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

Coronary chronic total occlusion (CTO) is characterized by the presence of collateral blood vessels which can provide additional blood supply to CTO-artery dependent myocardium. Successful CTO recanalization is followed by significant decrease in collateral donor artery blood flow and collateral derecruitment. Study aim was to assess time-dependent changes in coronary flow reserve (CFR) in collateral donor artery after CTO recanalization and identify factors that influence these changes. Our study enrolled 31 patients with CTO scheduled for percutaneous coronary intervention (PCI). Non-invasive CFR was measured before PCI in collateral donor artery, and 24h and 6 months post-PCI in CTO and collateral donor artery. Gated SPECT MIBI was performed before PCI, while quality of life was assessed by Seattle angina questionnaire (SAQ) pre-PCI, and 6 months after PCI. Collateral donor artery showed significant increase in CFR 24h after CTO recanalization compared to pre-PCI values (2.30±0.49 vs. 2.71±0.45, p=0.005), which remained unchanged after 6 months (2.68±0.24). Maximum baseline blood flow velocity of the collateral donor artery showed significant decrease measured 24h post-PCI compared to pre-PCI values (0.28±0.06 vs. 0.24±0.04m/s), and remained similar after 6-months. There was no significant difference in maximum hyperemic blood flow velocity pre-PCI, 24h and 6 months post-PCI. CFR change of the collateral donor artery 24h post-PCI compared to pre-PCI values showed inverse correlation with left ventricle ejection fraction (LVEF) measured on SPECT. CFR changes showed no correlation with the changes in quality of life assessed by SAQ post-PCI compared to pre-PCI. Significant increase in CFR of the collateral donor artery was observed within 24h after successful recanalization of CTO artery, which maintained constant after the 6 months follow-up. This increase was largely driven by the significant reduction in the maximum baseline blood flow velocity within 24h after CTO recanalization compared to pre-PCI values. Our results suggest that possible benefit of CTO recanalization could be the improvement in physiology of the collateral donor artery. Type of funding source: None

Background Coronary chronic total occlusion (CTO) is characterized by the presence of collateral blood vessels which can provide additional blood supply to CTO-artery dependent myocardium. Successful CTO recanalization is followed by significant decrease in collateral donor artery blood flow and collateral derecruitment, but data on coronary hemodynamic changes in relation to myocardial function are limited. We assessed changes in coronary flow velocity reserve (CFVR) by echocardiography in collateral donor and recanalized artery following successful opening of coronary CTO. Methods Our study enrolled 31 patients (60 ± 9 years; 22 male) with CTO and viable myocardium by SPECT scheduled for percutaneous coronary intervention (PCI). Non-invasive CFVR was measured in collateral donor artery before PCI, 24 h and 6 months post-PCI, and 24 h and 6 months in recanalized artery following successful PCI of CTO. Results Collateral donor artery showed significant increase in CFVR 24 h after CTO recanalization compared to pre-PCI values (2.30 ± 0.49 vs. 2.71 ± 0.45, p  = 0.005), which remained unchanged after 6-months (2.68 ± 0.24). Baseline blood flow velocity of the collateral donor artery significantly decreased 24 h post-PCI compared to pre-PCI (0.28 ± 0.06 vs. 0.24 ± 0.04 m/s), and remained similar after 6 months, with no significant difference in maximum hyperemic blood flow velocity pre-PCI, 24 h and 6 months post-PCI. CFVR of the recanalized coronary artery 24 h post-PCI was 2.55 ± 0.35, and remained similar 6 months later (2.62 ± 0.26, p = NS). Conclusions In patients with viable myocardium, prompt and significant CFVR increase in both recanalized and collateral donor artery, was observed within 24 h after successful recanalization of CTO artery, which maintained constant during the 6 months. Trial registration ClinicalTrials.gov (Number NCT04060615 ).

BACKGROUND Stroke volume response during stress is a major determinant of functional status in heart failure and can be measured by two-dimensional (2-D) volumetric stress echocardiography (SE). The present study hypothesis is that SE may identify mechanisms underlying the change in stroke volume by measuring preload reserve through end-diastolic volume (EDV) and left ventricular contractile reserve (LVCR) with systolic blood pressure and end-systolic volume (ESV). METHODS We enrolled 4,735 patients (age 63.6 ± 11.3 yrs, 2800 male) referred to SE for known or suspected coronary artery disease (CAD) and/or heart failure (HF) in 21 SE laboratories in 8 countries. In addition to regional wall motion abnormalities (RWMA), force was measured at rest and peak stress as the ratio of systolic blood pressure by cuff sphygmomanometer/ESV by 2D with Simpson's or linear method. Abnormal values of LVCR (peak/rest) based on force were ≤1.10 for dipyridamole (n=1,992 patients) and adenosine (n=18); ≤2.0 for exercise (n=2,087) or dobutamine (n=638). RESULTS Force-based LVCR was obtained in all 4,735 pts. Lack of stroke volume increase during stress was due to either abnormal LVCR and/or blunted preload reserve, and 57 % of patients with abnormal LVCR nevertheless showed increase in stroke volume. CONCLUSIONS Volumetric SE is highly feasible with all stresses, and more frequently impaired in presence of ischemic RWMA, absence of viability and reduced coronary flow velocity reserve. It identifies an altered stroke volume response due to reduced preload and/or contractile reserve.

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.

BACKGROUND Coronary collateral circulation exerts protective effects on myocardial ischaemia due to coronary artery disease and can be promoted by exercise with heparin co-administration. Whether this arteriogenetic effect is accompanied by functional improvement of left ventricle during stress and lessening of angina symptoms remains unknown. AIMS To evaluate the anti-ischaemic efficacy of heparin plus exercise in coronary artery disease. METHODS In a prospective, single-centre, randomized, double-blind study we recruited 32 'no-option' patients (27 males; mean age 61 ± 8 years) with stable angina, exercise-induced ischaemia and coronary artery disease not suitable for revascularization. All underwent a two-week cycle of exercise (two exercise sessions per day, five days per week) and were randomized (n = 16 per group) to intravenous placebo (0.9% saline) versus unfractionated heparin (5.000 IU intravenously), 10 min prior to exercise. We assessed Canadian Cardiovascular Society angina class, stress electrocardiogram and echo parameters (wall motion score index) and computed tomography angiography for collaterals. RESULTS After two-week cycle, Canadian Cardiovascular Society class statistically decreased in both groups (heparin plus exercise group: 2.6 ± 0.7 to 1.9 ± 0.7, p < 0.001, exercise group: 2.4 ± 0.7 to 2.1 ± 0.9, p = 0.046). Only the heparin plus exercise group improved time-to-ST segment depression (before 270, 228-327 s vs. after 339, 280-360 s, p = 0.012) and wall motion score index (before 1.38 ± 0.25 vs. after 1.28 ± 0.18, p = 0.005). By multi-slice computed tomography angiography, collaterals improved in 12/15 (80%) in the heparin plus exercise group versus 2/16 (12.5%) in the exercise group (p < 0.001). CONCLUSION A two-week, 10-test cycle of heparin plus exercise is better than exercise in improving angina class, myocardial ischaemia and collaterals by computed tomography angiography.

Abstract Background The ventricular stroke work (SW) refers to the work done by the left ventricle to eject the volume of blood during one cardiac cycle. The cath-lab relationship between SW and end-diastolic volume (EDV) is the preload-recruitable SW (PRSW). Recently a non-invasive single-beat PRSW (SBPRSW) has been proposed. However, the single beat formula needs mathematical skillness, and extra software. Aim of this study was to compare the non-invasive SBPRSW with the simpler non-invasive SW/EDVratio in the stress-echo lab. Methods We studied 692 patients, age 62 ± 12 years, ejection fraction 50 ± 17%, with negative stress echo (SE)(exercise, n = 130, dobutamine, n = 124, dipyridamole, n = 438) and follow-up data. The PRSW was estimated at rest and at peak stress by the SBPRSW technique and compared with the SW/EDV. All patients were followed-up. Event rates were estimated with Kaplan–Meier curves. Results SBPRSW and SW/EDV were linearly correlated at rest (r = 0.842, p < .001) and at peak stress (r = 0.860, p < .001). During a median follow-up of 20 months (first quartile 8, third quartile 40 months), 132 major events were registered: at receiver operating characteristic (ROC) analysis rest SBPRSW vs. SW/EDV (AUC 0.691 vs. 0.722) and peak stress (AUC 0.744 vs. 0.800) demonstrated both a significant prognostic power (all p < .001) with non-inferior survival prediction of the simpler SW/EDV ratio at Kaplan–Meier curves (Chi-square rest = 38, peak = 56) vs. SBPRSW (Chi-square rest = 14, peak = 42). Conclusions The data obtained with the non-invasive SBPRSW and by the simpler SW/EDV are highly comparable. PRSW with either SB or SW/EDV approach is effective in predicting follow-up events.

Introduction: Components of the metabolic syndrome (MetSy) have gone through myriad of changes ever since the initial cluster was defined. The Seven Countries Study taught us the basics of classical risk factors for atherosclerotic artery disease and their influence on both cardiovascular and cerebrovascular morbidity and mortality. Material and Methods: In a 3-continent, 7-country (USA, Japan, Greece, the Netherlands, Finland, Italy, and former Yugoslavia then, now Croatia and Serbia) sample of 12,763 participants -- all healthy men over 40 at entry -- systematic, quinquennial checkups were conducted over 4 decades and MetSy was defined using the IDF definition. ResultS: A total of 9,09% of participants were identified to have MetSy, while the detailed description of risk factors' combination is shown in Table 1 and Figure 1, below. Conclusion: The leading combination was hypertension (HTA), diabetes (DM) and dyslipidemia (HLP), while hypertension was the hallmark risk factor irrelevant of presence or absence of MetSy. The results of this study call for a contemporary comprehensive research involving both sexes that could elucidate better real life risk factors' relationships in aforementioned countries.

Coronary collateral circulation exerts protective effects on myocardial ischemia due to coronary artery disease (CAD) and can be promoted by exercise (E) with heparin (H) co-administration. Whether this arteriogenetic effects is accompanied by functional improvement of left ventricle (LV) during stress remains unknown. To establish the stress-induced functional effects on LV regional and global function of 2-week cycle of H+E in patients with “no-option” CAD. In a prospective, single-center, double-blind, randomized, parallel-group study we recruited 32 “no-option” patients (27 males; mean age of 61±8 years), with stable angina and CTO, refractory to OMT, not suitable for revascularization and with E-induced ischemia. All underwent 2-week cycle of E (2 E test per day, 5 days a week) and were pre-treated with i.v. 0.9% saline or unfractionated H (100 IU/kg up to maximum of 5.000IU, 10 min prior to E). Canadian Class Score (CCS) and 12-lead E-ECG for time-to-1 mm ST-segment depression were assessed at entry and after treatment. LV function was evaluated during treadmill exercise with conventional and advanced imaging indices: Wall Motion Score Index (WMSI); Ejection Fraction (EF); Force (systolic blood pressure/end-systolic volume); Global Longitudinal Strain (GLS). Post-treatment exercise-time and CCS improved in both groups. In H+E patients exercise-time improved from 369.8±107.8 sec to 475.3±114.6 sec (p=0.001) while in E patients improved from 384±152.7 sec to 464.8±134.1 sec (p=0.019). CCS score changed in H+E from 2.6±0.7 to 1.9±0.7 (p=0.000), and in E group from 2.4±0.7 to 2.1±0.9 (p=0.046). At peak exercise, H+E was different from E group for EF and GLS (see Table). Effects of H+E on SE parameters H+E p P+E p *H+E vs P+E STRESS Time 0 vs Time 1 Time 0 vs Time 1 Time 0 Time 1 WMSI 1.377 vs 1.279 0.005 1.404 vs 1.376 0.290 0.626 0.255 EF (%) 60.9 vs 64.8 0.016 61.2 vs 57.8 0.284 0.943 0.016 Force (mmHg/mL) 6.36 vs 6.5 0.158 5.82 vs 4.68 0.209 0.760 0.098 GLS (%) −16.96 vs −18.50 0.001 −15.79 vs −15.60 0.380 0.325 0.027 SE = stress echocardiography; H+E = heparin+exercise; P+E = placebo+exercise; Time 0 = before randomization; Time 1 = after 2-week therapy cycle. *p values. A 2-week, H+E cycle is associated with improvement in regional and global LV function during exercise, concordantly shown by conventional (WMSI, EF) and advanced (GLS) echocardiographic indices of LV function. This integrates and supplements the classical objective index based on ST-segment depression, unable to localize and quantify the functional consequences of therapy on myocardial ischemia.

Heart failure is a major cause of morbidity, mortality and re-hospitalizations and is highly prevalent in myocardial infarction survivors. Cardiac rehabilitation based on exercise training and heart failure self-care counseling have each been shown to improve clinical status and clinical outcomes. We designed our study with aim to evaluate the usefulness of exercise based in house cardiac rehabilitation/ secondary prevention program in patients with heart failure with mid-range ejection fraction (HFmrEF) after myocardial infarction. Out of 2753 patients who were admitted to our three weeks in- hospital secondary prevention program – exercised based cardiac rehabilitation, we analyze a total of 219 patients who were admitted early after coronary revascularization (percutaneus coronary interventions or coronary bypass surgery) with HFmrEF. The majority of patients were males (68%). Risk factors and co morbidities were noted. Patients were selected for exercise training after six minute walking test or exercise stress test (cardiopulmonary dominantly to evaluate unexpected exertional dyspnea). After 3 weeks in house cardiac rehabilitation the patients were re-tested. The major comorbidities in our patient population were as follows: hypertension, diabetes and dyslipidemia. Six minutes walking test was performed and the total distance walked ranged from 120 to 480 meters and the beginning of the program. Patient had 7 -days a week training program. After the 3 weeks in hospital exercise rehabilitation the improvement in the test was ∼32%. Cardiopulmonary test showed also improvement of functional capacity.We noted several rhythm disturbance complications by telemetry (VES, SVES). None had acutisation of heart failure (with peripheral edema and congestion). All patients fulfilled cardiac rehabilitation program. Supervised multidisciplinary cardiac rehabilitation program, including an individualized exercise component is effective and can improve functional status and exercise tolerance in patient with HFmrEF after myocardial infarction.