In the paper by Obradovic et al., the first name and surname of the authors have been interchanged. The correct names of the author are listed below: Slobodan Obradovic, Boris Dzudovic, Bojana Subotic, Jovan Matijasevic, Zorica Mladenovic, Aleksandar Bokan, Jadranka Trobok, Sandra Pekovic, Sonja Salinger-Martinovic, Ljiljana Jovanovic, Ljiljana Kos, Tamara Kovacevic-Preradovic, Maja Nikolic, Vladimir Miloradovic, Ana Kovacevic-Kuzmanovic, Zec Nenad, Natasa Markovic-Nikolic, Ilija Srdanovic, Zoran Gluvic, Srdjan Kafedzic, Sasa Pancevacki, Aleksandar Neskovic and Stavros Konstantinides.

Introduction: Over the past 15 years, direct oral anticoagulant (DOAC) drugs have replaced vitamin K antagonists in a number of indications requiring oral anticoagulant therapy. Review work: The article written is an overview of the most important information related to the use of DOAC drugs in the secondary prevention of venous thromboembolism (VTE). The first randomized studies with dabigatran, rivaroxaban and apixaban are presented, which introduced these drugs into clinical practice in the first step, and then enabled the prolonged safe use of these drugs in the secondary prevention of VTE. Studies have also been described as current attitudes for the use of DOAC in patients with VTE associated with malignancy and antiphospholipid syndrome. An assessment of the risk of bleeding in patients with DOAC is also presented. Finally, we briefly presented the results of the use of DOAC in the treatment of pulmonary embolism in a group of patients from the regional PE registry.

Abstract Aims Women’s participation is steadily growing in medical schools, but they are still not sufficiently represented in cardiology, particularly in cardiology leadership positions. We present the contemporary distribution of women leaders in cardiology departments in the World Health Organization European region. Methods and results Between August and December 2020, we applied purposive sampling to collect data and analyse gender distribution of heads of cardiology department in university/third level hospitals in 23 countries: Austria, Azerbaijan, Belgium, Bosnia-Herzegovina, Croatia, France, Germany, Greece, Italy, North Macedonia, Morocco, Poland, Portugal, Russia, Serbia, Slovakia, Slovenia, Spain, Switzerland, Tunisia, Turkey, Ukraine, and the UK. Age, cardiology subspecialty, and number of scientific publications were recorded for a subgroup of cardiology leaders for whom data were available. A total of 849 cardiology departments were analysed. Women leaders were only 30% (254/849) and were younger than their men counterpart (♀ 52.2 ± 7.7 years old vs. ♂ 58.1 ± 7.6 years old, P = 0.00001). Most women leaders were non-interventional experts (♀ 82% vs. ♂ 46%, P < 0.00001) and had significantly fewer scientific publications than men {♀ 16 [interquartile range (IQR) 2–41] publications vs. ♂ 44 (IQR 9–175) publications, P < 0.00001}. Conclusion Across the World Health Organization European region, there is a significant gender disparity in cardiology leadership positions. Fostering a diverse and inclusive workplace is a priority to achieve the full potential and leverage the full talents of both women and men.

Background: Two-dimensional volumetric exercise stress echocardiography (ESE) provides an integrated view of left ventricular (LV) preload reserve through end-diastolic volume (EDV) and LV contractile reserve (LVCR) through end-systolic volume (ESV) changes. Purpose: To assess the dependence of cardiac reserve upon LVCR, EDV, and heart rate (HR) during ESE. Methods: We prospectively performed semi-supine bicycle or treadmill ESE in 1344 patients (age 59.8 ± 11.4 years; ejection fraction = 63 ± 8%) referred for known or suspected coronary artery disease. All patients had negative ESE by wall motion criteria. EDV and ESV were measured by biplane Simpson rule with 2-dimensional echocardiography. Cardiac index reserve was identified by peak-rest value. LVCR was the stress-rest ratio of force (systolic blood pressure by cuff sphygmomanometer/ESV, abnormal values ≤2.0). Preload reserve was defined by an increase in EDV. Cardiac index was calculated as stroke volume index * HR (by EKG). HR reserve (stress/rest ratio) <1.85 identified chronotropic incompetence. Results: Of the 1344 patients, 448 were in the lowest tertile of cardiac index reserve with stress. Of them, 303 (67.6%) achieved HR reserve <1.85; 252 (56.3%) had an abnormal LVCR and 341 (76.1%) a reduction of preload reserve, with 446 patients (99.6%) showing ≥1 abnormality. At binary logistic regression analysis, reduced preload reserve (odds ratio [OR]: 5.610; 95% confidence intervals [CI]: 4.025 to 7.821), chronotropic incompetence (OR: 3.923, 95% CI: 2.915 to 5.279), and abnormal LVCR (OR: 1.579; 95% CI: 1.105 to 2.259) were independently associated with lowest tertile of cardiac index reserve at peak stress. Conclusions: Heart rate assessment and volumetric echocardiography during ESE identify the heterogeneity of hemodynamic phenotypes of impaired chronotropic, preload or LVCR underlying a reduced cardiac reserve.

Abstract In patients with pulmonary embolism (PE), the D-Dimer assay is commonly utilized as part of the diagnostic workup, but data on D-Dimer for early risk stratification and short-term mortality prediction are limited. The purpose of this study was to determine D-Dimer levels as a predictive biomarker of PE outcomes in younger (<50 years of age) compared to older patients. We conducted retrospective analysis for 930 patients diagnosed with PE between 2015 and 2019 as part of the Serbian University Multicenter Pulmonary Embolism Registry (SUPER).All patients had D-Dimer levels measured within 24 hours of hospital admission. The primary outcome was mortality at 30 days or during hospitalization. Patients were categorized into two groups based on age (≤ 50 and >50 years of age). Younger patients constituted 20.5% of the study cohort. Regarding all-cause mortality, 5.2% (10/191)of patients died in group under the 50 years of age; the short-term all-causemortality was 12.4% (92/739) in older group.We have found that there was significant difference in plasma D-Dimer level between patients ≤ 50 years of age and older group (>50), p= 0.006.D-Dimer plasma level had good predictive value for the primary outcome in younger patients (c-statistics 0.710; 95% CI, 0.640-0.773; p<0.031). The optimal cutoff level for D-Dimer to predict PE-cause death in patients aged > 50 years was found to be 8.8 mg/l FEU(c-statistics 0,580; 95% CI 0.544-0.616; p=0.049). In younger PE patients, D-Dimer levels have good prognostic performance for 30-day all-cause mortalityand concentrations above 6.3 mg/l FEU are associated with increased risk of death. D-Dimer in patients aged over 50 years does not have predictive ability for all-caused short-term mortality. The relationship between D-Dimer and age in patients with PE may need further evaluation.

Introduction: Since December 2019, the humanity is constantly under affection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite global dissemination, neither the treatment or the specific predictive factors have been found or strictly defined yet. Aim: Aim of this study was to assess the long-term (1 year) predictive value of high-sensitive Troponin T (hsTnT) in COVID-19 affected, hospitalised patients. Methods: Between 5 March 2020 and 31 March 2020, 87 consecutive patients hospitalised at University Clinical Centre of the Republic of Srpska due to SARS-CoV2caused pneumonia, in whom hsTnT was measured, were included. The Kaplan-Meier analysis was used to assess differences in all-cause mortality between the groups. Independent predictors of all-cause mortality were identified through univariateand multivariate Cox regression analysis. Results: Compared with patients who had normal hsTnT levels, patients with raised hsTnT were significantly older (70.7 ± 13.23 vs 49 ± 15.29; p < 0.001). Glucose values were significantly increased in patients with raised hsTnT (9.29 ± 5.14 vs 6.76 ± 2.46 [4.1-5.9] mmol/L; p = 0.005), as well as serum creatinine (179.07 ± 225.58 vs 87.53 ± 18.16 μmol/L; p = 0.01), hsTnT (187.43 ± 387.29 vs 7.58 ± 3.40 pg/mL; p = 0.003), D-dimer (5.94 ± 13.78 vs 1.04 ± 1.26 [0-0.50] mg/L; p = 0.024), C-reactive protein (125.92 ± 116.82 vs 69.97 ± 73.09) [< 5.0] mg/L; p = 0.009) and calcium (1.32 ± 0.46 vs 1.03 ± 0.173 [2.20-2.65] mmol/L; p = 0.001). Kaplan-Meier analysis revealed that the number of all-cause deaths at 1 year was 19 of whom 18 were presented with elevated hsTnT (log-rank p < 0.001). When univariate Cox regression was applied, multiple predictors of all-cause mortality have been identified ie age, haemoglobin, haematocrit, urea, CK-MB as well as hsTnT. In a multiple regression model, hsTnT remained an independent predictor of poor outcome. Conclusion: Results from this study showed that the value of hsTnT during hospitalisation is possibly associated with long-term poor outcome of COVID-19 patients. Therefore, hsTnT may appear as a surrogate factor to differentiate between patients at high risk who need more intensive follow-ups.

Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate.

Controversies exist how to predict medium term mortality (Mt) in diabetics (DM) with 3 vessel (3VD) and/or left main (LM) disease undergoing myocardial revascularization ranging from Syntax Score II (SSII) where DM was not predicative variable up to FREEDOM formula which was derived, just from population with DM (without LM), having DM patients (Pts) requirement of insulin as one of predicative variable. To compare predicative power of SSII, FREEDOM and formula developed in our institution in Pts post first isolated CABG with 3VD and/or LM with DM. From our prospective data base of 2455 consecutive pts who had the first isolated CABG in the period 01/2012–12/2014 with complex Ischemic Heart Disease with 100% follow up of 4 years all-cause Mt we created by random sampling Training (1321; Mt:10.4%; DM 511; Mt:13.3%) and Validation (1134; Mt:10.0%; DM 414; Mt: 11.8%) sets. After deriving predicative formula (Cox regression) from training population we validated FREEDOM, SSII and Our Formula in 414 pts with DM from the Validation set. Characteristics of pts, our formula, predicating power by C Statistics, Calibration plots and Brier scores are presented in Picture 1. FREEDOM formula designed just for DM pts with complex Ischemic Heart Disease without LM had the smallest standard error in the estimate, but moderate C statistics as Syntax Score II and our formula which may be used for pts with and without DM and 3VD and/or LM. Picture 1 Type of funding source: Public grant(s) – National budget only. Main funding source(s): Ministry of education, science and technology development, Republic of Serbia

Freedom formula (FF) was derived very recently to assist in decision making by Heart Team in patients (Pts) with diabetes (DM) who are in need for myocardial revascularization (Percutaneous Coronary Intervention or Coronary artery bypass grafting (CABG)) due to complex ischemic Heart disease (but without left main steam disease (LM)). In external validation moderate C statistics values were obtained. To validate FF predictive value in Pts with DM and more complex patients (three vessel (3VD) and/or LM as well lower left ventricular ejection fraction (LVEF)) than in FREEDOM population. From our prospective data base of 2455 consecutive pts who had the first isolated CABG in the period 01/2012–12/2014 with 3VD and/or LM with 100% follow up of 4 years All-cause Mortality (Mt) we retrieved 925 pts with DM. DM was present in 925 Pts (Mt: 12.6%). On insulin were 318 (34.3%; Mt 14.5%). We analysed the predicative value of FF in the whole group (925) of pts with DM as well as in subgroups with LM (294) and without LM (631; most similar to original Freedom population), separately. Characteristics of pts, Freedom formula, predicating power by C Statistics, Calibration plots and Brier scores are presented in Picture 1. Our external validation of FF was almost identical as previous published one. Furthermore, the FF may be of value even in pts with LM disease and other vessels involved. Of note our pts as seen by combined LVEF, ClCr and LM were sicker than pts in FREEDOM. Picture 1 Type of funding source: Public grant(s) – National budget only. Main funding source(s): Ministry of education, science and technological development, Republic of Serbia

Two-dimensional (2-D) volumetric exercise stress echocardiography (ESE) provides an integrated view of preload reserve through end-diastolic volume (EDV) and left ventricular contractile reserve (LVCR) through end-systolic volume (ESV) changes. To assess the dependence of stroke volume (SV) and cardiac output (CO) upon LVCR EDV changes and heart rate (HR) during ESE. We prospectively performed semi-supine bicycle or treadmill ESE in 1,344 patients (age 59.8±11.4 years; 550 female; ejection fraction = 62.5±8%) referred for known or suspected coronary artery disease in 20 quality controlled laboratories of 16 countries from 2016 to 2019. SV was calculated at rest and peak stress from raw measurement of LV EDV and ESV by biplane Simpson rule, 2-D echo. LVCR was the stress-rest ratio of force (systolic blood pressure by cuff sphygmomanometer/ESV, abnormal values <2.0 identify a “weak” heart). Preload reserve was defined by an increase in LV EDV. Abnormal values (lack of EDV increase, peak EDV ≤ rest EDV) identify a “stiff” heart. Cardiac output was calculated as SV * HR (measured with standard EKG). HR reserve (stress/rest ratio) <1.85 identifies a “slow” heart with chronotropic incompetence. By selection, all patients had negative SE by wall motion criteria. Of the 1,344 patients included in the study, 448 belonged to the lowest tertile of CO increase. Of them 326 (73%) achieved HR reserve <1.85; 220 (49%) had a blunted LVCR and 374 (83%) a reduction of preload reserve, with 348 patients (78%) showing ≥2 abnormalities. The more the abnormal criteria, the worse the CO response, which was lowest in slow, stiff and weak hearts: see figure. Patients with normal CO reserve during exercise usually have a fast, compliant and strong heart. Abnormal CO reserve is associated with heterogeneous hemodynamic responses, with slow, stiff and/or weak hearts. The clarification of underlying hemodynamic heterogeneity is the prerequisite for a personalized treatment, and can be easily extracted from a standard 2-D volumetric SE. Hearts with normal CO are all alike; every heart with abnormal CO is abnormal in its own way. CO % changes in subsets (*p<0.001) Type of funding source: None

Introduction Results of currently available trials have shown divergent outcomes in diabetic patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Current guidelines do not recommend PCI in patients with diabetes and a SYNTAX score ≥ 23. Aim To compare all-cause 4-year mortality after revascularization for complex coronary artery disease (CAD) in diabetics. Material and methods The study group comprised consecutive patients with three-vessel CAD and/or unprotected left main CAD (≥ 50% diameter stenosis) without major hemodynamic instability, who were treated in two institutions with PCI or referred for CABG. Results Out of 342 diabetics, 177 patients underwent PCI and 165 patients were referred for CABG. The incidence of all-cause death was different between diabetics treated with PCI or CABG at 4 years (16/177, 9.0% vs. 26/165, 15.8%, respectively, p = 0.03). The difference was not evident in non-diabetics (PCI: 41/450, 9.1% vs. CABG: 19/249, 7.6%, p = 0.173). In diabetics, there was a higher incidence of all-cause mortality in PCI patients with intermediate-high (≥ 23) SYNTAX scores compared with those with low (0–22) SYNTAX scores (10/56, 17.9% vs. 6/121, 5.0%, respectively, p < 0.01). On the other hand, diabetics who underwent CABG showed similar mortality rates irrespective of the SYNTAX scores (SYNTAX 0–22: 3/29, 10.3%; SYNTAX ≥ 23: 23/136, 11.9%, p = 0.46). In the subgroup analysis, there was no interaction according to presence or absence of left main CAD (p for interaction = 0.12) as well as according to diabetes status (p for interaction = 0.38), whereas gender and SYNTAX scores were differentiators between PCI and CABG with a p for interaction < 0.1. Conclusions Our analysis supports recent evidence that diabetes is not a differentiator between PCI and CABG.