Wiktor Kuliczkowski

Plasma adiponectin concentration in relation to severity of coronary atherosclerosis and cardiovascular risk factors in middle-aged men.

Adiponectin, an adipocyte-derived protein, seems to be a link between obesity, insulin resistance, and atherosclerosis. The present study investigated the association between adiponectin and coronary artery disease in middle-aged men. Material and methods: We examined 48 men (aged 40–60) with angiographically confirmed coronary atherosclerosis and 19 healthy men, matched by age, as a control group. Concentrations of glucose and lipids were estimated with enzymatic methods. Plasma level of adiponectin, total and free testosterone, estradiol, estrone, DHEA-S, and insulin were estimated with RIA commercial kits. Results: Men with coronary atherosclerosis had lower plasma adiponectin level than controls (16.2±9.2 vs 20.5±6.7 µg/mL; p<0.05). However, after including BMI and waist as covariate data in ANCOVA, the difference in adiponectin levels between men with CAD and controls lost statistical significance (respectively for BMI and waist: p=0.4 and p=0.7). Moreover, although not significant, adiponectin levels decreased as a function of the number of significantly narrowed coronary arteries. In a priori comparison the lowest adiponectin plasma concentration was in men with three-vessel coronary artery disease (14.3±9.8 µg/mL) and the highest in controls (20.5±6.8 µg/mL; p=0.09). Adiponectin plasma level correlated negatively (p<0.05) with BMI, waist, percentage of total fat, fasting-insulin-resistance index (FIRI), total cholesterol and triglycerides, and positively with quantitative insulin sensitivity check index (QUICKI), HDL cholesterol, total testosterone, and total testosterone/estradiol ratio. Conclusions: Our data suggest that low plasma adiponectin level is connected with insulin resistance syndrome and atherogenic lipid profile. It seems that adiponectin plays a role in pathogenesis of coronary atherosclerosis, especially in obese and insulin-resistant subjects.

Endothelial progenitor cells and left ventricle function in patients with acute myocardial infarction: potential therapeutic considertions.

Endothelial progenitor cells (EPCs) play a key role in angiogenesis and vascular repair, although their exact functions are still disputable. The impact of EPC on left ventricular ejection fraction (LVEF) during acute myocardial infarction (MI) in patients treated with primary percutaneous coronary intervention (PCI) is also under investigation. The aim of this study was to assess the impact of different populations of EPC on LVEF during and 6 months after acute MI treated with primary PCI. The study included 34 patients with documented acute anterior wall MI. The control group consisted of 19 apparently healthy subjects. Blood for EPC assessments was obtained during the first 24 hours after MI and at 7 days and 6 months after PCI. CD34+/CD133+/CD45−, CD34+/CD31+/CD45−, CD34+/CD105+/CD45−, and CD31+/CD133+/CD45− cell types were studied by flow cytometry. Echocardiography has been performed simultaneously with the EPC measurements. We observed a significant elevation of CD34+/CD133+/CD45−, CD34+/CD105+/CD45−, and CD31+/CD133+/CD45− EPC at 7 days after PCI in comparison with 24 hours and 6 months after the MI. Patients with preserved LVEF at 7 days after PCI had also higher levels of CD31+/CD133+/CD45−. Acute anterior wall MI treated with primary PCI is followed by enhanced mobilization of EPC among which a high level of CD31+/CD133+/CD45− subtype was strongly associated with the most preserved LVEF for up to 6 months after the index event. These data may provide some insight for future therapeutic strategies.

Predicting Bleeding Risk by Platelet Function Testing in Patients Undergoing Heart Surgery

Predicting bleeding events in patients with coronary artery bypass grafting (CABG) represents an unmet medical need that may improve CABG outcomes.

Rationale and Design of the Effectiveness of LowEr maintenanCe dose of TicagRelor early After myocardial infarction (ELECTRA) pilot study

Aims The degree and time course of platelet inhibition using ticagrelor can vary during the acute phase and the following stable period after acute myocardial infarction (AMI). The optimal level of platelet inhibition during the various stages of AMI remains an open question. The aim of the current study is to compare the antiplatelet efficacy of two ticagrelor maintenance dose regimens (60 mg b.i.d. vs. 90 mg b.i.d.) in stable patients following an initial strategy with ticagrelor 90 mg b.i.d. during the first month after AMI. Methods and results The Effectiveness of LowEr maintenanCe dose of TicagRelor early After myocardial infarction (ELECTRA) pilot study is a phase III, single-centre, randomized, open-label, pharmacokinetic/pharmacodynamic trial. The study population will include 50 patients with AMI treated with percutaneous coronary intervention. At Day 30 post-AMI, all trial participants will be randomly assigned in 1:1 ratio to receive either reduced (60 mg b.i.d.) or standard (90 mg b.i.d.) maintenance ticagrelor dose until Day 45 post-AMI. Platelet function testing in each patient will be performed using up to two different methods (the VASP assay and multiple electrode aggregometry). Pharmacokinetics of ticagrelor and its active metabolite (AR-C124910XX) will be assessed by liquid chromatography mass spectrometry. Conclusion A de-escalation strategy with reduced dose of ticagrelor (60 mg b.i.d.) following an initial standard dose (90 mg b.i.d.) during the first month after AMI may provide equally effective platelet inhibition as compared to maintenance with the standard ticagrelor dose. ClinicalTrials. gov Identifier NCT03251859.

Low platelet activity predicts 30 days mortality in patients undergoing heart surgery

Despite advanced techniques and improved clinical outcomes, patient survival following coronary artery bypass grafting (CABG) is still a major concern. Therefore, predicting future CABG mortality represents an unmet medical need and should be carefully explored. The objective of this study is to assess whether pre-CABG platelet activity corresponds with 30 days mortality post-CABG. Retrospective analyses of platelet biomarkers and death at 30 days in 478 heart surgery patients withdrawn from aspirin or/and clopidogrel. Platelet activity was assessed prior to CABG for aspirin (ASPI-test) with arachidonic acid and clopidogrel (ADP-test) utilizing Multiplate impedance aggregometer. Most patients (n = 198) underwent conventional CABG, off-pump (n = 162), minimally invasive (n = 30), artificial valve implantation (n = 48) or valves in combination with CABG (n = 40). There were 22 deaths at 30 days, including 10 in-hospital fatalities. With the cut-off value set below 407 area under curve (AUC) for the ASPI-test, the 30-day mortality was 5.90% for the lower cohort and 2.66% for patients with significantly higher platelet reactivity (P = 0.038). For the ADP-test with a cut-off at 400AUC, the 30-day mortality was 9.68% for the lower cohort and 3.66% for patients with higher platelet reactivity, representing a borderline significant difference (P = 0.046). Aside from the platelet indices, patients who received red blood cell (RBC) concentrate had a highly significant (P < 0.0001) risk of death at 30 days. Both aspirin and clopidogrel tests were useful in predicting 30 days mortality following heart surgery, suggesting the danger of diminished platelet activity prior to CABG in such high-risk patients. These preliminary evidence supports early discontinuation of antiplatelet therapy for elective CABG and requires adequately powered randomized trials to test the hypothesis and potentially improve survival.

Androgen receptor polymorphism and platelet reactivity in healthy men

There is established evidence of gender differences in the prevalence and severity of vascular thrombosis and mortality, with men having onset of coronary artery disease earlier in the life thanwomen, andwith first symptoms more often being myocardial infarction [1]. The impact of sex hormones on gender differences in platelet activity (one of the main factors in atherothrombosis) is also being increasingly recognized [2]. One of the “culprit” hormoneswhich could play a role in that setting is testosterone, which seems to have an influence on platelet activity, although the available data are conflicting. Some experimental studies show that in castrated rats given testosterone to physiological levels, enhanced platelet aggregation present after castration [3,4] and atherosclerotic plaque growth are inhibited [5]. Testosterone deprivation can also be harmful in men with prostate cancer treated with anti-androgenic therapy [6]. By contrast, in another study, exogenously administered testosterone up-regulated the population of thromboxane A2 (TXA2) receptors onplatelets in healthy youngmale volunteers, and this was concomitant with an enhanced aggregation response to TXA2mimetic I-BOP [7]. In yet another study, the reduction in circulating testosterone concentration following castration was associated with a significant reduction in platelet TXA2 receptor density and maximum aggregation response to TXA2-mimetic I-BOP[8]. Available data therefore suggest that testosterone influences platelet aggregation through increasing or decreasing TXA2 receptor density on the platelet surface. The mechanism for this action is largely obscure. A recent study has suggested the presence of androgen receptors (ARs) within platelets. In this study ADP-induced platelet aggregation was associated with platelet cytosolic binding to radiolabeled testosterone [9]. What is more, humanmegakaryocytes generated ex vivo expressed RNA for AR, confirmed by Western immunoblotting to be present in humanplatelets in another study [10]. These in vitro effects of testosteroneonplatelet aggregation suggestnon-genomic actionsonplatelets, or the presence of functional AR within platelets, which modulate the response to TXA2-induced platelet aggregation [10]. One possible pathway could involve testosterone linking to ARs in platelet cytosol, which in turn up-load TXA2 receptors onto the platelet surface, enhancing aggregation induced by I-BOP (TXA2-receptor agonist). The strength of the testosterone action in vivo is dependent on testosterone level and AR density and structure. ARs are expressed in vascular endothelium, in smooth muscle cells, and presumably within platelets.Genetically, theyareencodedonchromosomeX(locusq11–12). The polyglutaminic sequence coding region is the mostly polymorphic one in that gene and accounts for the transcript activity of the final product. It consists of a periodically repeating nucleotide triplet, the socalled CAG (cytosine, adenine, guanine) repeats [11]. Genetic variations of the AR gene – principally fewer CAG repeats in the amino-terminal domain – has been associated with higher testosterone levels in women

Treatment of patients with acute coronary syndrome: Recommendations for medical emergency teams: Focus on antiplatelet therapies. Updated experts’ standpoint

A group of Polish experts in cardiology and emergency medicine, encouraged by the European Society of Cardiology (ESC) guidelines, have recently published common recommendations for medical emergency teams regarding the pre-hospital management of patients with acute coronary syndrome. Due to the recent publication of the 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation and 2017 focused update on dual antiplatelet therapy in coronary artery disease the current panel of experts decided to update the previous standpoint. Moreover, new data coming from studies presented after the previous document was issued were also taken into consideration.

Anti-aggregation therapy in patients with acute coronary syndrome — recommendations for medical emergency teams. Experts’ standpoint

Jacek Kubica, Piotr Adamski, Przemysław Paciorek , Jerzy R. Ładny, Zbigniew Kalarus, Waldemar Banasiak, Wacław Kochman, Jarosław Gorący, Beata Wożakowska-Kapłon, Eliano Pio Navarese, Andrzej Kleinrok, Robert Gil, Maciej Lesiak, Jarosław Drożdż, Aldona Kubica, Krzysztof J. Filipiak, Jarosław Kaźmierczak, Aleksander Goch, Stefan Grajek, Andrzej Basiński, Łukasz Szarpak, Grzegorz Grześk, Piotr Hoffman, Wojciech Wojakowski, Zbigniew Gąsior, Sławomir Dobrzycki, Jolanta M. Siller-Matula, Adam Witkowski, Wiktor Kuliczkowski, Marcin Gruchała, Dariusz Timler, Grzegorz Opolski, Dariusz Dudek, Jacek Legutko, Marzenna Zielińska, Jarosław Wójcik

Relationship between high on aspirin platelet reactivity and oxidative stress in coronary artery by-pass grafted patients.

The aim of the study was to assess the responsiveness of blood platelets to acetylsalicylic acid (ASA) in patients following coronary artery bypass grafting (CABG) surgery with relation to oxidative and antioxidative plasma status. The study included 37 patients treated with the CABG procedure. During the first 24 h after CABG patients were given 300 mg of ASA with the following dose of 150 mg daily. The blood was collected before the procedure and 10 days after. Whole blood platelet aggregation induced with arachidonic acid, collagen and adenosine diphosphate (ADP) was performed together with whole blood generation of thromboxane B2 (TxB2). Oxidative stress was measured before and 10 days after CABG with total oxidative plasma status (TOS) and total antioxidative status of the plasma (TAS). TOS/TAS index was calculated. We observed a significant increase in the TOS and TOS/TAS index and ADP-induced aggregation 10 days after CABG in comparison with its level before operation. There was a significant decrease in the arachidonic acid-induced aggregation and serum TxB2 level. Patients with ADP-induced and collagen-induced aggregation in the upper quartile had significantly higher TOS and TOS/TAS index before (ADP) and after the operation (ADP and collagen). There were 19 patients (51%) with high on aspirin platelet reactivity after CABG who had also higher TOS and TOS/TAS index and lower TAS value in comparison with aspirin responders. Despite ASA use, increased oxidative stress after CABG can overcome its antiplatelet effect and increase platelet activation through other pathways.

Activated Hemostatic Biomarkers in Patients with Implanted Left Ventricle Assist Devices: Are Heparin and/or Clopidogrel Justified?

Background: Adequate anticoagulation represents a major problem for left ventricle assist device (LVAD) utilization in patients awaiting heart transplantation as well as for regeneration of the native heart. The proper management of hemostatic abnormalities during LVAD support may improve survival by reducing the incidence of hemorrhagic and/or thromboembolic complications. Case Report: A 40-year-old man with implanted pulsatile LVAD due to dilated cardiomyopathy received aspirin and warfarin. The patient underwent serial weekly monitoring of hemostatic biomarkers including international normalization ratio, prothrombin time, prothrombin activity, activated partial thromboplastin time, fibrinogen, D-dimer, platelet aggregation induced by adenosine diphosphate and arachidonic acid, platelet count, and mean platelet volume. The external pump was exchanged three times - twice because of a clot formation in the blood chamber of the pump, and once according to the standard protocol. Results: LVAD use was consistently associated with enhanced adenosine diphosphate-induced platelet aggregation independent from the timing of clot formation or external pump exchange. Among coagulation indices, increased D-dimer holds predictive value for clot formation. The fibrinogen level peaked before the first pump exchange and was twice as high than the average values. Gradual improvement in exercise capacity was observed 2 years after implantation, after which the patient underwent a controlled stress test in the stop mode of the LVAD and the device was successfully explanted. Conclusions: Serial assessment of hemostatic biomarkers may benefit and triage LVAD patients. Consistent platelet activation during long-term LVAD may justify the addition of clopidogrel, while high D-dimer and/or elevated fibrinogen may indicate adding heparin to the conventional antithrombotic regimen. Randomized evidence is needed to test such a hypothesis.