Atrial expression of the CCN1 and CCN2 proteins in chronic heart failure

Previous studies have reported the upregulation of CCN proteins early after acute heart injury. The aim of the present work was to evaluate the expression of the CCN1 and CCN2 proteins and their regulation by angiotensin II in the atrial myocardium of a chronically failing heart. Male adult mice were subjected to ligation of the left coronary artery to produce myocardial infarction (the MI group), and 16 of them were treated for 12 weeks with the AT1 receptor antagonist telmisartan (the MI-Tel group). Sham-operated mice served as controls. The expression of proteins was evaluated by immunohistochemistry 12 weeks after the operation. In shamoperated mice, stainings for CCN1 and CCN2 proteins were positive within atrial cardiomyocytes. CCN1-positive reaction revealed diffused cytoplasmic localization, while CCN2 was present mainly within the perinuclear cytoplasm. CCN1 was upregulated in the MI group, while CCN2 remained at basal level. Telmisartan prevented the upregulation of CCN1 and decreased CCN2 level. We compared the experimental data with the expression of CCN1 and CCN2 proteins in human right atrial appendages. We found an inverse, but not significant, relation between the level of either protein and the left ventricular ejection fraction. This suggests a similar atrial regulation of CCN1 and CCN2 expression also in humans. We conclude that in the murine atria, CCN1 and CCN2 proteins are expressed constitutively. In chronic heart failure, CCN proteins tend to be upregulated, which may be related to the action of angiotensin II

Czy obecność zmian w tętnicach wieńcowych predysponuje do migotania przedsionków?

Cel pracy: Rola niedokrwienia jako czynnika sprzyjającego migotaniu przedsionków (AF, atrial fibrillation) nie jest w pełni ustalona. Celem pracy było porównanie częstości występowania AF u pacjentów ze zmianami w naczyniach wieńcowych i bez nich. Szczególną uwagę zwrócono na duże naczynia zaopatrujące przedsionki serca, tzn. prawą tętnicę wieńcową i gałąź okalającą lewej tętnicy wieńcowej. Materiał i metody: Dokonano retrospektywnej analizy badania koronarograficznego, które przeprowadzono u 1314 pacjentów. Wydzielono 191 chorych ze zmianami miażdżycowymi w prawej tętnicy wieńcowej oraz gałęzi okalającej &#8212; grupa I, oraz 278 osób, u których nie stwierdzono zmian miażdżycowych w powyższych naczyniach &#8212; grupa II. W obu grupach określono częstość AF i uwzględniono jedynie tych chorych, u których niemiarowość całkowitą stwierdzono podczas hospitalizacji oraz osoby z napadowym AF w wywiadzie udokumentowanym elektrokardiograficznie. Prześledzono obecność innych czynników ryzyka wystąpienia AF, takich jak wady zastawki dwudzielnej, niewydolność serca, przebyty zawał serca. Analizy statystycznej dokonano przy użyciu testu c2 i testu t-Studenta. Wyniki: Migotanie przedsionków występowało u 11 pacjentów (5,2%) z grupy I oraz u 30 (10,8%) z grupy II (różnica nieistotna statystycznie). Jednocześnie niedomykalność mitralną stwierdzono u 61% chorych z AF oraz u 14,5% z rytmem zatokowym (p < 0,001). U 42,5% pacjentów z AF występowały objawy niewydolności serca. Wnioski: Badanie nie potwierdziło faktu, że niedokrwienie przedsionków predysponuje do migotania przedsionków. Uzyskane dane wskazują na związek AF z wadami zastawki dwudzielnej oraz niską frakcją wyrzutową

Myocardial Expression of PPAR γ

Activation of PPARs may be involved in the development of heart failure (HF). We evaluated the relationship between expression of PPARγ in the myocardium during coronary artery bypass grafting (CABG) and exercise tolerance initially and during follow-up. 6-minute walking test was performed before CABG, after 1, 12, 24 months. Patients were divided into two groups (HF and non-HF) based on left ventricular ejection fraction and plasma proBNP level. After CABG, 67% of patients developed HF. The mean distance 1 month after CABG in HF was 397±85 m versus 420±93 m in non-HF. PPARγ mRNA expression was similar in both HF and non-HF groups. 6MWT distance 1 month after CABG was inversely correlated with PPARγ level only in HF group. Higher PPARγ expression was related to smaller LVEF change between 1 month and 1 year (R=0.18, p<0.05), especially in patients with HF. Higher initial levels of IL-6 in HF patients were correlated with longer distance in 6MWT one month after surgery and lower PPARγ expression. PPARγ expression is not related to LVEF before CABG and higher PPARγ expression in the myocardium of patients who are developing HF following CABG may have some protecting effect

Mitochondrial Dysfunction in Atrial Fibrillation—Mechanisms and Pharmacological Interventions

Despite the enormous progress in the treatment of atrial fibrillation, mainly with the use of invasive techniques, many questions remain unanswered regarding the pathomechanism of the arrhythmia and its prevention methods. The development of atrial fibrillation requires functional changes in the myocardium that result from disturbed ionic fluxes and altered electrophysiology of the cardiomyocyte. Electrical instability and electrical remodeling underlying the arrhythmia may result from a cellular energy deficit and oxidative stress, which are caused by mitochondrial dysfunction. The significance of mitochondrial dysfunction in the pathogenesis of atrial fibrillation remains not fully elucidated; however, it is emphasized by the reduction of atrial fibrillation burden after therapeutic interventions improving the mitochondrial welfare. This review summarizes the mechanisms of mitochondrial dysfunction related to atrial fibrillation and current pharmacological treatment options targeting mitochondria to prevent or improve the outcome of atrial fibrillation

Atrial expression of the CCN1 and CCN2 proteins in chronic heart failure

Previous studies have reported the upregulation of CCN proteins early after acute heart injury. The aim of the present work was to evaluate the expression of the CCN1 and CCN2 proteins and their regulation by angiotensin II in the atrial myocardium of a chronically failing heart. Male adult mice were subjected to ligation of the left coronary artery to produce myocardial infarction (the MI group), and 16 of them were treated for 12 weeks with the AT1 receptor antagonist telmisartan (the MI-Tel group). Sham-operated mice served as controls. The expression of proteins was evaluated by immunohistochemistry 12 weeks after the operation. In shamoperated mice, stainings for CCN1 and CCN2 proteins were positive within atrial cardiomyocytes. CCN1-positive reaction revealed diffused cytoplasmic localization, while CCN2 was present mainly within the perinuclear cytoplasm. CCN1 was upregulated in the MI group, while CCN2 remained at basal level. Telmisartan prevented the upregulation of CCN1 and decreased CCN2 level. We compared the experimental data with the expression of CCN1 and CCN2 proteins in human right atrial appendages. We found an inverse, but not significant, relation between the level of either protein and the left ventricular ejection fraction. This suggests a similar atrial regulation of CCN1 and CCN2 expression also in humans. We conclude that in the murine atria, CCN1 and CCN2 proteins are expressed constitutively. In chronic heart failure, CCN proteins tend to be upregulated, which may be related to the action of angiotensin II

Adenosine Receptor Agonist HE-NECA Enhances Antithrombotic Activities of Cangrelor and Prasugrel in vivo by Decreasing of Fibrinogen Density in Thrombus

Blood platelets’ adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y12 could serve as components of dual anti-platelet therapy. We have found that a selective A2A agonist 2-hexynyl-5’-N-ethylcarboxamidoadenosine (HE-NECA) improved the anti-thrombotic properties of either cangrelor or prasugrel in the model of ferric chloride-induced experimental thrombosis in mice. Importantly, HE-NECA was effective not only when applied in bolus as other AR agonists in the up-to-date published studies, but also when given chronically. In vitro thrombus formation under flow conditions revealed that HE-NECA enhanced the ability of P2Y12 inhibitors to decrease fibrinogen content in thrombi, possibly resulting in their lower stability. Adenosine receptor agonists possess a certain hypotensive effect and an ability to increase the blood–brain barrier permeability. Therefore, the effects of anti-thrombotic doses of HE-NECA on blood pressure and the blood–brain barrier permeability in mice were tested. HE-NECA applied in bolus caused a significant hypotension in mice, but the effect was much lower when the substance was given in doses corresponding to that obtained by chronic administration. At the same time, no significant effect of HE-NECA was observed on the blood–brain barrier. We conclude that chronic administration of the A2A agonist can be considered a potential component of a dual antithrombotic therapy. However, due to the hypotensive effect of the substances, dosage and administration must be elaborated to minimize the side-effects. The total number of animals used in the experiments was 146

Pharmacological Reports

Copyright © 2007 by Institute ofPharmacology Polish Academy ofSciences Preconditioning with the low dose of lipopolysaccharide attenuates apoptosis in the heart during septic shock in mic

Original articleThe effect of glycoprotein IIIa A1/A2 gene polymorphism on one-year outcome in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention

Introduction: Glycoprotein IIb/IIIa (GP IIb/IIIa) is a platelet receptor composed of two subunits coded by individual genes. GP IIIa gene has two alleles: A1 and A2. The A2 allele determines higher platelet activity and was investigated many times as a potential risk factor of ACS. The influence of A1/A2 polymorphism on the prognosis in patients with ST-segment elevation myocardial infarction (STEMI) has not been analysed so far. Aim: Evaluation of the relationship between GP IIb/IIIa A1/A2 gene polymorphism and one-year prognosis in patients with STEMI treated with primary percutaneous coronary intervention (pPCI). Methods: 171 patients (23.9% &#8211; women, 39.7% &#8211; anterior MI) with STEMI treated successfully with pPCI as well as 121 healthy subjects from a reference group were enrolled in the study. Genotyping was performed using restriction fragment length polymorphism analysis (RFLP). In one-year follow-up the primary end point included deaths and infarctions. The following methods were used in statistical analysis: c2 as well as Mann-Whitney test, Kaplan-Meier survival analysis, Cox regression model and multivariate analysis. Results: The percentage of A2 allele carriers was similar in STEMI patients and in subjects from the reference group (27.4% vs. 21.5%, p=0.24). No statistically significant difference in the incidence of primary end point between the A1A1 homozygotes and A2 allele carriers (A1A2/A2A2 genotype) was observed among STEMI patients. In Cox regression analysis, the variables associated with death or MI were: ejection fraction (RR 0.912, p=0.01) and systolic blood pressure on admission (RR 0.97, p=0.049). The variables categorised as unfavourable predictors included: Killip class >2 and heart ratio on admission >100/min (pWstęp: Glikoproteina IIb/IIIa (GPIIb/IIIa) jest receptorem płytek krwi zbudowanym z 2 podjednostek kodowanych przez oddzielne geny. Gen GPIIIa ma allele A1 i A2. Allel A2 warunkuje wyższą aktywnoś&#230; płytek i był wielokrotnie badany jako potencjalny czynnik ryzyka ostrych zespołów wieńcowych. Dotychczas nie oceniano wpływu polimorfizmu A1/A2 na rokowanie pacjentów z zawałem serca z uniesieniem odcinka ST (STEMI). Cel: Zbadanie związku między polimorfizmem A1/A2 genu GPIIIa a rocznym rokowaniem pacjentów ze STEMI leczonych pierwotną przezskórną interwencją wieńcową (pPCI). Metodyka: Do badania włączono 171 chorych ze STEMI skutecznie leczonych pPCI (23,9% kobiet, 39,7% zawał przedni) oraz 121 osób z grupy referencyjnej. Genotyp oznaczano metodą polimorfizmu długości fragmentów restrykcyjnych (RFLP). W rocznej obserwacji pierwotny punkt końcowy uwzględniał zgony i zawały. W analizie statystycznej użyto testów &#967;2 i Manna-Whitneya, analizy przeżycia Kaplana-Meiera, modelu regresji Coxa oraz analizy wieloczynnikowej. Wyniki: Odsetek nosicieli allela A2 był zbliżony u chorych ze STEMI i w grupie referencyjnej (27,4% vs 21,5%; p=0,24). Wśród pacjentów ze STEMI nie obserwowano istotnej statystycznie różnicy w występowaniu dodatniego punktu końcowego między grupą homozygot A1A1 i nosicieli allela 2 (genotyp A1A2/A2A2). W modelu regresji Coxa zmiennymi związanymi z wystąpieniem zgonu lub zawału były: frakcja wyrzutowa (RR 0,912; p=0,01) i ciśnienie skurczowe przy przyjęciu (RR 0,97; p=0,049). Ze zmiennych kategoryzowanych z niepomyślnym rokowaniem wiązały się klasa wg Killipa >2 oraz HR przy przyjęciu >100/min (