Histochemical and immunohistochemical analyses of the myocardial scar fallowing acute myocardial infarction

Background/Aim. The heart has traditionally been considered as a static organ without capacity of regeneration after trauma. Currently, the more and more often asked question is whether the heart has any intrinsic capacities to regenerate myocytes after myocardial infarction. The aim of this study was to present the existence of the preserved muscle fibers in the myocardial scar following myocardial infarction as well as the presence of numerous cells of various size and form that differently reacted to the used immunohistochemical antibodies. Methods. Histological, histochemical and immunohistochemical analyses of myocardial sections taken from 177 patients who had died of acute myocardial infarction and had the myocardial scar following myocardial infarction, were carried out. More sections taken both from the site of acute infarction and scar were examined by the following methods: hematoxylin-eosin (HE), periodic acid schiff (PAS), PAS-diastasis, Masson trichrom, Malory, van Gieson, vimentin, desmin, myosin, myoglobin, alpha actin, smoth muscle actin (SMA), p53, leukocyte common antigen (LCA), proliferating cell nuclear antigen (PCNA), Ki-67, actin HHF35, CD34, CD31, CD45, CD45Ro, CD8, CD20. Results. In all sections taken from the scar region, larger or smaller islets of the preserved muscle fibers with the signs of hypertrophy were found. In the scar, a large number of cells of various size and form: spindle, oval, elongated with abundant cytoplasm, small with one nucleus and cells with scanty cytoplasm, were found. The present cells differently reacted to histochemical and immunohistochemical methods. Large oval cells showed negative reaction to lymphocytic and leukocytic markers, and positive to alpha actin, actin HHF35, Ki-67, myosin, myoglobin and desmin. Elongated cells were also positive to those markers. Small mononuclear cells showed positive reaction to lymphocytic markers. Endothelial and smooth muscle cells in the blood vessel walls were positive to CD34 and CD31, and smooth muscle cells to SMA. Oval and elongated cells were positive to PCNA and Ki-67. The preserved muscle fibers in the scar were positive to myosin, myoglobin and desmin as well as elongated and oval cells. Other cells were negative to these markers. Conclusion. Our findings speak that myocardial regeneration is maybe possible and develops in human ischemic heart damages and that the myocardium is not a static organ without capacity of cell regeneration

Sudden death: Neurogenic causes, prediction and prevention

Sudden death is a major health problem all over the world. The most common causes of sudden death are cardiac but there are also other causes such as neurological conditions (stroke, epileptic attacks and brain trauma), drugs, catecholamine toxicity, etc. A common feature of all these diverse pathologies underlying sudden death is the imbalance of the autonomic nervous system control of the cardiovascular system. This paper reviews different pathologies underlying sudden death with emphasis on the autonomic nervous system contribution, possibilities of early diagnosis and prognosis of sudden death using various clinical markers including autonomic markers (heart rate variability and baroreflex sensitivity), present possibilities of management and promising prevention by electrical neuromodulation

Diagnosis and results of treatment of heart myxoma

Background/Aim. Myxoma is the most common benign primary cardiac neoplasm, and usually originates from the left atrial septum. Early diagnosis of cardiac myxomas depends on a high index of a clinical suspicion. Surgical management must be done as soon as possible after diagnosis. The aim of this retrospective study was to present diagnostics and treatment outcome data of 61 patients with cardiac myxoma treated in the Military Medical Academy, Belgrade during a 49-years period. Methods. Intrahospital diagnosis was established in all the patients by the cardiologist. Diagnostic methods were various, in dependence on the examination period and suspected diagnosis. Results. Within a 49-years period (1961-2009) heart myxoma was diagnozed and treated in 61 patients in the Military Medical Academy, Belgrade. Most of the operated patients were females (38 or 62.3%). The operated patients were 19-68 years old. Average age of all the patients was 47.9%. The great majority of them (98.4%) had atrial, and only one operated patient had ventricular myxoma. In 13 (21.3%) of the patients heart myxoma was found out accidentally due to no previous cardiologic symptomatology. In most patients (27.44%) symptomatology was presented as thromboembolic disease. Because of the suspected ventricular myxoma in one patient, the patient was operated on, but Hodgkin's lymphoma was found out which, according to the subsequent course of the disease, could be justifiably recognized as primary heart lymphoma. This study presented brief descriptions of the course of the disease in 4 patients with myxomas in each of the cardiac cavities. Conclusion. The only diagnostic difficulty in cardiac myxoma is due to its asymptomatic and oligosymptomatic presence within the longer period of time, namely, its growth period. Echocardiography should be the standard method of cardiologic examination of these patients, which could considerably contribute to early diagnosis and treatment of heart myxoma. Surgical extirpation of myxoma is the only and very successful therapeutic method

Mechanisms of endothelium-dependent vasorelaxation induced by procyanidin B2 in venous bypass graft

Cardioprotective abilities of procyanidins, might, at least in part, attribute to their vasodilator properties. The present study was undertaken to assess the vasorelaxant effect of procyanidin B2 on isolated human saphenous vein (HSV) and its underlying mechanisms. Procyanidin B2 relaxed phenylephrine-induced contraction of HSV rings in concentration-dependent manner. The relaxation was dependent on the presence of endothelium and was strongly affected by l-NAME, hydroxocobalamin or ODQ, the inhibitors of NO/cGMP pathway. Indomethacin significantly affected only the relaxation produced by the highest concentrations of procyanidin B2. Apamin and TRAM-34 combination, in the presence of l-NAME and indomethacin, did not additionally decreased procyanidin B2-induced relaxation. In the presence of K+ channel blockers, relaxation induced by procyanidin B2 was partially attenuated by 4-aminopyridine, significantly inhibited by glibenclamide and almost abolished by iberiotoxin. Procyanidin B2 also relaxed the contractions induced by phenylephrine or caffeine in Ca2+-free solution. Finally, nifedipine slightly, while thapsigargin strongly antagonized HSV relaxation. Our results indicate that procyanidin B2 induces endothelium-dependent relaxation of HSV, which results primarily from stimulation of NO production, as well K+ channels opening, especially BKCa, and partially KATP and KV. Regulation of the intracellular Ca2+ release and inhibition of Ca2+ influx probably cont

Contemporary approach to primary prophylaxis of venous thromboembolism regarding the impact of risk factors on anticoagulation therapy duration

Odgovarajuća tromboprofilaksa podrazumeva pravovremeno identifikovanje reverzibilnih i ireverzibilnih faktora rizika za venski tromboembolizam (VTE), kao i njihovu kategorizaciju. Podaci da najveći procenat plućnih embolija nastaje kod bolesnika sa nehirurškim oboljenjima i da se kod hirurški lečenih bolesnika VTE uglavnom javlja posle otpusta iz bolnice nameću potrebu za odgovarajućom zaštitom od VTE osoba obolelih od inflamatornih oboljenja, akutnih bolesti i drugih nehirurških oboljenja, kao i produženjem i optimalizacijom antikoagulantnog režima posle hirurških intervencija u primarnoj profilaksi VTE. Kao gotovo potpuno neprepoznate i u praksi zanemarene značajne faktore rizika za VTE posebno ističemo hroničnu opstruktivnu bolest pluća (HOBP) i insuficijenciju srca, naročito kod bolesnika koji pripadaju trećoj i četvrtoj funkcionalnoj klasi prema klasifikaciji Njujorškog udruženja za srce (NYHA III i IV) sa značajno smanjenom funkcijom leve komore. Postoji opasnost da se kod bolesnika sa HOBP znaci dispneje i kašalj jednostrano pogrešno protumače kao tipični simptomi uzrokovani isključivo osnovnom respiratornom bolešću, a da se znaci pogoršanja oboljenja kod osoba s insuficijencijom srca pripišu samo pogoršanju kardijalnog statusa, zanemarujući mogućnost da je u osnovi reč o plućnom tromboembolizmu koji nije na odgovarajući način prepoznat i lečen. Savremeni način života pogoduje nastanku novih faktora rizika za VTE, kao što je 'putnička' tromboza, naročito kod osoba koje lete na dugačkim avionskim linijama, kao i ljudi koji veći deo dana sede ispred kompjutera (engl. e-thrombosis). Utvrđivanje i prepoznavanje faktora rizika za VTE, naročito zanemarenih nehirurških, i istovremenog postojanja višestrukih faktora rizika u određenom vremenskom intervalu neophodno je radi određivanja odgovarajućeg antikoagulantnog terapijskog režima kod bolesnika s nehirurškim oboljenjima i onih koji su hirurški lečeni u primarnoj prevenciji VTE.Adequate thromboprophylaxis primarily requires timely detection of reversible and irreversible risk factors of venous thromboembolism (VTE) and their categorization. It is important to note that the highest percentage of VTE episodes occur in non-surgical (medical) patients and that VTE develops in a large number of surgical patients upon hospital discharge; this emphasizes the need for adequate VTE prevention in inflammatory diseases, acute medical illness and other medical diseases as well as for prolonging and optimizing the anticoagulant regimen after surgical intervention in the primary VTE prophylaxis. As almost completely unrecognized and neglected major risk factors of VTE in clinical practice, we particularly point out the chronic obstructive pulmonary disease (COPD) and heart failure, especially in NYHA functional class III and IV patients with significantly reduced left heart ventricle. It is necessary to raise clinicians' awareness of a potential danger from wrongly and one-sidedly interpreted dyspnea and coughing signs in patients with COPD as typical symptoms of basic respiratory disease as well as from ascribing the signs of disease aggravation in heart failure patients exclusively to cardial status worsening, neglecting the possibility of having unrecognized and untreated pulmonary embolism at issue. Contemporary way of life enhances the development of new VTE risk factors such as traveler's thrombosis, in particular during long-haul flights as well as in individuals sitting at a computer for prolonged periods (e-thrombosis). Determining and recognizing VTE risk factors, especially those formerly neglected nonsurgical ones and simultaneous presence of multiple risk factors within a given period is required for defining an adequate anticoagulant regimen in primary VTE prophylaxis for surgical and non-surgical (medical) patients

Novi lekovi u terapiji dislipidemija

Dyslipidemia is the leading risk factor for the development of atherosclerosis and associated consequences, such as coronary heart disease, ischemic cerebrovascular and peripheral vascular disease. These diseases are the major cause of mortality in the world and in Europe as well, where they are responsible for around 45% of all deaths. Treatment of dyslipidemia includes the use of statins, ezetimibe, fibrates, niacin, bile acids sequestrants and omega-3 fatty acids. Although statins play the major role in dyslipidemia treatment by reducing the risk of cardiovascular (CV) events by 30%, there is a need for additional new drugs that reduce the residual risk even more. PCSK9 inhibitors, apolipoprotein B (apoB) synthesis inhibitors, MTP inhibitors and CETP inhibitors are already approved for the specific indications, or are in the advanced stages of clinical investigation. Two PCSK9 inhibitors, alirocumab and evolocumab are approved for use in combination with statins for the treatment of heterozygous familial hypercholesterolemia (FH), but also in patients with clinical atherosclerotic CV diseases who require additional low-density lipoprotein cholesterol (LDL-C) level reduction. In addition, evolocumab is approved for use in patients with homozygous FH. Mipomersen, apoB synthesis inhibitor, lomitapide, and oral MTP inhibitor are currently approved in the treatment of patients with homozygous FH as an adjunct to the maximum tolerated doses of statins and other lipid-lowering drugs. Although the new lipid-lowering agents produce significant LDL-C level reduction, more clinical studies are necessary to confirm their efficacy and safety in dyslipidemia treatment.Dislipidemije su vodeći faktor rizika za razvoj ateroskleroze i njenih posledica, kao što su koronarna bolest srca, ishemična cerebrovaskularna i periferna vaskularna bolest. Ove bolesti su glavni uzrok mortaliteta, kako u svetu tako i u Evropi, gde su odgovorne za 45% ukupne smrtnosti. Terapija dislipidemija uključuje primenu: statina, ezetimiba, fibrata, niacina, smola koje vezuju žučne kiseline i omega-3 masnih kiselina. Od pomenutih lekova, vodeću ulogu u terapiji dislipidemija imaju statini. Treba istaći da uprkos primeni statina, koji redukuju rizik od pojave kardiovaskularnih (KV) događaja za oko 30%, još uvek ostaje tzv. rezidualni rizik za nastanak KV događaja, što ukazuje da su potrebni novi lekovi koji će dalje redukovati rezidualni rizik. Novi lekovi u terapiji dislipidemija uključuju PCSK9 inhibitore, inhibitore sinteze apolipoproteina B (apoB), MTP inhibitore i CETP inhibitore, koji su ili već odobreni za primenu u određenim indikacijama, ili se nalaze u odmaklim fazama kliničkog ispitivanja. Alirokumab i evolokumab, dva PCSK9 inhibitora, odobrena su za primenu, u kombinaciji sa statinima, u terapiji heterozigotne familijarne hiperholesterolemije (FH), kao i kod bolesnika sa kliničkim aterosklerotičnim KV bolestima koji zahtevaju dodatnu redukciju nivoa lipoproteina male gustine (low-density lipoprotein cholesterol, LDL-C). Pored toga, evolokumab je odobren za primenu kod bolesnika sa homozigotnom FH. Mipomersen, inhibitor sinteze apoB, i lomitapid, oralni MTP inhibitor, su, odobreni za primenu samo kod bolesnika sa homozigotnom FH kao dodatak maksimalnoj tolerišućoj dozi statina i drugih hipolipemika. Iako novi hipolipemici značajno redukuju nivo LDL-C, neophodno je sprovesti studije, duže i sa većim brojem ispitanika, koje će potvrditi njihovu efikasnost i bezbednost i time omogućiti njihovu širu primenu u terapiji dislipidemija

Wine polyphenol resveratrol inhibits contractions of isolated rat uterus by activation of smooth muscle inwardly rectifying potassium channels

Resveratrol is a phytoalexin produced in a number of plant species including grapes. The benefit of resveratrol to health is widely reported. Resveratrol has been found to promote relaxation of non-pregnant and pregnant uterus, but its mechanism of action is unclear. The aims of our study were to investigate the involvement of inwardly rectifying potassium channels (Kir) in inhibitory effects of resveratrol on three models of contractions of non-pregnant rat uterus: the spontaneous rhythmic contractions (SRC), oxytocin-elicited phasic contractions and tonic oxytocin-elicited contractions. Uterine strips were obtained from virgin female Wistar rats in oestrus. Strips were mounted into organ bath for recording isometric tension in Krebs-Ringer solution. Experiments followed a multiple curve design. In order to test the involvement of Kirchannels in a mechanism of action of resveratrol (1-100 μM),BaCl2 (1 mM),a antagonist of inwardly rectifying potassium channels was used. Resveratrol induced a concentration-dependent relaxation of all models of contractions. BaCl2 antagonized the response to resveratrolon SRC and oxytocin-elicited phasic contractions. Relaxation achieved by resveratrolon tonic oxytocin-elicited concentrations was insensitive to BaCl2.The antagonism of resveratrol effects by inwardly rectifying potassium channels antagonist suggests that Kir channels are involved in resveratrol action on phasic contractions of rat uterus. Inhibitory effect of resveratrol on tonic contractions did not include Kir channels

Mehanizam vazorelaksacije humane vene safene izazvane procijanidinom B2

Findings from epidemiological studies indicate that polyphenols, widespread in human diet and with numerous biological activities, act cardioprotectively. Procyanidins are subclass of polyphenols with high content in commonly consumed foods and beverages, such as grapes, tea, chocolate, nuts and apples. Cardioprotective abilities of procyanidins, might, at least partly, attribute to their vasodilator properties. Since exact mechanisms of procyanidin B2-induced vasorelaxation are unknown, our study aimed to investigate relaxant effect of procyanidin B2 on isolated human saphenous vein (HSV) and its underlying mechanisms. Discarded segments of HSV were collected from patients undergoing bypass surgery and studied in organ baths. Procyanidin B2 caused concentration-dependent relaxation of HSV precontracted by phenylephrine. The relaxation was strongly affected by inhibitors of NO/cGMP pathway, L-NAME, hydroxocobalamin and ODQ. Indomethacin, a cyclooxygenase inhibitor, significantly reduced only relaxation produced by the highest concentrations of procyanidin B2. Combination of apamin and TRAM-34, selective blockers of small- and intermediate-conductance Ca 2+ -activated K+ (KCa ) channels (SKCa and IK Ca ), in the presence of L-NAME and indomethacin, did not additionally affect procyanidin B2-induced relaxation. Additionally, relaxation induced by procyanidin B2 was partially attenuated by 4- aminopyridine, predominant blocker of voltage-gated K+ (KV) channels, significantly inhibited by glibenclamide, selective ATP-sensitive K+ (KATP) channels inhibitor, and almost abolished by iberiotoxin, highly selective blocker of large-conductance KCa (BKCa ). Our results revealed that procyanidin B2 acts as a potent vasodilator on isolated human venous graft. Mechanism of this relaxation of HSV probably involves stimulation of NO production, as well K+ channels opening, especially BK Ca , and partially KATP and KVNalazi epidemioloških studija ukazuju da polifenoli, široko rasprostranjeni u ljudskoj ishrani i sa brojnim biološkim aktivnostima, deluju kardioprotektivno. Procijanidini su podklasa polifenola sa visokim sadržajem u često konzumiranoj hrani i pićima, kao što su grožđe, čaj, čokolada, orašasti plodovi i jabuke. Kardioprotektivno delovanje procijanidina može se, bar delimično, pripisati njihovim vazodilatatornim svojstvima. S obzirom da tačni mehanizmi pomoću kojih procijanidin B2 izaziva vazorelaksaciju nisu poznati, cilj naše studije bio je da istražimo relaksantni efekat procijanidina B2 na izolovanoj humanoj veni safeni (HSV) i njegove osnovne mehanizme.Neiskorišćeni segmenti HSV su uzimani od pacijenata u toku bajpas operacija i ispitivani u kupatilu za izolovane organe. Procijanidin B2 izazvao je koncentracijski-zavisnu relaksaciju HSV prekontrahovane fenilefrinom. Na relaksaciju su snažno uticali inhibitori NO/cGMP puta, L-NAME, hidroksokobalamin i ODQ. Indometacin, inhibitor ciklooksigenaze, značajno je umanjio samo relaksaciju izazivanu najvećim koncentracijama procijanidina B2. Kombinacija apamina i TRAM-34, selektivnih blokatora Ca 2+ -zavisnih K+ (KCa ) kanala male i srednje provodljivosti (SKCa i IK Ca ), u prisustvu L-NAME i indometacina, nije dodatno uticala na relaksaciju uzrokovanu procijanidinom B2. Osim toga, procijanidinom B2 izazvana relaksacija bila je delimično umanjena 4- aminopiridinom, dominantnim blokatorom voltažno-zavisnih K+ (KV) kanala, značajno inhibirana glibenklamidom, selektivnim inhibitorom ATP-zavisnih K+ (KATP) kanala, i skoro potpuno blokirana iberiotoksinom, selektivnim blokatorom K Ca velike provodljivosti (BK Ca). Naši rezultati pokazuju da procijanidin B2 deluje kao moćni vazodilatator na izolovanom humanom venskom graftu. Mehanizam ove relaksacije HSV verovatno uključuje stimulaciju proizvodnje NO, kao i otvaranje K+ kanala, posebno BK Ca , i delimično KATP i KVVIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Nicorandil directly and cyclic GMP-dependently opens K+ channels in human bypass grafts

As we previously demonstrated the role of different K+ channels in the action of nicorandil on human saphenous vein (HSV) and human internal mammary artery (HIMA), this study aimed to analyse the contribution of the cGMP pathway in nicorandil-induced vasorelaxation and to determine the involvement of cGMP in the K+ channel-activating effect of nicorandil. An inhibitor of soluble guanylate cyclase (GC), ODQ, significantly inhibited nicorandil-induced relaxation, while ODQ plus glibenclamide, a selective ATP-sensitive K+ (KATP) channel inhibitor, produced a further inhibition of both vessels. In HSV, ODQ in combination with 4-aminopyridine, a blocker of voltage-gated K+ (K-V) channels, did not modify the concentration-response to nicorandil compared with ODQ, whereas in HIMA, ODQ plus iberiotoxin, a selective blocker of large-conductance Ca2+-activated K+ (BKCa) channels, produced greater inhibition than ODQ alone. We showed that the cGMP pathway plays a significant role in the vasorelaxant effect of nicorandil on HSV and HIMA. It seems that nicorandil directly opens KATP channels in both vessels and BKCa channels in HIMA, although it is possible that stimulation of GC contributes to KATP channels activation in HIMA. Contrary, the activation of K-V channels in HSV is probably due to GC activation and increased levels of cGMP