Uloga PKCd i ERK1/2 u trombinom stimulisanoj proliferaciji glatkih mišićnih ćelija krvnih sudova

Kardiovaskularne bolesti predstavljaju najveći uzrok smrtnosti ljudske populacije, a jedna od njihovih najučestalijih patoloških komponenti je i sama ateroskleroza. Proliferacija ili deoba glatkih mišićnih ćelija krvnih sudova (VSMC) ključni je događaj u nastanku raznih vaskularnih oboljenja, uključujući aterosklerozu i hipertenziju. U procesu diferencijacije i abnormalne deobe VSMC povezanih sa hipertenzijom i aterosklerozom uključen je i trombin. Stimulisanje VSMC trombinom dovodi do aktivacije ekstracelularnim signalima regulisanih kinaza 1 i 2 (ERK1/2), preko transaktivacije receptora za epidermalni faktor rasta (EGFR). U našim ranijim studijama potvrdili smo na osnovu inhibicije ERK1/2 od strane PD9805 inhibitora, učešće ERK1/2 u regulaciji proliferacije VSMC izazvanoj trombinom. Takođe, protein kinaza C delta (PKCδ), detektovana je u VSMC i pokazano je da je i njena aktivnost takođe regulisana trombinom. U okviru ovog preglednog članka biće prikazani literaturni podaci koji se odnose na ulogu PKCδ i ERK1/2, u posredovanju proliferativnog efekta trombina na VSMC.Cardiovascular disease is the greatestest single cause of mortality and its major underlying pathology is atherosclerosis. The proliferation of vascular smooth muscle cells (VSMC) is a key event in the pathogenesis of various vascular diseases, including atherosclerosis and hypertension. Thrombin is involved in the differentiation and abnormal proliferation of VSMC associated with atherosclerosis and hypertension. Thrombin stimulation results in extracellular signal-regulated kinase (ERK1/2) activation through transactivation of the epidermal growth factor receptor (EGFR). Based on our reacent studies in which PD98059 used to inhibit ERK1/2, we have shown previously that ERK1/2 was involved in the regulation by thrombin of VSMC’s proliferation. In addition, protein kinase C delta (PKCδ) have also been detected in VSMC and shown to be regulated by thrombin. In this review, we are presenting literature data relating to role of PKCδ and ERK1/2 in mediating the mitogenic action of thrombin in VSMC

Uticaj glikemije i nivoa HbA1C na prijemu na dužinu i ishod hospitalizacije kod obolelih od insulin-nezavisnog dijabetesa sa NSTEMI/STEMI

This study aims to examine the influence of admission glycaemia and glycosylated haemoglobin (HbA1C) levels on the length of hospitalization and its outcome in insulin-independent diabetes mellitus (DM) patients suffering from ST-Segment Elevation Myocardial Infarction (STEMI)/Non-STEMI (NSTEMI). This cross-sectional study included 103 subjects with a history of insulin-independent DM, currently hospitalized due to acute myocardial infarction (AMI). Out of 103 subjects, 59 (57%) were men and 66 (64.1%) of them suffered from STEMI. Mean age of study population was 67±9 years. The following parameters were monitored: demographic, coronary, cardiovascular and DM risk factors history, as well as laboratory, clinical, echocardiography and angiography parameters. DM mean duration was 7 (1-30) months, and it influenced the length of hospitalization (r=0.232, p0.05). Mean length of hospitalization was 8 and 8.5 days in STEMI and NSTEMI patients respectively, with no difference between groups (log-rank ch2= 0.476, p>0.05). HbA1C values influenced the length of hospitalization (r=0.213, p0.05). Duration of DM and the level of HbA1C prolong the length of hospitalization, but do not influence the clinical outcome of AMI patients suffering from insulin-independent DM.Cilj prikazane studije je izučavanje uticaja glikemije i glikoziliranog hemoglobina (HbA1C) pri prijemu u bolnicu na dužinu trajanja hospitalizacije, kao i njen ishod kod kod obolelih od insulin-nezavisnog dijabetesa sa NSTEMI/STEMI. Materijal i metode: Ova studija je uključila 103 ispitanika, od kojih su 59 (57%) ispitanici muškog pola, a 66 (64.1%) ispitanika imalo STEMI. Prosečna životna dob ispitivane populacije je bila 67±9 godina. Praćeni su sledeći parametri: demografske karakteristike, anamneza o koronarnim, kardiovaskularnim i rizičnim faktorima za dijabetes, kao i laboratorijski, klinički, ehokardiografski parametri. Rezultati: Prosečno trajanje dijabetesa kod osoba uključenih u studiju je bilo 7 (1-30) meseci i imalo je uticaj na dužinu hospitalizacije (r=0.232, p0.05). Prosečno trajanje hospitalizacije je bilo 8 i 8.5 dana kod ispitanika sa STEMI i NSTEMI i nije se razlikovalo među grupama ispitanika (log-rank ch2= 0.476, p>0.05). Nivoi HbA1C su uticali na dužinu trajanja hospitalizacije (r=0.213, p0.05). Zaključak: Dužina trajanja DM i nivo HbA1C produžavaju dužinu hospitalizacije, ali ne utiču na klinički ishod ispitanika sa insulin-nezavisnim dijabetesom koji su doživeli AIM

Biomarkers of cardiovascular diseases

Biomarkeri predstavljaju indikatore normalnih bioloških procesa, patogenih procesa ili farmakoloških odgovora na terapijske intervencije. Interleukin-6 (IL6, engl. Interleukin-6) je biomarker, čija sinteza može biti aktivirana različitim stimulusima, kao što su: interferon-g (IFN-g, engl. Interferon-g), faktor tumorske nekroze (TNF, engl. Tumor Necrosis Factor) i/ili interleukin-1 (IL-1, engl. Interleukin-1). IL-6 svoje efekte ostvaruje preko IL-6 receptora (IL-6R, engl. IL-6 Receptor). Pokazano je da kod transgenih miševa, kod kojih je indukovana ekspresija IL-6 i IL-6R, dolazi do hipertrofije miokarda. U mehanizmu hipertrofije miokarda bitnu ulogu ima i novootkriveni kardiotrofin1 (CT-1, engl. Cardiotrophin-1) koji je jedan od članova IL-6 familije. Aktivnost IL-6 vezuje se za razvoj aneurizme abdominalne aorte (AAA, engl. Abdominal Aortic Aneurysm), zapravo, pokazano je da su aneurizme mesta odakle cirkuliše IL-6, a takođe se smatra da je koncentracija IL-6 u pozitivnoj korelaciji sa dijametrim AAA. C-reaktivni protein (CRP, engl. CReactive Protein) je jedan od mnogobrojnih biomarkera kardiovaskularnih bolesti. Uloga CRP-a je u nastanku i progresiji kardiovaskularnih bolesti. Lokalna produkcija CRP-a od strane glatkih mišićnih i endotelnih ćelija krvnog suda, u velikoj meri utiče na razvoj procesa ateroskleroze. Važnu ulogu u nastanku ateroskleroze, osim CRP-a, ima i oksidovani lipoprotein male gustine (ox-LDL, engl. Oxidized Low Density Lipoprotein). Oksidaciju LDL-a vrše različiti enzimi. Ox-LDL nakon što prođe u intimu krvnog suda indukuje sakupljanje monocita, tj. monociti se prevode u makrofage koji vezuju ox-LDL. Kada se makrofagi napune ox-LDL-om, dolazi do pokretanja signala ćelijske smrti i stvaraju se forme penušavih ćelija koje čine početni deo aterosklerotičnog plaka. Nova saznanja o mehamizmu delovanja kao i uloge biomerkera u nastanku kardiovaskularnih bolesti, svakako će pružiti jednu od mogućnosti prevencije nastanka ovih poremećaja, a takođe i adekvatnu terapiju u lecenju kardiovaskularnih oboljenja, što i jeste jedan od glavnih ciljeva intezivnih istraživanja u oblasti biomarkera. U ovom preglednom članku, opisana su tri biomarkera kardiovaskularnih bolesti: IL-6, CRP i LDL.Biomarkers are indicators of normal biological processes, pathogenic processes or pharmacologic responses to therapeutic interventions. Interleukin-6 (IL - 6) is a biomarker whose synthesis could be activated by various stimuli, such as interferon-g (IFN - g), tumor necrosis factor (TNF) and/or interleukin - 1 (IL - 1). IL - 6 achieves its effects through the IL-6 receptor (IL - 6R). It has been shown that transgenic mice, which have induced expression of IL - 6 and IL - 6R develop myocardial hypertrophy. In myocardial hypertrophy, an important role is played by a newly discovered cardiotrophin-1, a member of the IL - 6 family. The activity of IL - 6 is associated with the development of abdominal aortic aneurysm (AAA); in fact, it has been shown that the concentration of IL - 6 positively correlates with AAA diameters. C-reactive protein (CRP) is one of the biomarkers of cardiovascular diseases. Local production of CRP by the smooth muscular and endothelial cells of the vessel leads to the development of atherosclerosis to a large extent. Oxidized low-density lipoprotein (ox - LDL) also has an important role in the development of atherosclerosis. After penetrating the intima of the vessel, ox - LDL induces monocyte collection, i.e. monocytes are translated into macrophages that bind ox - LDL. Having filled the macrophages with ox - LDL, the signals of cell death are activated, which leads to the creation of foamy cells that make up the initial part of the atherosclerotic plaque. New knowledge about the mechanism of action and the role of biomarkers in the development of cardiovascular diseases will certainly provide an opportunity to prevent the onset of these disorders, as well as an adequate therapy in the treatment of cardiovascular diseases, which is one of the main goals of intensive research in the field of biomarkers

Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial

AIMS: Various beta-blockers with distinct pharmacological profiles are approved in heart failure, yet they remain underused and underdosed. Although potentially of major public health importance, whether one agent is superior in terms of tolerability and optimal dosing has not been investigated. The aim of this study was therefore to compare the tolerability and clinical effects of two proven beta-blockers in elderly patients with heart failure. METHODS AND RESULTS: We performed a double-blind superiority trial of bisoprolol vs. carvedilol in 883 elderly heart failure patients with reduced or preserved left ventricular ejection fraction in 41 European centres. The primary endpoint was tolerability, defined as reaching and maintaining guideline-recommended target doses after 12 weeks treatment. Adverse events and clinical parameters of patient status were secondary endpoints. None of the beta-blockers was superior with regards to tolerability: 24% [95% confidence interval (CI) 20-28] of patients in the bisoprolol arm and 25% (95% CI 21-29) of patients in the carvedilol arm achieved the primary endpoint (P= 0.64). The use of bisoprolol resulted in greater reduction of heart rate (adjusted mean difference 2.1 b.p.m., 95% CI 0.5-3.6, P= 0.008) and more, dose-limiting, bradycardic adverse events (16 vs. 11%; P= 0.02). The use of carvedilol led to a reduction of forced expiratory volume (adjusted mean difference 50 mL, 95% CI 4-95, P= 0.03) and more, non-dose-limiting, pulmonary adverse events (10 vs. 4%; P < 0.001). CONCLUSION: Overall tolerability to target doses was comparable. The pattern of intolerance, however, was different: bradycardia occurred more often in the bisoprolol group, whereas pulmonary adverse events occurred more often in the carvedilol group. This study is registered with controlled-trials.com, number ISRCTN34827306

Hand-held echo is not so handy in everyone’s hands: Misdiagnosing congenital septal defects in patients with heart murmurs

Introduction. Echocardiography is a highly operator-dependant technique which requires adequate training and skills that are frequently not present, considering the widespread use of cardiovascular ultrasound. This could particularly be true for hand-held echo devices which made echocardiography more accessible but are frequently used by non-cardiologists and non-experts. Outline of Cases. We present a 45-year-old female and a 37-year-old male with heart murmurs due to atrial and ventricular septal defect, respectively. Congenital septal defects were undiagnosed in both patients during several outpatient examinations due to challenging image acquisition. Careful re-evaluation revealed that, depending on the scanning technique, it was possible to detect or overlook the real cause of the murmur using either hand-held or high-end echo device. Conclusion. Our report underlines the need of adequate knowledge and training of medical professionals performing pocket-size hand-held echocardiography, since potential misdiagnoses may not be related to limited imaging capabilities of pocket-sized echo devices only, but also to inability of insufficiently trained users to obtain good quality images and interpret them adequately. [Projekat Ministarstva nauke Republike Srbije, br. 175099

Application of ultrasound diagnostics in cardiopulmonary resuscitation

Ultrasound is becoming increasingly available and incorporated into emergency medicine. Focused echocardiographic evaluation in resuscitation (FEER) is a training program available to emergency doctors in order to ensure adequate application of echocardiography in the cardiac arrest setting. The FEER protocol provides an algorithm, whereby a “quick view” can be provided in 10 seconds during minimal interruptions in chest compressions. Performing ultrasound in the cardiac arrest setting is challenging for emergency doctors. The International Liaison Committee on Resuscitation recommend the ‘quick look’ echocardiography view can be obtained during the 10-second pulse check, minimizing the disruption to cardiopulmonary resuscitation

Short QT interval is unreliable marker of anabolic androgenic steroid abuse in competitive athletes

Introduction. Previous animal and human studies provided the evidence that testosterone may affect ventricular repolarization by shortening of the QT interval. Synthetic derivatives of testosterone, modified to enhance its anabolic properties, are occasionally abused by some competitive athletes. Objective. We assessed whether the QT interval duration could discriminate androgenic anabolic steroids (AAS)-using strength athletes (SA) from drug-free endurance athletes (EA), by comparing 25 formulas for QT interval correction. Methods. We recruited 22 elite male athletes involved in long-term strength or endurance training and 20 sedentary controls. All elit

Efekti karvedilola na aktivnost/ekspresiju inducibilne azot oksid sintetaze (iNOS) kod bolesnika sa hroničnom srčanom insuficijencijom (HSI)

Previous studies have reported increased myocardial inducible nitric oxide synthase (iNOs) expression and activity in chronic heart failure (ChF). Nitric oxide (NO) is a free radical which reacts with various molecules to cause multiple biological effects. Carvedilol is a α1-, β1-, and β2-adrenergic antagonist, used in therapy of hypertension and ChF. recently, it has been shown that carvedilol has an effect as NO quenching agent. Carvedilol presents several other mechanisms of action that converge to improve the symptomatology of hypertension and CHF. In addition to the adrenergic antagonism, carvedilol is also an antioxidant and endothelin suppressor. The molecular mechanism for the NO quenching potency of carvedilol remains to be determined. In cardiac cells the major pathway responsible for the regulation of iNOS activity/expression involves the activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt). Thus, in our current ongoing and future studies, we will test the hypothesis that in disease states such as CHF where the PI3K/Akt pathway is interrupted, the regulation of iNOS activity/expression will be abolished. as a corollary of this primary hypothesis, we postulate that in CHF carvedilol stimulates cardiovascular iNOS via a mechanism involving activation of PI3K/akt cascade and further amplifies iNOS activity/expression. Moreover, since the PI3K/akt pathway have been acknowledged as a critically important mediator of cardiac iNOS regulation, PI3K/akt are identified as one of key targets for novel therapeutic interventions to minimize irreversible tissue damage associated with CHF and hypertension. A safer technology to regulate in vivo synthesis of PI3K/akt by generic manipulation would be a welcome work.Azot oksid (NO) je slobodni radikal čije reakcije dovode do različitih bioloških dejstava. Karvedilol je antagonist α1-, β1-,i β2 adrenergičkih receptora koji se koristi u terapiji hipertenzije i nedavno je pokazano da hemijski reaguje sa NO. Pored adrenergičke blokade karvedilol doprinosi poboljšanju hipertenzije i HSI drugim mehanizmima. Takođe, pokazano je da karvedilol ima ulogu antioksidansa i ulogu u supresiji endotelina. Precizan mehanizam interakcije karvedilola i NO do sada nije u potpunosti razjašnjen. aktivnost/ekspresija inducibilne azot oksid sintetaze (iNOS) u kardiomiocitima dominantno je regulisana aktivacijom fosfatidilinozitol 3-kinaze (PI3K) i protein kinaze B (akt). U našim tekućim i planiranim istraživanjima, polazimo od hipoteze da je u HSI poremećen PI3K/akt signalni put, a time konsekventno i smanjena aktivnost/ekspresija iNOS-a. Takođe, naša hipoteza se bazira na pretpostavci da karvedilol u HSI stimuliše iNOS u kardiovaskularnom sistemu preko aktivacije PI3K/Akt kaskade. U zaključku, regulacija PI3K/Akt signalnog puta ima veoma bitnu ulogu u regulaciji iNOS-a u stanjima HSI. S obzirom da PI3K/Akt signalni put ima biološku ulogu kao kritično-važni signalni put u delovanju adrenergičkih lekova, kao što je karvedilol, to ga čini ključnim za terapeutske intervencije u cilju minimalizacije ireverzibilnih tkivnih i ćelijskih oštećenja koja su asocirana sa HSI i hipertenzijom

Effect of myocardial revascularisation on left ventricular systolic function in patients with and without viable myocardium: should non-viable segments be revascularised?

Objective To assess the effect of surgical revascularisation on left ventricular (LV) systolic function in patients with viable and non-viable dysfunctional LV segments determined by low dose dobutamine stress echocardiography (DSE). Design Prospective observational cohort study. Setting Single tertiary care centre. Patients Consecutive patients referred to surgical revascularisation (n=115). Interventions DSE and surgical revascularisation. Main outcome measures Functional recovery defined as increase in ejection fraction 5% 1year after revascularisation in patients with and without viable myocardium (viability defined as improvement of contractility in 4 LV segments on DSE). Results The mean age, ejection fraction and wall motion score index (WMSi) of patients were 599years, 44 +/- 9% and 1.82 +/- 0.31, respectively. There was no difference between DSE positive and DSE negative patients for any of those parameters at baseline study (p>0.05 for all). After 12months, the ejection fraction increased 11 +/- 1% in patients with viable myocardium vs 7 +/- 1% in patients without viable myocardium (p=0.002). Moreover, in patients with viable myocardium, the greatest increase of ejection fraction occurred 1month after surgery (9 +/- 1%), whereas in those patients with negative DSE the ejection fraction increased more gradually (2 +/- 1% after 1month, p=0.002 between groups for 1month vs preoperative value), but still improved after 12months follow-up (p lt 0.0001 in time for both groups). Conclusions It appears that patients with LV dysfunction, but without viable myocardium, may also benefit from myocardial revascularisation. Functional recovery continuously occurs throughout the first year after surgical treatment

Pseudopacemaker syndrome and marked first-degree atrioventricular block: Case report

Introduction. Pacemaker syndrome consists of the symptoms and signs present in the single chamber (VVI) pacemaker patient with electrode placed in the right ventricular apex. It is caused by inadequate timing of atrial and ventricular contractions. Pacemaker syndrome without a pacemaker (or pseudopacemaker syndrome) refers to occurrence of symptoms in the presence of marked first-degree atrioventricular (AV) block, when P wave is too close to the preceding QRS complex producing the same haemodynamic disturbance as artificial pacemaker cardiac stimulation with retrograde VA conduction. Case Outline. We present the patient with acute inferior myocardial infarction due to late bare metal stent thrombosis, treated with primary pectutaneous coronary intervention. Hospital course was complicated by complete heart block which was treated with temporary pacing. During the stand-by mode of temporary pacing, sinus rhythm with marked first-degree AV block (PQ interval 480 ms) was observed while the patients re-experienced the symptoms that were present prior to pacemaker implantation. Temporary pacing was continued for the next 24 hours when spontaneous shorteninig of PQ interval (250-270 ms) was noticed; since the patient was asymptomatic during the stand-by mode, the pacemaker electrodes were removed and the patient discharged 11 days after admission. Conclusion. Conduction disturbances, such as the varying degrees of AV blocks, are relatively common in acute inferior myocardial infarction. The first degree AV blok is usually asymptomatic and does not require treatment, unless when it is associated with pseudopacemaker syndrome. In that case, temporary pacing provides haemodynamic stability until conduction system recovers