing technologies (named next‐generation sequencing – NGS) have dramatically improved the availability of molecular testing, the efficiency of genetic analyses, and moreover reduced the cost for genetic testing. Due to this development, genetic testing has become increasingly accessible and NGS‐based sequencing is now applied in clinical routine diagnostics. One of the most common reasons of heart failure are cardiomyopathies such as the dilated or the hypertrophic cardiomyopathy. Nearly 100 disease‐associated genes have been identified for cardiomyopathies. The knowledge of a pathogenic mutation can be used for genetic counselling, risk and prognosis determination, therapy guidance and hence for a more effective treatment. Besides, family cascade screening for a known familial, pathogenic mutation can lead to an early diagnosis in affected individuals. At that timepoint, a preventative intervention could be used to avoid or delay disease onset or delay disease progression. Understanding the cellular basis of genetic heart failure syndromes in more detail may provide new insights into the molecular biology of physiological and impaired cardiac (cell) function. As our understanding of the molecular and genetic pathophysiology of heart failure will increase, this might help to identify novel therapeutic targets and may lead to the development of new and specific treatment options in patients with heart failure.

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Monocytes are critically involved in cardiovascular wound healing processes. Human monocytes can be classified into two subsets based on the expression of CD14 and CD16. Here, we examined the temporal and spatial distribution of CD14⁺ and CD16⁺ cells after myocardial infarction (MI) in human heart and spleen tissue and correlated it with markers of cardiac repair. Heart samples obtained at autopsy were histologically classified into acute (AMI; n = 11), subacute (SAMI; n = 10) and old (OMI; n = 16) MI, or control myocardium (CONTR; n = 8). Histochemical analyses revealed marked fibrosis in OMI (p < 0.001 vs. CONTR). The adhesion molecule CD56 was also strongly expressed in OMI (p < 0.01 vs. CONTR) and found to correlate with fibrosis (p < 0.001). The number of capillaries was reduced in OMI (p < 0.01 vs. CONTR; p < 0.05 vs. AMI), whereas the hypoxia indicator carbonic anhydrase IX was predominantly expressed in AMI (p < 0.01 vs. OMI and CONTR) and SAMI (p < 0.05 vs. OMI and CONTR). The monocyte chemoattractrant osteopontin was also more highly expressed in hearts of SAMI patients (p < 0.01 vs. CONTR). Numbers of CD14⁺ monocytes were found to correlate with CD16⁺ cells (p < 0.05) and inversely with fibrosis (p < 0.05). Regarding a MI-associated release of monocytes from spleen reservoirs, a non-significant reduction of splenic CD14⁺ and CD16⁺ cells was detected in subjects with AMI. In conclusion, disease stage-specific alterations in CD14⁺ and CD16 cells in human heart may contribute to cardiac repair processes following MI.