Organ Damage in Sepsis: Molecular Mechanisms

Sepsis is one of the most common reasons for hospitalisation. This condition is characterised by systemic inflammatory response to infection. International definition of sepsis mainly points out a multi-organ dysfunction caused by a deregulated host response to infection. An uncontrolled inflammatory response, often referred to as “cytokine storm”, leads to an increase in oxidative stress as a result of the inhibition of cellular antioxidant systems. Oxidative stress, as well as pro-inflammatory cytokines, initiate vascular endothelial dysfunction and, in consequence, impair microcirculation. Microcirculation damage leads to adaptive modifications of cell metabolism. Moreover, mitochondrial dysfunction takes place which results in increased apoptosis and impaired autophagy. Non-coding RNA, especially miRNA and lncRNA molecules, may play an important role in the pathomechanism of sepsis. Altered expression of various ncRNAs in sepsis suggest, that these molecules can be used not only as diagnostics and prognostic markers but also as the target points in the pharmacotherapy of sepsis. The understanding of detailed molecular mechanisms leading to organ damage can contribute to the development of specific therapy methods thereby improving the prognosis of patients with sepsis

Czy nie-HDL cholesterol lepiej niż cholesterol frakcji LDL odzwierciedla ryzyko sercowo-naczyniowe?

The concentration of lipids and lipoproteins in plasma is essential in the treatment of lipid disorders. The routine lipidpanel includes total cholesterol, triglycerides, cholesterol of low-density lipoprotein (LDL-C) and cholesterol of high--density lipoprotein (HDL-C). The latest guidelines of the European Society of Cardiology (valid until 2020) indicate thatbesides many players in the lipid arena (apolipoprotein, concentration and size of LDL particles) another parameter,non-HDL-cholesterol (non-HDL-C), is very important. This parameter, being easily available for routine clinical use, hasbeen highlighted as a key secondary goal of therapy in patients with cardiometabolic risk.Non-HDL-C is a superior parameter to LDL-C, especially the one estimated using Friedewald formula for prediction of cardiovascular events, because non-HDL-C is an integrated complex of all lipoprotein particles containing apolipoprotein B,i.e.: LDL, very low-density lipoproteins, intermediate-density lipoproteins, chylomicrons, remnants and Lp(a). Crucially, itcan be calculated directly from the values of routine lipid panels, without additional cost.In our opinion, non-HDL-C should be presented in all routine lipid profiles conducted by diagnostic laboratories. Wealso propose a new presentation of the results of routine lipid panel, which allows a significant change in treatmentgoals, taking into account the hierarchy of values of individual concentrations of lipoprotein fractions and how they areinterpreted in the management of dyslipidaemia for optimal prevention of atherosclerosis and cardiovascular diseases.W leczeniu zaburzeń lipidowych zasadnicze znaczenie ma stężenie lipidów i lipoprotein osocza. Rutynowy panel lipidowy obejmuje: cholesterol całkowity, triglicerydy, cholesterol frakcji lipoprotein o niskiej gęstości (LDL-C) oraz cholesterol frakcji lipoprotein o wysokiej gęstości (HDL-C). W najnowszych wytycznych Europejskiego Towarzystwa Kardiologicznego (obowiązujące do 2020 r.) wskazano, że oprócz licznych parametrów na arenie lipidowej (apolipoproteiny, stężenie i wielkość cząstek LDL) niezwykle istotny jest kolejny parametr — cholesterol nie-HDL. Ten łatwo dostępny do rutynowego zastosowania klinicznego parametr wyróżniono jako kluczowy drugorzędowyy cel terapii u pacjentów obciążonych ryzykiem kardiometabolicznym. Cholesterol nie-HDL (nie-HDL-C) jest lepszym parametrem niż LDL-C, szczególnie gdy jest wyliczany zgodnie ze wzorem Friedewalda w przewidywaniu zdarzeń sercowo-naczyniowych, ponieważ nie-HDL-C jest zintegrowanym kompleksem wszystkich cząstek lipoprotein zawierających apolipoproteinę B, czyli: LDL, VLDL, IDL, chylomikrony, remnanty oraz lipoproteinę (a). Można go obliczyć bezpośrednio z wartości rutynowych paneli lipidowych bez dodatkowych kosztów. W opinii autorów nie-HDL-C powinien być prezentowany we wszystkich rutynowych profilach lipidowych wykonywanych w medycznych laboratoriach diagnostycznych. Zaproponowano również nową prezentację wyników rutynowego panelu lipidowego, która pozwala na istotną zmianę celów leczenia, biorąc pod uwagę hierarchię wartości stężeń poszczególnych frakcji lipoprotein i sposób ich interpretacji w zarządzaniu dyslipidemią w celu optymalnego zapobiegania miażdżycy i chorobom układu sercowo-naczyniowego

Czy nie-HDL cholesterol lepiej niż cholesterol frakcji LDL odzwierciedla ryzyko sercowo-naczyniowe?

W leczeniu zaburzeń lipidowych zasadnicze znaczenie ma stężenie lipidów i lipoprotein osocza. Rutynowy panel lipidowy obejmuje: cholesterol całkowity, triglicerydy, cholesterol frakcji lipoprotein o niskiej gęstości (LDL-C) oraz cholesterol frakcji lipoprotein o wysokiej gęstości (HDL-C). W najnowszych wytycznych Europejskiego Towarzystwa Kardiologicznego (obowiązujące do 2020 r.) wskazano, że oprócz licznych parametrów na arenie lipidowej (apolipoproteiny, stężenie i wielkość cząstek LDL) niezwykle istotny jest kolejny parametr — cholesterol nie-HDL. Ten łatwo dostępny do rutynowego zastosowania klinicznego parametr wyróżniono jako kluczowy drugorzędowyy cel terapii u pacjentów obciążonych ryzykiem kardiometabolicznym. Cholesterol nie-HDL (nie-HDL-C) jest lepszym parametrem niż LDL-C, szczególnie gdy jest wyliczany zgodnie ze wzorem Friedewalda w przewidywaniu zdarzeń sercowo-naczyniowych, ponieważ nie-HDL-C jest zintegrowanym kompleksem wszystkich cząstek lipoprotein zawierających apolipoproteinę B, czyli: LDL, VLDL, IDL, chylomikrony, remnanty oraz lipoproteinę (a). Można go obliczyć bezpośrednio z wartości rutynowych paneli lipidowych bez dodatkowych kosztów. W opinii autorów nie-HDL-C powinien być prezentowany we wszystkich rutynowych profilach lipidowych wykonywanych w medycznych laboratoriach diagnostycznych. Zaproponowano również nową prezentację wyników rutynowego panelu lipidowego, która pozwala na istotną zmianę celów leczenia, biorąc pod uwagę hierarchię wartości stężeń poszczególnych frakcji lipoprotein i sposób ich interpretacji w zarządzaniu dyslipidemią w celu optymalnego zapobiegania miażdżycy i chorobom układu sercowo-naczyniowego

Interindividual variability of atorvastatin treatment influence on the MPO gene expression in patients after acute myocardial infarction

Myeloperoxidase (MPO) and C-reactive protein (CRP) may play critical roles in generation of oxidative stress and the development of the systemic inflammatory response. The aim of the study was to determine the effect of atorvastatin therapy on the MPO gene expression and its plasma level in relation to lipids level lowering and an anti-inflammatory response in patients after acute myocardial infarction. The research material was represented by 112 samples. Thirty-eight patients with first AMI receiving atorvastatin therapy (40 mg/day) and followed up for one month were involved in the study. The relative MPO gene expression in peripheral blood mononuclear cells (PBMCs) was examined using RT-qPCR in 38 patients before-, 38 patients after-therapy and in 36 patients as the control group. The plasma concentrations of MPO and serum concentrations of biochemical parameters were determined using commercially available diagnostic tests. After one month of atorvastatin therapy, in 60.5% patients a decrease of MPO gene expression, whereas in 39.5% patients an increase, was observed. The plasma MPO levels behaved in the same way as the MPO gene expression. However, the serum lipids and CRP concentrations were significantly lower after one month of atorvastatin therapy in both groups of patients - with decreased and increased MPO gene expression. Atorvastatin exhibited a different effect on MPO gene expression and its plasma level. Short-term atorvastatin therapy resulted in lipid lowering and anti-inflammatory activity in patients after AMI, independently of its effect on MPO gene expression. The molecular mechanisms of this phenomenon are not yet defined and require further research

Release kinetics of circulating miRNA-208a in the early phase of myocardial infarction

Wstęp: Biochemiczne potwierdzenie zawału serca bazuje na oznaczaniu stężenia troponin sercowych: cTnI lub cTnT. Wiele badań wskazuje, że nowym obiecującym biomarkerem uszkodzeń narządowych mogą być cząsteczki mikroRNA (miRNA). Cel: Celem badania było określenie kinetyki ekspresji krążącego miRNA-208a oraz weryfikacja hipotezy, że krążące cząsteczki sercowo swoistego miRNA-208a mogą być użytecznym markerem diagnostycznym zawału serca z przetrwałym uniesieniem odcinka ST (STEMI). Metody: Przebadano 19 pacjentów z STEMI (4 kobiety i 15 mężczyzn w wieku 44–85 lat), 12 osób ze stabilną chorobą wieńcową (CAD) oraz 8 osób z negatywną obserwacją CAD jako grupę kontrolną. Krew pobierano w momencie zgłoszenia (czas 0) oraz po 3, 6, 12, 24 i 48 godzinach; w grupie CAD i kontrolnej krew do badań pobierano jednorazowo. Osoczowy miRNA-208a oznaczano w rekcji RT-PCR i obliczano jego względny przyrost. W próbkach surowicy krwi oznaczano stężenie cTnI i CK-MBmass. Wyniki: Oznaczalne, podwyższone stężenie miRNA-208a stwierdzono u pacjentów z STEMI w momencie przyjęcia, podczas gdy w grupie CAD i kontrolnej było bardzo niskie, w wielu przypadkach nieoznaczalne. Najwyższe stężenia miRNA-208a zaobserwowano w trzeciej godzinie po reperfuzji (p < 0,001). Tradycyjne biomarkery cTnI i CK-MBmass wzrastały później, osiągając maksimum w 6. godzinie po reperfuzji. Stężenie krążącego miRNA-208a silnie korelowało ze stężeniami uwolnionych z obszaru zawału cTnI i CK-MBmass. Wnioski: Uzyskane wyniki wskazują, że miRNA-208a jest obiecującym markerem uwalnianym do krążenia we wczesnej fazie zawału, który może być przydatny w jego diagnostyce.Background: The biochemical confirmation of myocardial infarction is based on cardiac troponin (cTnI or cTnT) determination. Recent scientific results suggested that microRNAs (miRNAs) might become a new biomarker of tissue injury. Aim: To evaluate the release kinetics of circulating heart-specific miRNA-208a and also to test the hypothesis that miRNA-208a can serve as an accessible, diagnostically sensitive plasma biomarker of ST-elevation acute myocardial infarction (STEMI). Methods: Nineteen STEMI patients (four women and 15 men, aged 44–85 years), 12 patients with stable coronary artery disease (CAD), and eight patients with a negative observation of CAD as a control group were studied. Blood samples were collected on admission and at three, six, 12, 24, and 48 h afterwards; in the CAD and control group blood samples were taken only once. Plasma levels of miRNA-208a determined by real-time polymerase chain reaction and their relative fold changes were calculated. cTnI and creatinine kinase (CK)-MB mass were also measured in the patients’ serum samples. Results: miRNA-208a was increased in STEMI patients at the time of admission and nearly undetectable in CAD patients and controls. The peak of miRNA-208a was observed at 3 h after reperfusion (p < 0.001). The traditional biomarkers (cTnI and CK-MBmass), which increase later in comparison to miRNA-208a reaching the maximum concentrations 6 h after reperfusion, were observed. Circulating miRNA-208a levels strongly correlated with cTnI and CK-MBmass released from the infarcted area. Conclusions: These results demonstrate that plasma miRNA-208a is an interesting and promising candidate for a new biomarker released early after onset of myocardial infarction

Immature platelet fraction in cardiovascular diagnostics and antiplatelet therapy monitoring

Immature platelet fraction (IPF), circulating platelets still containing RNA, can be easily calculated by automated flow cytometry, this makes them an accessible biomarker. Higher IPF concentrations were reported in patients with thrombocytopenia, patients who were smokers, and also those who were diabetics. Several studies have reported their diagnostic and prognostic importance in patients presenting with acute coronary syndromes, especially ST-segment myocardial infarction, where increased IPF level is an independent predictor of cardiovascular death. In addition, higher IPF were reported in patients with inadequate response to either clopidogrel or prasugrel, suggesting their potential role in antiplatelet therapy monitoring. Their prognostic significance was also observed in both coronary artery disease and postcardiac surgery status, where their higher levels correlated with the risk of major adverse cardiac events. The present review aims to present the current evidence on diagnostic, prognostic and potentially therapeutic roles of IPF in cardiovascular medicine

Circulating miR-30a-5p as a prognostic biomarker of left ventricular dysfunction after acute myocardial infarction

Left ventricular (LV) dysfunction after acute myocardial infarction (AMI) is associated with an increased risk of heart failure (HF) development. Diverse microRNAs (miRNAs) have been shown to appear in the bloodstream following various cardiovascular events. The aim of this study was to identify prognostic miRNAs associated with LV dysfunction following AMI. Patients were divided into subgroups comprising patients who developed or not LV dysfunction within six months of the infarction. miRNA profiles were determined in plasma and serum samples of the patients on the first day of AMI. Levels of 14 plasma miRNAs and 16 serum miRNAs were significantly different in samples from AMI patients who later developed LV dysfunction compared to those who did not. Two miRNAs were up-regulated in both types of material. Validation in an independent group of patients, using droplet digital PCR (ddPCR) confirmed that miR-30a-5p was significantly elevated on admission in those patients who developed LV dysfunction and HF symptoms six months after AMI. A bioinformatics analysis indicated that miR-30a-5p may regulate genes involved in cardiovascular pathogenesis. This study demonstrates, for the first time, a prognostic value of circulating miR-30a-5p and its association with LV dysfunction and symptoms of HF after AMI

Involvement of circRNAs in the Development of Heart Failure

In recent years, interest in non-coding RNAs as important physiological regulators has grown significantly. Their participation in the pathophysiology of cardiovascular diseases is extremely important. Circular RNA (circRNA) has been shown to be important in the development of heart failure. CircRNA is a closed circular structure of non-coding RNA fragments. They are formed in the nucleus, from where they are transported to the cytoplasm in a still unclear mechanism. They are mainly located in the cytoplasm or contained in exosomes. CircRNA expression varies according to the type of tissue. In the brain, almost 12% of genes produce circRNA, while in the heart it is only 9%. Recent studies indicate a key role of circRNA in cardiomyocyte hypertrophy, fibrosis, autophagy and apoptosis. CircRNAs act mainly by interacting with miRNAs through a “sponge effect” mechanism. The involvement of circRNA in the development of heart failure leads to the suggestion that they may be promising biomarkers and useful targets in the treatment of cardiovascular diseases. In this review, we will provide a brief introduction to circRNA and up-to-date understanding of their role in the mechanisms leading to the development of heart failure