A Wegener granulomatózis és a gyulladásos miopátiák tüdőmanifesztációjának klinikai megjelenésével és ezek kialakulásához vezető immunológiai eltérésekkel kapcsolatos vizsgálatok

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Zero and Minimal Fluoroscopic Approaches During Ablation of Supraventricular Tachycardias : A Systematic Review and Meta-Analysis

Catheter ablations for cardiac arrhythmias are conventionally performed under fluoroscopic guidance. To guide these procedures, zero/minimal fluoroscopy (Z/MF) approaches have become available, using three-dimensional electroanatomical mapping systems. Our aim was to conduct a meta-analysis comparing these two different methods for the treatment of paroxysmal supraventricular tachycardia (SVT).Electronic databases were searched and systematically reviewed for studies comparing procedural parameters and outcomes of conventional, fluoroscopy-guided vs. Z/MF approaches in patients undergoing electrophysiology (EP) procedures for SVTs. The random-effects model was used to derive mean difference (MD) and risk ratios (RRs) with 95% confidence interval (CI).Twenty-four studies involving 9,074 patients met our inclusion criteria. There was no difference between the groups in terms of acute success rate (RR = 1.00, 95% CI, 0.99-1.01; p = 0.97) and long-term success rate (RR: 1.01, 95% CI, 1.00-1.03; p = 0.13). Compared to the conventional method, zero-and-minimal fluoroscopy (Z/MF) ablation significantly reduced fluoroscopic time [MD: -1.58 min (95% CI, -2.21 to -0.96 min; p < 0.01)] and ablation time [MD: -25.23 s (95% CI: -42.04 to -8.43 s; p < 0.01)]. No difference could be detected between the two groups in terms of the procedure time [MD: 3.06 min (95% CI: -0.97 to 7.08; p = 0.14)] and the number of ablation applications [MD: 0.13 (95% CI: -0.86 to 1.11; p = 0.80)]. The complication rate was 1.59% in the entire study population and did not differ among the groups (RR: 0.68, 95% CI: 0.45-1.05; p = 0.08).The Z/MF approach for the catheter ablation of SVTs is a feasible method that reduces radiation exposure and ablation time without compromising the acute and long-term success or complication rates

A szívizom-kontraktilitás endogén peptiderg szabályozó mechanizmusainak vizsgálata = Studies on endogenous peptidergic regulation of myocardial contractility

Célunk a szívizom-összehúzódás erejét szabályozó mechanizmusok feltárása volt. Eredményeink szerint a közelmúltban izolált prolaktin-releasing peptid (PrRP) és a neuronostatin (NST) funkcionális szereppel bír a szívben. Izolált patkányszíven a PrRP fokozta a kontrakciók erejét, az NST csökkentette azt. Az endothelin-1 (ET-1), az adrenomedullin (AM), a PrRP és az NST hatását közvetítő intracelluláris jelátvivő utak karakterizálása révén új serkentő illetve ellenszabályozó mechanizmusokat azonosítottunk. Kimutattuk, hogy az ERK1/2 mitogénaktivált-proteinkináz (MAPK) közvetíti az ET-1 és az AM inotrop hatását. A NAD(P)H-oxidáz által termelt reaktív oxigén gyökök, mint jelátvivő molekulák, serkentik az ERK1/2 aktivációját. Leírtuk, hogy az ERK1/2 foszforilációjához elengedhetetlen az epidermális növekedési faktor-receptor transzaktivációja. Az ERK1/2 a Na+-H+ cseremechanizmus fokozása révén növeli a kontrakciók erejét ET-1 illetve AM adásakor. Kimutattuk, hogy a p38-MAPK illetve az nNOS-NO-szolubilis guanilátcikláz-cGMP-proteinkináz-G jelátviteli út aktivációja ellensúlyozni képes az ET-1 inotrop hatását. Továbbá, a proteinkináz-C- és a proteinfoszfatáz-1 gyengíti a PrRP hatását. Kimutattuk, hogy az AM adaptív illetve maladaptív válaszokat vált ki a kamrai remodelláció során kontextusfüggő módon. Az azonosított jelátviteli mechanizmusok szelektív serkentése illetve gátlása a szívizom-kontraktilitás fokozásának új útjait jelentheti a szívelégtelenség kezelésében. | Our aim was to identify novel mechanisms regulating cardiac contractility. We have provided evidence for the functional significance of the recently isolated prolactin-releasing peptide (PrRP) and neuronostatin (NST) in the myocardium. PrRP increased cardiac contractility, whereas NST decreased it in isolated rat heart preparation. We have identified new positive and negative regulators of contractility by characterizing the signaling mechanisms of endothelin-1 (ET-1), adrenomedullin (AM), PrRP and NST. We have demonstrated that the mitogen-activated protein kinase (MAPK) ERK1/2 is an important mediator of the positive inotropic effect of ET-1 and AM. NAD(P)H oxidase-derived reactive oxygen species can act as signaling molecules activating ERK1/2. Moreover, epidermal growth factor receptor transactivation is required for ERK1/2 activation, which enhances contractility via the Na+-H+ exchanger. We have reported that activation of p38-MAPK and nNOS–NO–guanylyl cyclase–cGMP–protein kinase G pathway can counterbalance the inotropic response to ET-1. Moreover, the inotropic effect of PrRP was attenuated by protein kinase C? and protein phosphatase-1. In addition to control contractility, we have shown that AM can induce a context-dependent adaptive or maladaptive response during left ventricular remodeling. The selective activation or inhibition of the identified pathways may represent novel means to support cardiac function in the failing heart

Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial

BACKGROUND: 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 anti-ischaemic 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). METHODS: In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. FINDINGS: Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0.0004; hazard ratio [HR] 0.81 [95% CI 0.62-1.06], psuperiority=0.12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0.0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0.82 [95% CI 0.59-1.13]; p=0.23). INTERPRETATION: Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. FUNDING: Klinikum der Universitat Munchen, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo

Novel Mechanisms of Sildenafil in Pulmonary Hypertension Involving Cytokines/Chemokines, MAP Kinases and Akt

Pulmonary arterial hypertension (PH) is associated with high mortality due to right ventricular failure and hypoxia, therefore to understand the mechanism by which pulmonary vascular remodeling initiates these processes is very important. We used a well-characterized monocrotaline (MCT)-induced rat PH model, and analyzed lung morphology, expression of cytokines, mitogen-activated protein kinase (MAPK) phosphorylation, and phosphatidylinositol 3-kinase-Akt (PI-3k-Akt) pathway and nuclear factor (NF)-κB activation in order to elucidate the mechanisms by which sildenafil's protective effect in PH is exerted. Besides its protective effect on lung morphology, sildenafil suppressed multiple cytokines involved in neutrophil and mononuclear cells recruitment including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α/β, tissue inhibitor of metalloproteinase (TIMP)-1, interleukin (IL)-1α, lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-1α, and MIP-3α. NF-κB activation and phosphorylation were also attenuated by sildenafil. Furthermore, sildenafil reduced extracellular signal-regulated kinase (ERK)1/2 and p38 MAPK activation while enhanced activation of the cytoprotective Akt pathway in PH. These data suggest a beneficial effect of sildenafil on inflammatory and kinase signaling mechanisms that substantially contribute to its protective effects, and may have potential implications in designing future therapeutic strategies in the treatment of pulmonary hypertension