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Meta-Analysis of Impact of Different Types and Doses of Statins on New-Onset Diabetes Mellitus

Recent reports indicate that statins are associated with an increased risk for new-onset diabetes mellitus (DM) compared with placebo and that this relation is dose dependent. The aim of this study was to perform a comprehensive network meta-analysis of randomized controlled trials (RCTs) investigating the impact of different types and doses of statins on new-onset DM. RCTs comparing different types and doses of statins with placebo were searched for using the MEDLINE, Embase, and Cochrane databases. A search of RCTs pertinent to this meta-analysis covering the period from November 1994 to October 2012 was conducted by 2 independent investigators using the MEDLINE, Cochrane, Google Scholar, and Embase databases as well as abstracts and presentations from major cardiovascular meetings. Seventeen RCTs reporting the incidence of new-onset DM during statin treatment and including a total of 113,394 patients were identified. The RCTs compared either a statin versus placebo or high-dose versus moderate-dose statin therapy. Among different statins, pravastatin 40 mg/day was associated with the lowest risk for new-onset DM compared with placebo (odds ratio 1.07, 95% credible interval 0.86 to 1.30). Conversely, rosuvastatin 20 mg/day was numerically associated with 25% increased risk for DM compared with placebo (odds ratio 1.25, 95% credible interval 0.82 to 1.90). The impact on DM appeared to be intermediate with atorvastatin 80 mg/day compared with placebo (odds ratio 1.15, 95% credible interval 0.90 to 1.50). These findings were replicated at moderate doses. In conclusion, different types and doses of statins show different potential to increase the incidence of DM.

Genetic determinants of platelet response to clopidogrel

Antiplatelet agents are the mainstay treatment in the prevention and management of atherothrombotic complications. However, a substantial interpatient variability in response to clopidogrel has been reported. Furthermore, patients with coronary artery disease and lesser platelet inhibition in response to clopidogrel are at increased risk for cardiovascular events. Clopidogrel after absorption requires two-step oxidation by the hepatic cytochrome P450 to generate its active metabolite. Polymorphisms of genes encoding the cytochrome enzymes and P-glycoprotein involved in clopidogrel absorption are regarded as major determinants of the interindividual variability in the clopidogrel-induced platelet inhibition. In our review we discuss the prevalence and clinical significance of various alleles of the genes: CYP2C19 and ABCB1 in the setting of coronary artery disease. Allele CYP2C19*2 is associated with excess of ischaemic events including myocardial infarction and stent thrombosis. On the other hand, CYP2C19*17 allele poses a serious threat of bleeding. Data concerning the prognostic value of genetic variant 3435C→T of ABCB1 remain inconclusive.

Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: A placebo-controlled study in rats

INTRODUCTION Off-target effects of novel antiplatelet agents due to their potential clinical benefits are currently an area of intensive investigation. We aimed to compare the effects of different P2Y(12) antagonists on the reactivity of vascular smooth muscle cells. MATERIALS AND METHODS Wistar rats (n=30) were pretreated with an investigated drug or placebo. Clopidogrel (50mg/kg, n=7), prasugrel (10mg/kg, n=7), ticagrelor (10mg/kg, n=7) or placebo (n=9) were administered orally 12 and 2 hours before experiments. Constrictions of rat tail arteries induced with a stable analogue of adenosine diphosphate (2-MeS-ADP), phenylephrine and arginine vasopressin were measured as an increase in perfusion pressure. Effects of ticagrelor were assessed in the presence of ticagrelor (1μM/L) added to the perfusion solution as this drug reversibly inhibits the P2Y(12) receptor. RESULTS Pretreatment with clopidogrel and prasugrel did not inhibit 2-MeS-ADP-induced contraction while ticagrelor did. Experiments employing endothelium-deprived arteries provided similar results. Clopidogrel and prasugrel did not influence concentration-response curves in the presence of neither phenylephrine nor arginine vasopressin. The curves obtained for both vasopressors in the presence of ticagrelor and 2-MeS-ADP were shifted to the right with a significant reduction in the maximal response. CONCLUSIONS Oral administration of ticagrelor, in contrast to clopidogrel and prasugrel, prevents adenosine diphosphate-induced contraction of vascular smooth muscle cells in a rat model. Both the clinical significance and detailed mechanism of our findings warrant further investigation.

ACS network-based implementation of therapeutic hypothermia for the treatment of comatose out-of-hospital cardiac arrest survivors improves clinical outcomes: the first European experience

BackgroundThere is a paucity of data regarding clinical outcomes associated with the integration of a mild therapeutic hypothermia (MTH) protocol into a regional network dedicated to treatment of patients with acute coronary syndromes (ACS). Additionally, a recent report suggests that the neurological benefits of MTH therapy in interventionally managed ACS patients resuscitated from out-of-hospital cardiac arrest (OHCA) may be potentially offset by the catastrophic occurrence of stent thrombosis. The goal of this study was to share our experience with the implementation of an MTH program using a previously established ACS network in consecutive comatose OHCA survivors undergoing interventional management due to an initial diagnosis of ACS and to assess the clinical effectiveness and safety of MTH.MethodsWe conducted a retrospective historically controlled single centre study. Hospital survival with a favourable neurological outcome (Cerebral Performance Category of 1 or 2) and all-cause in-hospital mortality were the primary and secondary efficacy end points, respectively. Occurrence of definite stent thrombosis was the primary safety end point while the development of pneumonia, presence of positive blood cultures, occurrence of probable stent thrombosis, any bleeding complications, need for red blood cell transfusion and presence of rhythm and conductions disorders during hospitalisation constituted secondary safety end points.ResultsComatose OHCA survivors (n = 32) were referred to our Department based on ECG recording transmissions and/or phone consultations or admitted from the Emergency Department. Compared with controls (n = 33), they were significantly more likely to be discharged from hospital with a favourable neurological outcome (59 vs. 27%; p < 0.05; number needed to treat [NNT] = 3.11) and experienced lower all-cause in-hospital mortality (13 vs. 55%; p < 0.05; NNT = 2.38). Rates of all safety end points were similar in patients treated with and without MTH.ConclusionsOur study indicates that a regional system of care for OHCA survivors may be successfully implemented based on an ACS network, leading to an improvement in neurological status and to a reduction of in-hospital mortality in patients treated with MTH, without any excess of complications. However, our findings should be verified in large, prospective trials.

Intracoronary versus intravenous abciximab administration in STEMI patients: overview of current status and open questions

Abstract Objectives: To perform a systematic review to provide rationale for intracoronary (IC) abciximab administration in patients with ST-segment elevation myocardial infarction (STEMI), to summarize recent studies comparing IC vs. intravenous (IV) abciximab administration in this setting and to define questions that need to be answered in future trials determining the optimal abciximab regimen. Methods: A search covering the period from January 1993 to June 2011 was conducted by two independent investigators using MEDLINE, CENTRAL and Google Scholar databases. Proceedings from the scientific sessions of ACC, AHA, ESC, TCT and EuroPCR were also considered. Results: IC administration allows one to obtain a much higher concentration of abciximab than IV injection at the culprit lesion. Therefore it is hypothesized that IC abciximab administration provides more efficient GP IIb/IIIa receptor inhibition and more pronounced additional dose-dependent antiplatelet, antithrombotic, and anti-inflammatory effects when compared to the IV route. Numerous observational and randomized studies comparing IC vs. IV abciximab in STEMI patients indicated improvement in different surrogate end points (infarct size, obstruction of coronary microcirculation, ST segment resolution, inflammatory mediators and markers of platelet activation) related to IC administration. The evidence supporting clinical benefits associated with IC injection of abciximab comes from one randomized and several non-randomized trials as most of the studies were underpowered to assess clinical outcomes. No difference in bleeding complications was observed between IC and IV regimens. Issues that need to be addressed in future studies include: the use of IC abciximab in combination with thrombectomy, the role of selective delivery systems, and the necessity of a prolonged IV infusion of abciximab after IC bolus administration. Conclusions: An accumulating body of evidence suggests the superiority of IC over IV abciximab administration in STEMI patients. However, further trials are warranted to establish the optimal strategy of abciximab treatment in this setting.

Role of nitric oxide and cGMP in the modulation of vascular contraction induced by angiotensin II and Bay K8644 during ischemia/reperfusion

Vascular smooth muscle tone changes under the influence of numerous contracting and relaxing factors. The purpose of the present study was to determine the modulating effect of ischemia and reperfusion (I/R) on contraction triggered by angiotensin II (ANG II) and Bay K8644 as well as to investigate the importance of nitric oxide (NO) and cGMP in these reactions. Experiments were performed on isolated and perfused Wistar rat tail arteries. The contraction triggered by ANG II and Bay K8644 with the use of intracellular (in calcium-free physiological salt solution; FPSS) and extracellular (in physiological salt solution; PSS) pools of calcium ions after I/R and in the presence of sodium nitroprusside (SNP), 8Br-cGMP, an endothelial NO synthase (NOSe) inhibitor (L-NG-nitroarginine methyl ester; L-NAME) or ODQ [an inhibitor of soluble guanylyl cyclase (GC)] was evaluated. ANG II triggered contraction in FPSS and PSS, but Bay K8644 only in PSS. Ischemia reduced and reperfusion intensified the response of the artery to ANG II, but did not change the action of Bay K8644. SNP and 8Br-cGMP reduced the response of the vessels to ANG II and did not change the modulating effect of ischemia, but reduced the intensifying action of reperfusion on contraction caused by the presence of ANG II. SNP lowered the action of Bay K8644 in PSS. In PSS, L-NAME and ODQ intensified the action of ANG II, eliminating the reducing effect of ischemia on the contraction caused by ANG II, but did not influence the intensifying reaction caused by reperfusion. L-NAME and ODQ did not influence the action of Bay K8644. I/R modulated the contraction of arteries triggered by ANG II, but did not influence the response to Bay K8644. The intra- and extracellular pools of calcium ions mediate the action of ANG II, but Bay K8644 stimulated contraction only with participation of calcium ions flowing into the cell. Control of the vascular smooth muscle tone associated with the action of NO and cGMP is subject to modulation under conditions of I/R.

Phenotype of NK Cells Determined on the Basis of Selected Immunological Parameters in Children Treated due to Acute Lymphoblastic Leukemia.

AbstractAcute lymphoblastic leukemia (ALL) is the most frequent pediatric malignancy. The chemotherapy for ALL is associated with a profound secondary immune deficiency.We evaluated the number and phenotype of natural killer (NK) cells at diagnosis, after the intensive chemotherapy and following the completion of the entire treatment for patients with ALL. The fraction, absolute number, and percentage of NK cells expressing interferon-&ggr; were determined in full blood samples. The fraction of NK cells expressing CD158a, CD158b, perforin, A, B, and K granzymes was examined in isolated NK cells.We have shown that patients assessed at ALL diagnosis showed significantly lower values of the fraction of NK cells and percentage of NK cells with the granzyme A expression. Additionally, the absolute number of NK cells, the expression of CD158a, CD158b, perforin, and granzyme A were significantly lower in patients who completed intensive chemotherapy. Also, there was a significantly higher fraction of NK cells expressing granzyme K in patients who completed the therapy.Abnormalities of NK cells were found at all stages of the treatment; however, the most pronounced changes were found at the end of intensive chemotherapy.

Role of endothelium, acetylocholine and calcium ions in Bay K8644- and KCl-induced contraction

The aim of this study was to establish the involvement of acetylcholine (Ach) and calcium ions in modulating contractions induced by Bay K8644 (an agonist of calcium channels located in the cell membrane) and KCl (at depolarizing concentrations), and also to examine the importance of the vascular endothelium in the activity of Bay K8644. The study was performed on perfused Wistar rat tail arteries. Contraction induced by Bay K8644 with the participation of intracellular (in calcium‑free physiological salt solution, FPSS) and extracellular (in physiological salt solution, PSS, following the emptying of the cellular Ca2+ stores) pools of Ca2+ and the addition of nitro-L-arginine (L‑NNA; nitric oxide synthase inhibitor) or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; an inhibitor of soluble guanylyl cyclase) was studied. In addition, the effect of Ach on the contraction response was analyzed and the results were compared with the depolarizing action of KCl. The effects of 8Br‑cGMP on the artery contraction induced by Bay K8644 prior to and following removal of the endothelium were compared. Bay K8644 and KCl in PSS induced vascular contraction, which was reduced with the addition of Ach. The spasmolytic Ach action did not occur in the presence of L‑NNA and ODQ. 8Br‑cGMP reduced the contraction of arterial walls (with and without endothelium) induced by Bay K8644. The increase in vascular tone induced by Bay K8644 and KCl was independent of the intracellular calcium ion pool. The relaxant effect of Ach on the responses stimulated by Bay K8644 and KCl indicated the participation of nitric oxide in modulating the reactivity of the arteries to the factors examined, resulting in an influx of Ca2+ into the cell.

Rho-kinase inhibitor reduces hypersensitivity to ANG II in human mesenteric arteries retrieved and conserved under the same conditions as transplanted organs.

Rho-kinase and GTP-ase Rho are important regulators of vascular tone and blood pressure. The aim of this study was to investigate the role of Rho-kinase in artery reactions induced by angiotensin II (ANG II) and the effects of ischemia-reperfusion injury as well as the function of intra- and extracellular calcium in these reactions. Experiments were performed on mesenteric superior arteries procured from cadaveric organ donors and conserved under the same conditions as transplanted kidneys. The vascular contraction in reaction to ANG II was measured in the presence of Rho-kinase inhibitor Y-27632, after ischemia and reperfusion, in Ca2+ and Ca2+-free solution. The maximal response to ANG II was reduced after ischemia, while an increase was observed after reperfusion. Vascular contraction induced by ANG II was decreased by Y-27632. Y-27632 reduced vascular contraction after reperfusion, both in Ca2+ and Ca2+-free solution. Reperfusion augments vascular contraction in reaction to ANG II. The Rho-kinase inhibitor Y-27632 reduces the hypersensitivity to ANG II after reperfusion mediated by both intra- and extracellular calcium. These results confirm the role of Rho-kinase in receptor-independent function of ANG II and in reperfusion-induced hypersensitivity.