Institute for Cardiovascular Diseases Dedinje

Belgrade, Serbia

Institute for Cardiovascular Diseases Dedinje

Belgrade, Serbia
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Gojkovic-Bukarica L.,University of Belgrade | Savic N.,University of Belgrade | Peric M.,Institute for Cardiovascular Diseases Dedinje | Markovic-Lipkovski J.,Institute of Pathology | And 7 more authors.
European Journal of Pharmacology | Year: 2011

In order to discover an agent that can prevent spasm of the human radial artery, the aim of our study was to evaluate the effect of the K+ channel opener, pinacidil, on contractions in the radial artery. Contractions of the radial artery were evoked by exogenously applied noradrenaline or by electrical field stimulation (EFS, 20 Hz, neurogenic). Pinacidil induced concentration-dependent inhibition of both EFS- and noradrenaline-evoked contractions of the radial artery. Glibenclamide, a selective blocker of ATP-sensitive K+ channels (Kir6.x containing subunit) antagonized in the same manner the pinacidil-induced inhibition of neurogenic contractions and contractions evoked by exogenous noradrenaline. The inhibition of pinacidil relaxation by tetraethylammonium (TEA), a blocker of Ca-sensitive K+ (KCa) channels, was more pronounced in EFS-contracted preparations. A blocker of voltage-sensitive K+ (KV) channels, 4-aminopyridine (4-AP), inhibited pinacidil relaxation only in EFS-contracted preparations. In order to test the presence of different K+ channels, immunohistochemistry of K+ channels expression in the radial artery was performed. The vascular wall of the human radial artery showed variable positivity with the following applied antibodies: Kv1.2, Kv1.3, Kir6.1, and KCa1.1. The antibodies against Kv1.6, Kv2.1, and Kir6.2 channel subunits were completely negative. These results suggest that the inhibitory effect of pinacidil on contractions of the human radial artery might be postsynaptic and associated with opening of smooth muscle Kir6.1-containing KATP channels. TEA- and 4-AP-sensitive K+ channels may also contribute to pinacidil effect in the human radial artery. © 2011 Elsevier B.V.


Novakovic A.,University of Belgrade | Marinko M.,University of Belgrade | Jankovic G.,University of Belgrade | Stojanovic I.,University of Belgrade | And 9 more authors.
European Journal of Pharmacology | Year: 2017

The aim of the present study was to investigate and characterize vasorelaxant effect of procyanidin B2 on human internal mammary artery (HIMA) as one of the mechanisms of its protective effect against vascular risk. Procyanidin B2 induced strong concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Pretreatment with L-NAME, a NO synthase inhibitor, hydroxocobalamin, a NO scavenger, and ODQ, an inhibitor of soluble guanylate cyclase, significantly inhibited procyanidin B2-induced relaxation of HIMA, while indomethacin, a cyclooxygenase inhibitor, considerably reduced effects of low concentrations. Among K+ channel blockers, iberiotoxin, a selective blocker of large conductance Ca2+-activated K+ channels (BKCa), abolished procyanidin B2-induced relaxation, glibenclamide, a selective ATP-sensitive K+(KATP) channels blocker, induced partial inhibition, while 4-aminopyridine, a blocker of voltage-gated K+(KV) channels, and TRAM-34, an inhibitor of intermediate-conductance Ca2+-activated K+(IKCa) channels, slightly reduced maximal relaxation of HIMA. Further, procyanidin B2 relaxed contraction induced by phenylephrine in Ca2+-free Krebs solution, but had no effect on contraction induced by caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, significantly reduced relaxation of HIMA produced by procyanidin B2. These results demonstrate that procyanidin B2 produces endothelium-dependent relaxation of HIMA pre-contracted by phenylephrine. This effect is primarily the result of an increased NO synthesis and secretion by endothelial cells and partially of prostacyclin, although it involves activation of BKCa and KATP, as well as KV and IKCa channels in high concentrations of procyanidin B2. © 2017 Elsevier B.V.


PubMed | Clinique Saint Hilaire, Papworth Hospital, Vivantes Netzwerk fur Gesundheit GmbH, Dorset County Hospital and 6 more.
Type: | Journal: Medical devices (Auckland, N.Z.) | Year: 2015

This study investigates the safety and efficacy of a third-generation drug-eluting stent (DES) with biodegradable polymer in the complex patient population of diabetes mellitus (DM).ISRCTN81649913.Percutaneous coronary interventions in patients with DM are associated with a higher incidence of death, restenosis, and stent thrombosis as compared to non-diabetic patients. The use of a DES has been shown to improve outcomes in diabetic patients.Out of 3,067 patients, enrolled in 126 centers worldwide in the NOBORI 2 registry, 888 patients suffered from DM, 213 of them (14%) being insulin-dependent DM (IDDM). Two years follow-up has been completed in this study.At 1- and 2-year follow-up, 97% and 95% of the patients, respectively, were available. The reported target lesion failure (TLF) rates at 1- and 2-year follow-up were 6.0% and 7.2% in the DM group, respectively, and 3.0% and 4.2% in the non-DM group, respectively (P<0.001 for both years). Inside the DM group, the TLF rates of 9.9% and 11.7% at the 1- and 2-year follow-ups, respectively, in patients with IDDM were significantly higher than the TLF rates of 4.7% and 5.8%, respectively, in the non-IDDM subgroup (P<0.01 for both years). The rate of stent thrombosis at the 2-year follow-up was 1.0% in the DM group and 0.7% in non-DM patients. There were no cases of late, or very late stent thrombosis in IDDM patients.The Nobori DES performed well in patients with DM. As expected, patients with DM, particularly those with IDDM, had worse outcomes. However, the absence of late, and very late stent thrombosis in IDDM patients merits further investigation, as this finding might have significant clinical value.


Novakovic A.,University of Belgrade | Marinko M.,University of Belgrade | Vranic A.,University of Belgrade | Jankovic G.,University of Belgrade | And 11 more authors.
European Journal of Pharmacology | Year: 2015

Evidences have suggested that flavanol compound (-)-epicatechin is associated with reduced risk of cardiovascular diseases. One of the mechanisms of its cardioprotective effect is vasodilation. However, the exact mechanisms by which (-)-epicatechin causes vasodilation are not yet clearly defined. The aims of the present study were to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human internal mammary artery (HIMA) and to determine the mechanisms underlying its vasorelaxation. Our results showed that (-)-epicatechin induced a concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Among the K+ channel blockers, 4-aminopyridine (4-AP) and margatoxin, blockers of voltage-gated K+ (KV) channels, and glibenclamide, a selective ATP-sensitive K+ (KATP) channels blocker, partly inhibited the (-)-epicatechin-induced relaxation of HIMA, while iberiotoxin, a most selective blocker of large conductance Ca2+-activated K+ channels (BKCa), almost completely inhibited the relaxation. In rings pre-contracted by 80 mM K+, (-)-epicatechin induced partial relaxation of HIMA, whereas in Ca2+-free medium, (-)-epicatechin completely relaxed HIMA rings pre-contracted by phenylephrine and caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca2+-ATPase inhibitor, slightly antagonized (-)-epicatechin-induced relaxation of HIMA pre-contracted by phenylephrine. These results suggest that (-)-epicatechin induces strong endothelium-independent relaxation of HIMA pre-contracted by phenylephrine whilst 4-AP- and margatoxin-sensitive KV channels, as well as BKCa and KATP channels, located in vascular smooth muscle, mediate this relaxation. In addition, it seems that (-)-epicatechin could inhibit influx of extracellular Ca2+, interfere with intracellular Ca2+ release and re-uptake by the sarcoplasmic reticulum. © 2015 Elsevier B.V. All rights reserved.


Novakovic A.,University of Belgrade | Pavlovic M.,University of Belgrade | Stojanovic I.,Institute for Cardiovascular Diseases Dedinje | Stojanovic I.,University of Belgrade | And 11 more authors.
Journal of Cardiovascular Pharmacology | Year: 2011

The drug nicorandil is a vasodilator approved for the treatment of angina. In addition to its well-known effect on the opening of ATP-sensitive K +(K ATP) channels, nicorandil-induced vasorelaxation also involves the opening of Ca 2+-activated K + channels. The aim of this study was to investigate the effects of nicorandil on the isolated human internal mammary artery (HIMA) and the human saphenous vein (HSV) and to define the contribution of different K + channel subtypes in the nicorandil action on these arterial and venous grafts. Our results show that nicorandil induced a concentration-dependent relaxation of HSV and HIMA rings precontracted by phenylephrine. Glibenclamide, a selective K ATP channels inhibitor, partially inhibited the response to nicorandil in both HSV and HIMA. Iberiotoxin, a most selective blocker of large-conductance Ca 2+-activated K + (BK Ca) channels, partly antagonized relaxation of HIMA. A nonselective blocker of voltage-gated K + channels, 4-aminopyridine caused partial inhibition of the nicorandil-induced relaxation of HSV but did not antagonize relaxation of HIMA induced by nicorandil. Margatoxin, a potent inhibitor of K V1.3 channels, did not abolish the effect of nicorandil on HSV and HIMA. Our results showed that nicorandil induced strong endothelium-independent relaxation of HSV and HIMA contracted by phenylephrine. It seems that K ATP and 4-aminopyridine-sensitive K + channels located in the smooth muscle of HSV mediated relaxation induced by nicorandil. In addition, K ATP and BK Ca channels are probably involved in the nicorandil action on HIMA. © 2011 Lippincott Williams & Wilkins.


Nenezic D.,Institute for Cardiovascular Diseases Dedinje | Tanaskovic S.,Institute for Cardiovascular Diseases Dedinje | Gajin P.,Institute for Cardiovascular Diseases Dedinje | Ilijevski N.,Institute for Cardiovascular Diseases Dedinje | Vucurevic G.,Institute for Cardiovascular Diseases Dedinje
Srpski Arhiv za Celokupno Lekarstvo | Year: 2010

Introduction Multislice CT angiography (CTA) is a noninvasive and quick technique to image carotid artery stenosis, as well as intracerebral vasculature. Modern multidetector CTA produces images with a high resolution of, not only the contrast-filled lumen, but also of the vessel wall and the surrounding soft tissues. Multiple studies have verified the ability of CTA to provide an accurate representation of the degree of carotid stenosis in comparison to digital subtraction angiography, both for moderate and high-grade stenosis. Because of its fast and accurate vessel imaging, CT angiography is increasingly used in the assessment of carotid artery stenosis. Case Outline A 37-year-old female patient was admitted at the Vascular Surgery Clinic of the Institute for Cardiovascular Diseases "Dedinje", Belgrade, for angiography and endovascular procedure of a high-grade stenosis of the left commoncarotid artery based on Multislice CT findings brought by the patient. She complained of problems which we considered to be the result of cerebral circulation ischemia. After detailed diagnostic procedures, we concluded that no pathological lesions could be verified either on the left common carotid artery or other supraaortic branches. Therefore, the patient was discharged for further neurological examinations. Conclusion Although Multislice CTA has many advantages over classical angiography, its validity should be taken with reserve, especially in younger patients.


Sarajlic A.,Imperial College London | Gligorijevic V.,Imperial College London | Radak D.,Institute for Cardiovascular Diseases Dedinje | Przulj N.,Imperial College London
Integrative Biology (United Kingdom) | Year: 2014

Recent studies suggest a protective role of diabetes in the development of aneurysm, but the biological mechanisms behind this are still unknown. This type of association is not present in the case of diabetes and atherosclerosis despite similar risk factors for aneurysm and atherosclerosis. We postulate the existence of genes that disrupt the pathways needed for the onset of aneurysm in the presence of diabetes. Motivated by the significance of genetic interactions in understanding disease-disease associations, we tackle this problem by integrating protein-protein interaction and genetic interaction data, i.e., we examine the biological pathways related to the three diseases that contain genes involved in the following genetic interactions: one gene in a genetic interaction is part of a diabetes pathway, the other gene is part of an aneurysm, or an atherosclerosis pathway. We create a protein-protein interaction sub-network that contains disease pathways described above. We then use a "brokerage" measure-a topological measure that identifies proteins in this sub-network whose removal severely affects the interconnectedness of their neighbourhood, enabling such proteins to disrupt the pathway they are in. We identify a set of proteins with high brokerage values and find this set to be enriched in biological functions, including cell-matrix adhesion, which facilitates mechanisms that have already been suggested as possible causes of diabetes-aneurysm association. We further narrow down our set to 16 proteins that are involved in an aneurysm or an atherosclerosis pathway and are encoded by genes participating in genetic interactions with a gene in a diabetes pathway. This set is enriched in kinases and phosphorylation processes, with two pleiotropic kinases that are involved in both aneurysm and atherosclerosis pathways. Kinases can turn on or off proteins, explaining how functional changes of such proteins could result in the disruption of pathways. So if in an aneurysm-related pathway a gene is turned off, the onset of the disease could be prevented. However, mutations of pleiotropic genes could have effects only on one of the traits, which explains why pleiotropic kinases that are involved in both aneurysm and atherosclerosis pathways could disrupt aneurysm pathways explaining the reduced risk of aneurysm in diabetes patients, but not affect the atherosclerosis pathways. © 2014 the Partner Organisations.


Vukajlovic D.,Institute for Cardiovascular Diseases Dedinje | Milasinovic G.,Pacemaker Center | Angelkov L.,Institute for Cardiovascular Diseases Dedinje | Ristic V.,Institute for Cardiovascular Diseases Dedinje | And 3 more authors.
Archives of Medical Science | Year: 2014

Introduction: In this study, we sought to determine whether myocardial contractile reserve (CR) assessed by dobutamine stress echocardiography (DSE) can identify patients who experience nearly complete normalization of left ventricular (LV) function after the implantation of a cardiac resynchronization therapy (CRT) pacemaker. Material and methods: The study group consisted of 55 consecutive patients with non-ischemic dilated cardiomyopathy, LV ejection fraction (LVEF) < 35%, and prolonged QRS complex duration, who were scheduled for CRT pacemaker implantation. The DSE (20 μg/ kg/min) was performed in all patients. The CR assessment was based on a change in the wall motion score index ( ΔWMSI) and ΔLVEF during DSE. Super-response was defined as an increase in LVEF to > 50% and reduction in left ventricular end-systolic dimension to < 40 mm 12 months following the CRT implantation. Results: A total of 7 patients (12.7%) were identified as super-responders to CRT. When compared to non-super-responders, these patients had significantly higher values of the dobutamine-induced change in ΔWMSI (1.031 ±0.120 vs. 0.49 ±0.371, p < 0.01), and ΔEF (17.9 ±2.2 vs. 8.8 ±6.2, p < 0.01). Receiver operating characteristic analysis showed that dobutamine-induced changes in ΔWMSI ≥ 0.7 and ≥ 14% for ΔEF are the best discriminators for a super-response. Patients with ΔWMSI ≥ 0.7 and ΔEF ≥ 14% are significantly less often hospitalized (p < 0.01) for worsening of heart failure during 28.5 ±3.0 months of the follow-up. Conclusions: Contractile reserve assessed by DSE can identify patients with dilated cardiomyopathy who are likely to experience near normalization of LV function following CRT. Copyright © 2014 Termedia & Banach.


PubMed | Institute for Cardiovascular Diseases Dedinje and Pacemaker Center
Type: Journal Article | Journal: Archives of medical science : AMS | Year: 2014

In this study, we sought to determine whether myocardial contractile reserve (CR) assessed by dobutamine stress echocardiography (DSE) can identify patients who experience nearly complete normalization of left ventricular (LV) function after the implantation of a cardiac resynchronization therapy (CRT) pacemaker.The study group consisted of 55 consecutive patients with non-ischemic dilated cardiomyopathy, LV ejection fraction (LVEF) < 35%, and prolonged QRS complex duration, who were scheduled for CRT pacemaker implantation. The DSE (20 g/kg/min) was performed in all patients. The CR assessment was based on a change in the wall motion score index (WMSI) and LVEF during DSE. Super-response was defined as an increase in LVEF to > 50% and reduction in left ventricular end-systolic dimension to < 40 mm 12 months following the CRT implantation.A total of 7 patients (12.7%) were identified as super-responders to CRT. When compared to non-super-responders, these patients had significantly higher values of the dobutamine-induced change in WMSI (1.031 0.120 vs. 0.49 0.371, p < 0.01), and EF (17.9 2.2 vs. 8.8 6.2, p < 0.01). Receiver operating characteristic analysis showed that dobutamine-induced changes in WMSI 0.7 and 14% for EF are the best discriminators for a super-response. Patients with WMSI 0.7 and EF 14% are significantly less often hospitalized (p < 0.01) for worsening of heart failure during 28.5 3.0 months of the follow-up.Contractile reserve assessed by DSE can identify patients with dilated cardiomyopathy who are likely to experience near normalization of LV function following CRT.


PubMed | Institute for Cardiovascular Diseases Dedinje
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

7566 Background: The incidence of malignant melanoma is increasing every year. An accurate and timely diagnosis is important to reduce the morbidity and mortality associated with malignant melanoma. Revealing melanoma in situ on time is increasing good prognosis of these patients.To evaluate the role of digital epiluminescence microscopy (DELM) in the differential diagnosis of cutaneous pigmented lesions and to improve the early diagnosis of melanoma in situ, 9879 pigmented lesions from 4726 consecutive patients were evaluated using DELM, in the period of five years (1999-2004), in a prospective study at the Department of Surgical Oncology of the UMC Bezanijska Kosa. After clinical examination and skin-surface microscopy of the pigmented skin lesions, suspicious skin lesions, undergone to further surgical procedures of removing skin lesions, with ex tempore biopsy.From the total number of 4726 patients, we were suspicious about the malignancy of the pigmented skin lesion in about 172 patients. 172 patients underwent to the surgical treatment, from which all of 169 patients (98.3%) had pigmented skin lesion diagnosed by ex tempore biopsy, during surgical management, as a malignant pigmented skin tumor (malignant melanoma). From the total number of patients with suspicious pigmented skin tumors (172 patients) on 98.3% patients diagnosis made by DELM was the same as diagnosis got from ex tempore biopsy, which means that this procedure is highly accurate, especially if we know that all 24 patients with melanoma in situ verified with ex tempore biopsy, was diagnosed prior with DELM, what is 100% accuracy.Digital epiluminescence microscopy is helpful device to the surgeon oncologist in deciding which pigmented lesions need surgical excision, as well as in diagnosing of early cutaneous malignant melanoma (melanoma in situ) which use will increase, with adequate surgical procedure, a 5 year survival period of these patients. No significant financial relationships to disclose.

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