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Funding Acknowledgements Type of funding sources: None. European Society of Cardiology has recently introduced new SCORE 2 algorhythm for cardiovascular risk assessment in apparently healthy individuals. However, there are limited data from high risk countries on CV risk stratification and potential gender differences in risk estimation using SCORE 2 model. The aim of the current study was to compare risk prediction using SCORE 2 and previous SCORE model and to assess the potential gender differences in risk estimation. Methods Our study included 1361 apparently healthy individuals (mean age 56±9 years, 61% women) without known CV disease or risk factors aged 40 to 70 years old. Data on CV risk factors were prospectively collected in 20 primary care centers throughout Serbia from January 2020 to December 2020. CV risk was assessed both by SCORE and SCORE 2 model. Based on CV risk profile individuals were stratified in three categories: low to intermediate, high and very high risk category. Results In overall population using SCORE model 57.6% of individuals were in low-intermediate group, 20.9% were classified as high risk group and 21.5% as very high risk group. By the use of SCORE 2 model 1046/1361 (77%) individuals were shifted to higher risk category (Figure). In comparison to men women had lower both systolic (139 ± 19 mmHg vs 144 ± 18 mmHg in men p < 0.001) and diastolic (84 ± 9 mmHg vs 88 ± 10mmHg in men, p < 0.001 )blood pressure, lower BMI (26.4 ± 0.5 kg/m2 vs 27.4 ± 5.0 kg/m2 in men, p= 0.036) and higher values of HDL cholesterol (1.5 ± 0.5 mmol/L vs. 1.3 ± 0.4 mmol/L in men, p < 0.001). Smoking was more prevalent in men (49%) than in women (42%), p=0.04. There were no gender differences in age (56 ± 9 years for both genders) and non-HDL cholesterol ( 4.86 ± 1.24 mmol in men vs. 4.75 ± 1.23 mmol/l in women, p= 0.100). More women (85.9%) than men (62.6%) were shifted in higher risk category using SCORE 2 in comparison to SCORE (p < 0.001) (Figure). Conclusion By the use of SCORE 2 instead of SCORE prediction model for CV risk stratification in contemporary high risk European population significant proportion of apparently healthy individuals are shifted to higher risk category. In spite of having better CV risk factors profile, more women than men were shifted in higher risk category.

Background Left bundle branch block (LBBB) can be isolated thing, but it is also often associated with underlying coronary artery disease (CAD). Stress echocardiography (SECHO) is widely used as an imaging method for the diagnosis of CAD. However, the diagnostic value of stress echocardiography in patients (pts) with LBBB is limited. Purpose To evaluate negative prognostic value of coronary flow reserve (CFR) in pts with LBBB without inducible ischemia and without known CAD. Methods This retrospective study included 224 pts (98, 43.8% male gender, average age 66±11 years) with LBBB and without known CAD. All the pts had negative SECHO test according the Bruce protocol. Risk factors for CAD (diabetes, smoking, hypertension, high cholesterol and positive family history of CAD), Duke treadmill score, functional capacity (Metabolic Equivalents - METs) were recorded in all pts. Out of 224 pts, in 64 (29.5%) coronary flow reserve on the left anterior descending artery was assessed using pulsed Doppler echocardiography with adenosine in a dose of 140μcg/kg/body weight during 3 minutes. As the normal value we took value of CFR ≥2. Median follow up of the pts was 72 months (IQR 56.25–132 months) for the occurrence of MACE (cardiovascular death (CVD), non-fatal myocardial infarction (nfMI), coronary artery bypass graft (CABG) and percutaneous coronary revascularization (PCI). Results Out of 224 pts, 6 (2.7%) had positive SECHO test, 2 pts (0.9%) had died due to non-cardiac causes and 11 pts (4.9%) were lost to follow up so they were excluded from further analysis. The remaining 204 pts were divided in 2 groups: 1. pts with only negative SECHO (n=144, 68.8%); 2. pts with negative SECHO and normal CFR (n=64, 31.2%). During the follow-up period 22 out of 205 pts (10.7%) had an adverse event (6 CVD, 6 nfMI, 5 CABG, 8 PCI). Between the two groups there was no significant difference in risk factors and parameters of the SECHO test. Pts with CFR had significantly lower rate of MACE compared to the pts with only SECHO test (2, 3.1% vs 20, 14.2%, p=0.018, respectively). Using the Cox regression analysis, univariate predictors of MACE were insulin dependent diabetes (HR 10.851 [95% CI 2.095–56.220], p=0.004), Duke score (HR 0.603 [95% CI 0.414–0.878], p=0.008), and MET (HR 0.393 [95% CI 0.209–0.737], p=0.004). In the multivariate analysis only the insulin dependent diabetes remained an independent predictor of MACE (HR 6.906 [95% CI 1.100–43.363], p=0.039). Using the Kaplan-Meier survival curve we see that the pts with SECHO test and CFR had shorter event-free time compared to the pts with SECHO test (136.3±3.6 months vs 149.8±2.9 months, Log Rank 4.022, p=0.045) (Figure 1). Conclusion Normal value of CFR has good negative prognostic value in pts with LBBB without inducible ischemia and without known CAD, while pts with insulin dependent diabetes have more pronounced risk for the occurrence of adverse events. Funding Acknowledgement Type of funding sources: None.

Background Hyper-contractile phenotype of the left ventricle (LV) is generally considered prognostically benign, but recent data challenge this intuitive assumption. Aim To assess the effects of resting LV function on survival. Methods In a prospective, observational, multicenter study, we recruited 5,122 patients (age 65±11.1 years, 2974 males, 58%) with chronic coronary syndromes referred for resting transthoracic echocardiography with technically successful volumetric echocardiography in 14 accredited laboratories. All recruiting centers had a structured follow-up program with >90% follow-up rate. In each patient, we quantitatively assessed (by Simpson's biplane, apical single-plane or parasternal linear method) LV end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF). As a load-independent index of LV contractility, LV force was estimated as systolic blood pressure by cuff sphygmomanometer/ESV. All-cause death was the only considered outcome end-point. Results EF was 59±11% (normal reference sextile = 58.0–59.9%). Force was 4.51±2.11 mmHg/ml (normal reference sextile = 3.50–4.27 mmHg/ml). The correlation between EF and force was linear (r=0.585, p67%) and significantly higher in the lowest sextile (EF 6.36 mmHg/ml): see figure, right panel. At multivariable analysis, after adjustment for age, diabetes, EF, and prior myocardial infarction, both the highest sextile of force (HR 1.84, 95%, confidence intervals 1.12–3.03 p=0.015), and the lowest sextile of force (HR 1.77, 95%, confidence intervals 1.08–2.90 p=0.024) were associated with decreased survival. Conclusion Sub-normal values of resting ejection fraction and super- and sub-normal values of the force are associated with worse survival in patients with chronic coronary syndromes. This U-shaped curve of mortality is detectable only with the force, a load independent index of LV contractility: too much of a good thing such as LV contractility can be dangerous on the long-run. Funding Acknowledgement Type of funding sources: None.

Background Stress echocardiography (SE) was recently upgraded to include imaging-independent heart rate reserve (HRR) which assesses cardiac sympathetic balance and is simply based on one-lead electrocardiogram present in the echo monitor. The value of HRR for risk stratification of hypertensive patients remains undetermined. Aim To assess the prognostic value of SE with HRR in hypertensive patients in a prospective, large scale, multicenter, international, effectiveness study. Methods From July 2016 to December 2020, we enrolled 2747 hypertensives (age 66±10 years, 1599 males, 58.2%; ejection fraction 61±8%) referred from 12 certified laboratories. All patients underwent clinically indicated SE. The employed stress modality was exercise (n=754) or pharmacological stress (n=1993). Exercise modality was either semi-supine bike (n=674) or treadmill (n=80). Pharmacological stress was either vasodilator (n=1695, 1661 with dipyridamole and 34 with adenosine) or dobutamine (n=298). SE response included the evaluation of regional wall motion abnormality (RWMA) and non-imaging HRR (peak/rest heart rate), with stress-specific cutoff values abnormal response Results Rate of abnormal results was 17% for RWMA and 40% for HRR. During a median follow-up of 624 days (interquartile range: 380–1037 days), 60 deaths occurred. Global X2 was 25.0 considering clinical and resting echocardiographic variables, with no change after stress-induced RWMA and a significant increase after HRR (Figure 1). Annual mortality rate was 0.7% person/year for patients (n=1496) with normal HRR and absence of stress-induced RMWA, 0.4% for patients (n=151) with RWMA and normal HRR, up to 2.1% person/year for patients (n=1101) with abnormal HRR with (n=321) or without (n=780) RWMA. At multivariable analysis, only age (HR: 1.070, 95% CI: 1.039–1.101, p Conclusion SE with either exercise or pharmacological stress allows an effective prediction of survival in hypertensive patients with chronic coronary syndromes, but only when the conventional criterion of RWMA is complemented with imaging-independent HRR. Funding Acknowledgement Type of funding sources: None.

Background Left atrial volume index (LAVi), left atrial reservoir function assessed with global peak amplitude longitudinal strain (PALS), and B-lines at lung ultrasound are supplementary markers of left ventricular filling pressures. Aim To assess the relationship between LAVi, PALS and B-lines at rest and peak vasodilator stress. Methods A comprehensive dipyridamole stress echo was completed in 266 patients (187 male, 71%, age 65±10 years) with chronic coronary syndromes. LAVi was measured with the biplane disk summation method. PALS was measured from a single vendor with 2-dimensional speckle tracking echocardiography and expressed in % values as the mean of the 12 atrial segments from 4- and 2-chamber values. B-lines were assessed with the simplified 4-site scan in the third intercostal space, with global score from 0 to 40, and considered significant with global score ≥2 units. Results During dipyridamole, LAVi decreased (rest= 26±14 ml/m2 vs stress= 24±12 ml/m2, p42%). Conclusion Vasodilator stress echocardiography with combined assessment of left atrial volume, function and pulmonary congestion is feasible with high success rate in patients with chronic coronary syndromes. Pulmonary congestion is more frequent with dilated left atrium with reduced atrial contractile reserve, but it may occur in a minority of patients with normal LAVi and normal PALS. Funding Acknowledgement Type of funding sources: None.

Background Diastolic fractional flow reserve (d-FFR) during dobutamine provocation (DOB) was found to be a more reliable physiological index for the functional assessment of myocardial bridging (MB). However, d-FFR calculation is complicated and time-consuming, and therefore several authors have suggested the use of instantaneous wave-free ratio (iFR) to overcome these issues. Purpose The aim of our study was to assess diagnostic performance of d-FFR and iFR at rest and during DOB with exercise-induced myocardial ischemia as reference. Methods Twenty-four symptomatic patients (17 males, mean age 58±8 years) with MB and systolic compression ≥50% diameter stenosis on the left anterior descending (LAD) artery were included. Exercise stress-echocardiography test (SE), and both d-FFR and iFR in the distal segment of LAD at rest and peak DOB (30–50μg/kg/min), were performed in all patients. Optimal cut-off values and diagnostic performance of resting and hyperemic d-FFR and iFR were assessed using SE. Results Exercise-SE was positive for myocardial ischemia in 7/24 patients (29%). The area-under-the-receiver-operating-characteristic curve (ROC-AUC) for exercise-induced myocardial ischemia was 0.64 (95% CI: 0.400–0.885) for resting d-FFR, 0.62 (95% CI: 0.378–0.866) for resting iFR, 1.000 (95% CI: 0.999–1.000) for d-FFR at peak DOB, and 0.96 (95% CI: 0.895–1.000) for iFR at peak DOB. No significant difference in ROC-AUC was observed between d-FFR and iFR at peak DOB (p=0.243). The best cut-off value for both d-FFR and iFR at peak DOB was Conclusions iFR during DOB provocation showed similar diagnostic accuracy as d-FFR to identify the functionally significant MB when compared with exercise-induced myocardial ischemia. Funding Acknowledgement Type of funding sources: None.

Background B-lines detected by lung ultrasound (LUS) during exercise stress echocardiography (ESE), indicating pulmonary congestion, are present in 1 out of 3 patients with hypertrophic cardiomyopathy (HCM). Aim To assess the functional and anatomical correlates of exercise B-lines in HCM. Methods We enrolled 191 HCM patients (age 53±15 years, 123 males) consecutively referred for ESE (treadmill in 74, bicycle in 117 patients) in 11 quality-controlled centers from 8 countries. ESE assessment at rest and peak stress included: left ventricular (LV) outflow tract gradient, left atrial (LAVi) and LV end-diastolic volume index (EDVi), mitral regurgitation (MR, score from 0 to 3); E/e'; systolic pulmonary arterial pressure (SPAP) and LV force (LV outflow tract gradient+systolic blood pressure/LV end-systolic volume). B-lines at rest and at peak exercise were assessed by LUS with the 4-site simplified scan. B-lines positivity was considered if the sum of detected B-lines was ≥2. Results LUS was feasible in all subjects. B-lines were present in 55 (29%) patients during stress. When compared to patients without stress B-lines (n=136), patients with B-lines (n=55) at peak exercise had lower peak EDVi (43±17 vs 52±18 ml/m2, p=0.003) higher peak E/e' (16±6 vs 12±5, p Conclusion HCM patients with pulmonary congestion on exercise show different, and not mutually exclusive mechanisms of diastolic dysfunction and worsening mitral regurgitation. These different hemodynamic mechanisms may require personalized therapeutic actions beyond a pulmonary decongestion therapy with diuretics. Funding Acknowledgement Type of funding sources: None.

Background Stress echocardiography (SE) allows to assess simultaneously left ventricular contractile reserve (LVCR) and heart rate reserve (HRR) in dilated cardiomyopathy (DCM). Aim To assess the prognostic value of LVCR and HRR in DCM patients Methods We prospectively enrolled 395 DCM patients with ejection fraction ≤40% (age 62±27 years, 270 males, 68%; ejection fraction 35±9%) referred from 9 certified laboratories, 264 with nonischemic DCM (67%) and 131 (33%) with ischemic DCM. All patients underwent clinically indicated SE. The employed stress modality was exercise (n=63), or pharmacological stress (n=332, with vasodilator, n=232; or dobutamine, n=100). LVCR was present with a rest-stress decrease ≥0.20 in wall motion score index. HRR was normal with a peak-rest value ≥1.80 with exercise or dobutamine and ≥1.22 with dipyridamole or adenosine stress. Results New regional wall motion abnormality was present in 46 (12%), LVCR in 131 (33%) and abnormal HRR in 275 (70%) DCM patients. During a median follow-up of 950 days (interquartile range: 360–1187 days) 71 deaths occurred. Annual mortality was 10.5%/year in DCM patients with abnormal HRR (HRR−) and absence of LVCR (LVCR−), 5.4%/year in patients with either abnormal HRR or absent LVCR, and 2.5%/year in patients with normal HRR and presence of LVCR (Figure 1). At multivariable analysis, only abnormal HRR (HR: 2.952, 95% CI: 1.547–5.630, p=0.001) but not absence of LVCR (HR: 1.545, 95% CI: 0.929–2.568, p=0.094), was independent predictors of survival. Conclusion Abnormal HRR predicts adverse prognosis in DCM patients, in addition to the presence of LV CR. Funding Acknowledgement Type of funding sources: None.

Introduction In patients with angina and non-obstructed coronary arteries (ANOCA), functional dysregulation such as epicardial coronary spasm and microvascular dysfunction (microvascular spasm and /or impaired microvascular dilatation) frequently coexist. The aim was to analyse haemodynamic indicators of arteriolar dysregulation during combined hyperventilation and exercise stress echo test in patients with ANOCA. Methods In a prospective study we enrolled 38 patients (56±13 years, 31 females) with ANOCA, proven by normal coronary angiogram. Stress echocardiography protocol with Doppler measurements of coronary flow consisted of hyperventilation test for spasm provocation (HYP, respiratory rate of 30 per min for 5') followed by supine bicycle exercise test (HYP+EXE) for assessment of endothelium dependent function. Adenosine test was done (ADO 140 mcg/kg in 1 min) for estimation of endothelium independent vasodilatation. Coronary flow velocity (CFV) was assessed in distal LAD by Transthoracic Doppler echocardiography at the end of the each stage of the test. Abnormal response to HYP was a CFV ratio (stress/rest) Results The double product increased during HYP in comparison to rest (13263 vs 10321, p Conclusion Our results indicate that HYP induce microvascular dysfunction with vasospastic component which is reflected in reduced CFV ratio. This prevents the normal hyperemic response during EXE in more than a half of patients. Endothelial independent vasodilatation during ADO hyperemia was perserved in all patients, excluding structural microvasculature remodeling. HYP+EXE provocation with noninvasive measurement of coronary flow is a promising test for assessing mechanism of arteriolar dysregulation in ANOCA patients. Funding Acknowledgement Type of funding sources: None.

Background New SCORE 2 algorithm overperformed SCORE algorithm in population with decreasing prevalence of cardiovascular (CV) morbidity and mortality. However, there is limited data in risk stratification with SCORE 2 model in contemporary populations from very high risk countries. Aim The aim of this study was to compare risk prediction using SCORE 2 and SCORE model and to compare the proportions of patients requiring statin treatment in primary prevention. Methods Our study included 1317 patients (511, 38.8% male gender, average age 54±8) without known CV disease aged 40 to 70 years. Data on CV risk factors were prospectively collected in 20 primary care centers throughout the Serbia from January 2020. to December 2020. Based on the CV risk profile, patients were stratified into 4 categories: low, moderate, high and very high risk according to SCORE model and into 3 categories: low to moderate, high and very high risk according to SCORE 2 model. The number of patients requiring statin treatment was assessed according to the risk category and value of LDL cholesterol in SCORE model and the value of non-HDL cholesterol in SCORE 2 model. Results Overall, 589 patients (44.7%) were smokers, mean value of total cholesterol was 6.2±1.1 mmol/L, LDL 3.9±1.1, HDL 1.4±0.5, non HDL 4.8±1.2 mmol/L. Systolic blood pressure was 138.6±19.6, diastolic blood pressure was 85.3±10.4 mmHg and was BMI 26.9±5.2. Based on the SCORE model 166 patients (12.6%) were classified into low risk category, 658 (49.9%) into moderate, 276 (20.9%) into high risk and 217 (16.6%) into very high risk category. Based on the SCORE 2 model 30 (2.8%) patients were classified into low to moderate, 273 (18%) and 1014 (79.2%) into very high risk category. There was significantly less patients in low to moderate group in SCORE 2 model compared to SCORE model (30, 2.8% vs 824, 62.6%, p Conclusion The use SCORE 2 risk prediction tool, in comparison to SCORE model, results in significant higher proportion of patients being classified as very high risk category with the increase number of patients requiring statin treatment in primary prevention. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Krka Farma

Background Lung ultrasound (LUS) detects pulmonary congestion as B-lines at rest. Methods After preliminary exclusion of 154 patients lost to follow-up, we analyzed transthoracic echocardiography (TTE) plus LUS (4-site simplified scan) data in 5165 subjects (age 64±11 years) referred to 19 certified centers of 9 countries for known or suspected coronary artery disease (n=3891, 75%), dyspnea (n=591, 12%), or screening in asymptomatic patients with risk factors (n=667, 13%). We analyzed the anterior and lateral hemi-thoraces, scanning from mid-axillary to mid-clavicular lines on the third intercostal space. B-lines score ranged from 0 (normal) to 40 (severely abnormal). By selection, follow-up information was available in all. All-cause death was the predetermined end-point. Results Feasibility of B-lines was 100% in all subjects. B-lines (median) were 0.1 [0–1]. Rest B-lines (≥2) were present in 863 patients (16.7%). Ejection fraction was 61±10%. After a median follow-up of 690 (Interquartile range 420–1065) days, 96 all-cause deaths occurred. Two-year mortality was 3.6% in patients with and 1.5% in patients without B-lines (p Conclusion In all-comers referred for TTE, resting B-lines assessed by focused LUS with the simplified 4-site scan are detected in 1 out of 4 patients with symptos or coronary risk factors and are associated with worse survival. The severity of pulmonary congestion predicts the severity of outcomes. The prognostic value of resting B-lines is independent and additive over standard clinical and TTE predictors such as diabetes and ejection fraction. Focused LUS for pulmonary congestion can easily be incorporated in standard TTE examination. Funding Acknowledgement Type of funding sources: None.

Aim The aim of this study was to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicentre, international, effectiveness study. Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve. Methods and results From July 2016 to November 2020, we enrolled 3574 all-comers (age 65 ± 11 years, 2070 males, 58%; ejection fraction 60 ± 10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent clinically indicated ABCDE-SE. The employed stress modality was exercise (n = 952, with semi-supine bike, n = 887, or treadmill, n = 65 with adenosine for step D) or pharmacological stress (n = 2622, with vasodilator, n = 2151; or dobutamine, n = 471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only endpoint. Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D, and 37% for E steps. During a median follow-up of 21 months (interquartile range: 13–36), 73 deaths occurred. Global X2 was 49.5 considering clinical variables, 50.7 after step A only (P = NS (not significant)) and 80.6 after B–E steps (P, Graphical Abstract This study recruited 3,574 patients from 13 stress echo laboratories of 5 countries and shows the prognostic value of the new state-of-the art cardiac functional testing with stress echo ABCDE protocol: Step A for regional wall motion abnormalities; step B for B-lines obtained with 4-site simplified scan and lung ultrasound; step C for contractile reserve with volumetric echocardiography; step D for Doppler-based assessment of coronary flow reserve in mid-distal left anterior descending coronary artery; step E for EKG-based heart rate reserve.

Background: The assessment of coronary flow velocity reserve (CFVR) in left anterior descending coronary artery (LAD) expands the risk stratification potential of stress echocardiography (SE) based on stress-induced regional wall motion abnormalities (RWMA). Objectives: The purpose of this study was to assess the feasibility and functional correlates of CFVR. Methods: This prospective, observational, multicenter study initially screened 3,410 patients (2,061 [60%] male; age 63 ± 11 years; ejection fraction 61 ± 9%) with known or suspected coronary artery disease and/or heart failure. All patients underwent SE (exercise, n = 1,288; vasodilator, n = 1,860; dobutamine, n = 262) based on new or worsening RWMA in 20 accredited laboratories of 8 countries. CFVR was calculated as the stress/rest ratio of diastolic peak flow velocity pulsed-Doppler assessment of LAD flow. A subset of 1,867 patients was followed up. Results: The success rate for CFVR on LAD was 3,002 of 3,410 (feasibility = 88%). Reduced (≤2.0) CFVR was found in 896 of 3,002 (30%) patients. At multivariable logistic regression analysis, inducible RWMA (odds ratio [OR]: 6.5; 95% confidence interval [CI]: 4.9 to 8.5; p < 0.01), abnormal left ventricular contractile reserve (OR: 3.4; 95% CI: 2.7 to 4.2; p < 0.01), and B-lines (OR: 1.5; 95% CI: 1.1 to 1.9; p = 0.01) were associated with reduced CFVR. During a median follow-up time of 16 months, 218 events occurred. RWMA (hazard ratio: 3.8; 95% CI: 2.3 to 6.3; p < 0.001) and reduced CFVR (hazard ratio: 1.5; 95% CI: 1.1 to 2.2; p = 0.009) were independently associated with adverse outcome. Conclusions: CFVR is feasible with all SE protocols. Reduced CFVR is often accompanied by RWMA, abnormal LVCR, and pulmonary congestion during stress, and shows independent value over RWMA in predicting an adverse outcome.

Microvascular dysfunction (MVD) is associated with adverse prognosis and may account for abnormal stress tests and angina symptoms in women with cardiac syndrome X (CSX). The aim of our study was to assess MVD by coronary flow velocity reserve (CFVR) and left ventricular (LV) contractile function by LV global longitudinal strain (LVGLS) in CSX patients with respect to presence of slow coronary flow (SCF). It was of additional importance to evaluate clinical status of CSX patients using Seattle Angina Questionnaire.Study population included 70 women with CSX (mean age 61 ± 7 years) and 34 age-matched controls. CSX group was stratified into two subgroups depending on SCF presence: CSX-Thrombolysis In Myocardial Infarction (TIMI) 3- normal flow subgroup (n = 38) and CSX-TIMI 2- SCF subgroup (n = 32) as defined by coronary angiography. LVGLS measurements and CFVR of left anterior descending (LAD) and posterior descending (PD) artery were performed. CFVR-LAD and PD were markedly impaired in CSX group compared to controls (2.34 ± 0.25 vs 3.05 ± 0.21, p 0.001; 2.32 ± 0.24 vs 3.01 ± 0.13, p 0.001), and furthermore decreased in CSX-TIMI 2 patients. Resting, peak, and ΔLVGLS were all significantly impaired in CSX group compared to controls (for all p 0.001), and furthermore reduced in CSX-TIMI 2 subgroup. Strongest correlation was found between peak LVGLS and CFVR LAD (r = -0.784, p 0.001) and PD (r = -0.772, p 0.001). CSX-TIMI 2 subgroup had more frequent angina symptoms and more impaired quality of life.MVD in CSX patients is demonstrated by reduction in CFVR and LVGLS values. SCF implies more profound impairment of microvascular and LV systolic function along with worse clinical presentation.

BackgroundCoronary 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.MethodsOur 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.ResultsCollateral 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).ConclusionsIn 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 registrationClinicalTrials.gov (NumberNCT04060615).

Funding Acknowledgements Type of funding sources: None. OnBehalf Stress Echo 2030 study group of the Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI). Background The excessive cross-bridging of cardiac myosin and actin, resulting in increased left ventricular (LV) force development, is one of the biomechanical abormalities inhypertrophic cardiomyopathy (HCM). Purpose To assess the prognostic value of increased LV force development at rest in patients with HCM Methods We enrolled 918 HCM patients (age 48 ± 16 years, 502 males, New York Heart Association I or II, Class III in 48 patients, 6% and with LVOTG >30 mmHg in 211patients, 23%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 10 quality-controlled labs from 7 countries (Belgium, Hungary, Italy, Portugal, Serbia, Spain, Brazil). The maximal wall thickness was 21 ± 5 mm. TTE assessment included left ventricular outflow tract gradient (LVOTG, mmHg), EF (%), and LV force (systolic arterial pressure + LVOTG/LV endsystolic volume assessed with 2-D, mmHg/mL). All patients were followed-up. An age- and gender matched control group of 95 healthy subjects was also evaluated. Results. Compared to normals, HCM showed higher values of EF (68 ± 8 vs 65 ± 5%, p 8.5 mmHg/mL hazard ratio= 2.189 95% CI = 1.095-4.377, p = 0.027 and the intermediate quartile: Force 5.7-8.5 mmHg/mL hazard ratio= 2.525 95% CI = 1.2205.228, p = 0.013) were independent predictors of mortality with age (hazard ratio= 1.065 95% CI = 1.047-1.084, p Conclusion HCM patients with preserved baseline LV function and higher values of resting LV force ("too good to be normal") show a worse survival, highlighting the dark prognostic side of an excess of force. The hypercontractile phenotype possibly indicates an increased activity of myosin resulting in increased force production at the sarcomere and cellular levels that propagates at the whole-organ level with unfavorable long-term effects on outcome. Figure Mortality rate based on quartiles of resting LV Force in HCM. Abstract Figure. Mortality rate

Funding Acknowledgements Type of funding sources: None. OnBehalf Stress Echo 2020 study group of the Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI) Background The classical pathophysiological cornerstone of stress cardiac imaging is the ischemic cascade: alterations in coronary flow velocity reserve (CFVR) come first, regional wall motion abnormalities (RWMA) second, and global alterations of left ventricular diastolic and systolic function last. Aim To evaluate the ischemic cascade with stress echo (SE) assessed with ABCDE protocol. Methods We analyzed 1616 patients (age 66 ± 10 years, 1156, 72% males) with chest pain and angiographically documented coronary artery disease (CAD): 928 (57.4%) with previous myocardial infarction and 1451 (89.8%) with previous coronary revascularization. CAD patients were studied with ABCDE-SE protocol by 13 certified laboratories of 5 countries. Stress modality was exercise in 427 (26.4%) dobutamine in 173 (10.7%) and vasodilator stress in 1016 (62.9%) patients (dipyridamole in 982 – 60.8% and adenosine in 34 – 2.1% patients). Step A assessed RWMA; step B, B-lines (diastolic function); step C, left ventricular contractile reserve based on force; step D, CFVR in left anterior descending artery; step E, heart rate reserve. SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). Follow up was obtained in all patients. Results Results were abnormal in 350 (21.7) % for step A, 572 (35.4%) for B, 666 (41.2%) for C, 546 (33.5%) for D and 643 (39.8%) for E. The distribution of positivity is shown in figure. The dominant "solitary phenotype" (only one biomarker abnormal during the test) was step A in 10 (0.6%), step B in 124 (7.7%) step C in 100 (6.2%), step D in 64 (4.0%) and step E in 157 (9.7%) patients. The overall sensitivity for CAD detection including each step of ABCDE score (≥1) was 95.7%. During median follow-up of 22 months [IQ range: 13-37 months] 279 coronary revascularizations occurred. ABCDE score predicted coronary revascularization with score 1: HR: 3.182, 95% CI: 1.699-6.067; score 2: HR: 4.921, 95% CI: 2.571-9.420; score 3: HR: 7.234, 95% CI: 3.743-13.979; score 4: HR: 24.570, 95% CI: 13.390-45.086; and score 5: HR: 38.720, 95% CI: 20.975-71.478 Conclusion Inducible ischemia with CAD is characterized by the complexity and multiplicity of diagnostic phenotypes. The overall ABCDE score predicts clinically driven revascularization. Abstract Figure. The 5 circles of ischemia biomarkers

Funding Acknowledgements Type of funding sources: None. Introduction. Mechanism of ischemia in patients with angina and no obstructive coronary artery disease (ANOCA), is often unrecognized since invasive tests are seldom done and proper noninvasive test is not established yet. The aim of our study was to assess changes in ventricular function during hyperventilation test (HYP) designed to provoke vasoconstriction, immediately followed by supine bicycle exercise to increase ischemic stimuli in patients with ANOCA (HYP + EXE). Methods. : In a prospective study, we enrolled 29 ANOCA patients (age 59.6 ±11 years, 27 females) with previously normal angiograms. All patients underwent SE testing with hyperventilation (HYP, respiratory rate of 30 per min for 5"), immediately followed by supine bicycle exercise (HYP + EXE). Ventricular function was assessed based on left ventricular contractile reserve (LVCR), calculated by ratio of the ventricular force at the peak of the each stress level and rest. Force was assessed as the quotient between systolic arterial pressure and end-systolic volume determined by two-dimensional echocardiography. Values range from normal (> 2.0) to mild (1.5–2.0), moderate (1.01–1.49), and severe (≤1.0) dysfunction. For LVCR HYP values are shifted towards lower values (abnormal < 1.1). Results. Chest pain or dyspnea were present in 4/29 pts during HYP, and in 7/29 patients during HYP + EXE (13.8% vs 24.1 %, p = 0.001). Three patients showed wall motion abnormalities with hyperventilation and additional two patients with HYP + EXE. LVCR HYP response was normal in 19/29 (65.5%) pts and abnormal in 10/29 (34.5%) pts. LVCR HYP + EXE response was normal in 9/29 (31%) pts, 4/29 (13.8%) pts had mild, 11/29 (37.9%) pts had moderate and 5/29 (17.3%) pts had severe dysfunction. Conclusion. In patients with ANOCA subtle changes in LV function occurred with HYP and EXE stress more often than wall motion abnormality. Measurement of contractile reserve might be a useful tool in assessment of ischemia and ventricular dysfunction in patients with ANOCA. Abstract Figure 1. Abstract Figure 2.

We assessed feasibility and functional correlates of LAVI (left atrial volume index) changes during exercise stress echocardiography (ESE).ESE on bike or treadmill was performed in 363 patients with heart failure with preserved ejection fraction (HFpEF, n = 173), reduced ejection fraction (HFrEF, n = 59) or hypertrophic cardiomyopathy (HCM, n=131). LAVI stress-rest increase ≥ 6.8 ml/m2 was defined as dilation.LAVI measurements were feasible in 100%. LAVI did not change in HFrEF being at rest 32 (25-45) vs. at stress 36 (24 - 54) ml/m2, P = NS and in HCM at rest 35 (26 - 48) vs. at stress 38 (28 - 48) ml/m2, P = NS whereas it decreased in HFpEF from 30 (24 -40) to 29 (21 - 37) ml/m2 at stress, P = 0.007. LA dilation occurred in 107 (30%) patients (27% with treadmill vs. 33% with bike ESE, P = NS): 26 with HFpEF (15%), 26 with HFrEF (44%) and 55 with HCM (42%) with P < 0.001 for HFrEF and HCM vs. HFpEF. Multivariate analysis revealed as the predictors for LAVI dilation E/e' > 14 at rest with OR 4.4, LVEF < 50% with OR 2.9, and LAVI at rest < 35 ml/m2 with OR 2.7.LAVI assessment during ESE was highly feasible and dilation equally frequent with treadmill or bike. LA dilation was threefold more frequent in HCM and HFrEF and could be predicted by increased resting E/e' and impaired EF as well as smaller baseline LAVI.

Background Microvascular dysfunction might be a major determinant of clinical deterioration and outcome in patients with hypertrophic cardiomyopathy (HCM). However, long‐term prognostic value of transthoracic Doppler echocardiography (TDE) coronary flow velocity reserve (CFVR) on clinical outcome is uncertain in HCM patients. Therefore, the aim of our study was to assess long‐term prognostic value of CFVR on clinical outcome in HCM population. Methods and Results We prospectively included 150 HCM patients (82 women; mean age 48±15 years). Patients’ clinical characteristics, echocardiographic and CFVR findings (both for left anterior descending [LAD] and posterior descending artery [PD]), were assessed in all patients. The primary outcome was a composite of: HCM related death, heart failure requiring hospitalization, sustained ventricular tachycardia and ischemic stroke. Patients were stratified into 2 subgroups depending on CFVR LAD value: Group 1 (CFVR LAD>2, [n=87]) and Group 2 (CFVR LAD≤2, [n=63]). During a median follow‐up of 88 months, 41/150 (27.3%) patients had adverse cardiac events. In Group 1, there were 8/87 (9.2%), whereas in Group 2 there were 33/63 (52.4%, P P P Conclusions In patients with HCM, impaired CFVR LAD (≤2) is a strong, independent predictor of adverse cardiac outcome. When the aim of testing is HCM risk stratification and CFVR LAD data are available, the evaluation of CFVR PD is redundant.

Background Recent studies showed that coronary flow velocity reserve (CFVR) measurement by transthoracic Doppler echocardiography (TTDE) during inotropic stimulation with dobutamine (DOB), in comparison to vasodilation with adenosine, provides more reliable functional evaluation of myocardial bridging (MB). However, the adequate cut-off value of CFVR during DOB for diagnosing functional significant MB has not been fully established. Purpose The purpose of the study was to evaluate the adequate cut-off value of TTDE- CFVR during DOB for diagnosis of functional significant MB. Methods This prospective study included 79 patients (54 males, mean age 55±10 years) with angiographic evidence of isolated MB on the left anterior descending artery (LAD) and systolic compression ≥50% diameter stenosis. Exercise stress-echocardiography test (ExSE) and TTDE-CFVR in the distal segment of LAD during DOB infusion (DOB: 10–40μg/kg/min) were performed in all patients. Percent diameter stenosis (DS) of MB at end-systole and end-diastole were analyzed using quantitative coronary angiography. Results Exercise-SE was positive for myocardial ischemia in 22/79 (28%). CFVR during peak DOB was significantly lower in SE-positive group in comparison to SE-negative group (1.94±0.16 vs. 2.78±0.53, p Conclusion A cut-off value Funding Acknowledgement Type of funding sources: None.

Introduction In patients with angina and no obstructive coronary artery disease (ANOCA), different mechanisms of ischaemia, epicardial spasm, microvascular spasm, and impaired microvascular dilatation frequently coexist. The aim was to assess CFVR changes during coronary vasoconstrictor and vasodilator stimuli in patients with ANOCA. Methods In a prospective single center study, we enrolled 29 ANOCA patients (age 59.6±11 years, 27 females) with previously normal angiograms. All underwent SE testing with hyperventilation (HYP, respiratory rate of 30 per min for 5') followed by supine bicycle exercise (HYP+EXE); and adenosine CFV evaluation (ADO 140 mcg/kg in 1 min) on the other day. Coronary flow velocity (CFV) was assessed in distal LAD by Transthoracic Doppler echocardiography. The ratio of peak/rest changes of CFV during HYP in LAD was taken as an index of vasoconstriction, and CFV reserve was evaluated after EXE. An abnormal response to HYP was a CFV ratio Results The double product increased during HYP, in comparison to rest (13213 vs 10517, p Conclusion In patients with ANOCA, HYP+EXE is a more powerful ischemic stress than HYP alone. In over one-half of patients HYP+EXE unmasks abnormalities in CFVR response and/or regional wall motion, likely unmasking the underlying endothelium dependent microcirculatory dysfunction with enhanced vasoconstriction in 44% of the patients and mixed vasoconstriction and reduced relaxation in 65%. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): University Clinical Centre of Serbia, Faculty of Medicine

Background Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B-lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, EKG-based heart rate reserve. Aim: to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicenter, international, effectiveness study. Methods From July 2016 to November 2020, we enrolled 3,574 all-comers (age 65±11 years, 2,070 males, 58%; ejection fraction 60±10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent ABCDE-SE. The employed stress modality was exercise (n=952, with semi-supine bike, n=887, or treadmill, n=65 with adenosine for step D) or pharmacological stress (n=2,622, with vasodilator, n=2,151; or dobutamine, n=471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only end-point. Results Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D and 37% for E step. During a median follow-up of 21 months, 73 deaths occurred. At univariable analysis, predictors of all-cause mortality were step B (hazard ratio, HR: 2.621, 95% Confidence Intervals, CI: 1.654–4.152, p Conclusion ABCDE-SE allows an effective risk stratification of patient global vulnerability. Funding Acknowledgement Type of funding sources: None. Survival curves based on ABCDE score

Background Left atrial volume (LAV) may dilate acutely during exercise stress echocardiography (ESE) in chronic coronary syndromes. Purpose To assess the feasibility and functional correlates of LAV during ESE outside coronary artery disease. Methods We performed ESE (semi-supine bike in 159 or treadmill in 105 patients) in 264 patients (155 male, age 58±15 years) with heart failure with preserved ejection fraction (HFpEF, n=82), heart failure with reduced ejection fraction (HFrEF, n=51) or hypertrophic cardiomyopathy (HCM, n=131). LAV was measured with the biplane disk summation method. LAV-dilators were defined as those with stress-rest increase in LAV index ≥6.8 ml/m2, a cutoff derived from a calculated reference change value above the biological, analytical and observer variability of LAV. Average E/e', mitral regurgitation (MR, graded from 0 = absent to 3 = severe), left ventricular ejection fraction, systolic pulmonary arterial pressure (SPAP) from tricuspid regurgitant jet velocity and B-lines (4-sites simplified scan) were also measured. Results Measurement success rate was 264/264 (100%) in technically adequate images. At group analysis LAV changes during ESE were heterogeneous, with LAV index increase in HFrEF (rest = 41±26 vs stress = 44±27 ml/m2, p=0.563) and HCM (rest = 39±18 vs stress = 41±17 ml/m2, p=0.444) and mild decrease in HFpEF (rest= 28±12 vs stress = 26±11 ml/m2, p=0.020). At individual patient analysis, LAV dilation occurred in 88 (33%) patients: 9 with HFpEF (11%), 24 with HFrEF (47%), 55 with HCM (42%, p Conclusion LAV assessment during ESE is feasible with high success rate, and LAV dilation is equally frequent with upright treadmill or semi-supine bike exercise. LAV individual response to stress is unpredictable, with a significant dilation occurring more frequently in HCM and HFrEF compared to HFpEF patients. Across all conditions, LAV dilation is correlated to more advanced pulmonary and hemodynamic congestion, higher left ventricular filling pressures and more severe MR during stress. Funding Acknowledgement Type of funding sources: None. LAV dilators vs non-dilators comparison. SPAP value ≥40 mm Hg; E/e' ≥15; MR grade ≥2; B-lines >10 in patients with (blue bars) and without (red bars) LAV dilation.

Background Coronary flow velocity reserve (CFVR) and heart rate reserve (HRR) during vasodilator stress echocardiography (SE) assess coronary microvascular function and cardiac sympathetic reserve respectively. Both CFVR and HRR can be impaired in hypertrophic cardiomyopathy (HCM). Objectives To evaluate the prognostic value of CFVR and HRR during vasodilator SE in HCM. Methods We enrolled 244 HCM patients (age=51±15 years, 116 men) studied with vasodilator SE from 1999 to 2019 in 5 certified centers. Stress modality was either adenosine (Ado, 0.14 mg/kg/min in 2', n=171) or dipyridamole (Dip, 0.84 mg/kg in 6', n=73). Left ventricular outflow tract obstruction was present at rest in 80 patients (33%). We assessed CFVR in left anterior descending coronary artery (by TTE in 225, and TEE in 19 patients) and HRR (peak/rest heart rate). Abnormal values of HRR were based on receiver operating characteristics for Ado and Dip separately calculated. All patients completed the follow-up. Results CFVR was 2.17±0.46 for Dip and 2.13±0.43 for Ado (p=ns); HRR was 1.36±0.19 for Dip and 1.10±0.16 for Ado (p Conclusions A reduced CFVR and blunted HRR during vasodilator SE identify distinct phenotypes and show independent value in predicting outcome in HCM patients. Funding Acknowledgement Type of funding sources: None. Figure 1. Kaplan-Meier spontaneous event-free survival curves based on HRR and CFVR. Kaplan-Meier survival curves (considering spontaneous events) in patients stratified with the abnormal HRR and/or CFVR. Number of patients at risk per year is shown.

Objectives The purpose of this study was to assess the functional and prognostic correlates of B-lines during stress echocardiography (SE). Background B-profile detected by lung ultrasound (LUS) is a sign of pulmonary congestion during SE. Methods The authors prospectively performed transthoracic echocardiography (TTE) and LUS in 2,145 patients referred for exercise (n = 1,012), vasodilator (n = 1,054), or dobutamine (n = 79) SE in 11 certified centers. B-lines were evaluated in a 4-site simplified scan (each site scored from 0: A-lines to 10: white lung for coalescing B-lines). During stress the following were also analyzed: stress-induced new regional wall motion abnormalities in 2 contiguous segments; reduced left ventricular contractile reserve (peak/rest based on force, ≤2.0 for exercise and dobutamine, ≤1.1 for vasodilators); and abnormal coronary flow velocity reserve ≤2.0, assessed by pulsed-wave Doppler sampling in left anterior descending coronary artery and abnormal heart rate reserve (peak/rest heart rate) ≤1.80 for exercise and dobutamine (≤1.22 for vasodilators). All patients completed follow-up. Results According to B-lines at peak stress patients were divided into 4 different groups: group I, absence of stress B-lines (score: 0 to 1; n = 1,389; 64.7%); group II, mild B-lines (score: 2 to 4; n = 428; 20%); group III, moderate B-lines (score: 5 to 9; n = 209; 9.7%) and group IV, severe B-lines (score: ≥10; n = 119; 5.4%). During median follow-up of 15.2 months (interquartile range: 12 to 20 months) there were 38 deaths and 28 nonfatal myocardial infarctions in 64 patients. At multivariable analysis, severe stress B-lines (hazard ratio [HR]: 3.544; 95% confidence interval [CI]: 1.466 to 8.687; p = 0.006), abnormal heart rate reserve (HR: 2.276; 95% CI: 1.215 to 4.262; p = 0.010), abnormal coronary flow velocity reserve (HR: 2.178; 95% CI: 1.059 to 4.479; p = 0.034), and age (HR: 1.031; 95% CI: 1.002 to 1.062; p = 0.037) were independent predictors of death and nonfatal myocardial infarction. Conclusions Severe stress B-lines predict death and nonfatal myocardial infarction. (Stress Echo 2020 - The International Stress Echo Study [SE2020]; NCT03049995)

An enlarged left atrial volume index (LAVI) at rest mirrors increased LA pressure and/or impairment of LA function. A cardiovascular stress may acutely modify left atrial volume (LAV) within minutes. Aim of this study was to assess the feasibility and functional correlates of LAV-stress echocardiography (SE) Out of 514 subjects referred to 10 quality-controlled labs, LAV-SE was completed in 490 (359 male, age 67 ± 12years) with suspected or known chronic coronary syndromes (n = 462) or asymptomatic controls (n = 28). The utilized stress was exercise in 177, vasodilator in 167, dobutamine in 146. LAV was measured with the biplane disk summation method. SE was performed with the ABCDE protocol. The intra-observer and inter-observer LAV variability were 5% and 8%, respectively. ∆-LAVI changes (stress-rest) were negatively correlated with resting LAVI (r = −0.271, p < 0.001) and heart rate reserve (r = -.239, p < 0.001). LAV-dilators were defined as those with stress-rest increase ≥ 6.8ml/m2, a cutoff derived from a calculated reference change value above the biological, analytical and observer variability of LAVI. LAV dilation occurred in 56 patients (11%), more frequently with exercise (16%) and dipyridamole (13%) compared to dobutamine (4%, p < 0.01). At multivariable logistic regression analysis, B-lines ≥ 2 (OR: 2.586, 95% CI = 1.1293–5.169, p = 0.007) and abnormal contractile reserve (OR: 2.207, 95% CI = 1.111–4.386, p = 0.024) were associated with LAV dilation. In conclusion, LAV-SE is feasible with high success rate and low variability in patients with chronic coronary syndromes. LAV dilation is more likely with reduced left ventricular contractile reserve and pulmonary congestion.

The human gut microbiota is the microbial ecosystem in the small and large intestines of humans. It has been naturally preserved and evolved to play an important role in the function of the gastrointestinal tract and the physiology of its host, protecting from pathogen colonization, and participating in vitamin synthesis, the functions of the immune system, as well as glucose homeostasis and lipid metabolism, among others. Mounting evidence from animal and human studies indicates that the composition and metabolic profiles of the gut microbiota are linked to the pathogenesis of cardiovascular disease, particularly arterial hypertension, atherosclerosis, and heart failure. In this review article, we provide an overview of the function of the human gut microbiota, summarize, and critically address the evidence linking compositional and functional alterations of the gut microbiota with atherosclerosis and coronary artery disease and discuss the potential of strategies for therapeutically targeting the gut microbiota through various interventions.

Background Functional assessment of myocardial bridging (MB) remains clinically challenging because of the dynamic nature of the extravascular coronary compression with a certain degree of intraluminal coronary reduction. The aim of our study was to assess performance and diagnostic value of diastolic‐fractional flow reserve (d‐FFR) during dobutamine provocation versus conventional‐FFR during adenosine provocation with exercise‐induced myocardial ischemia as reference. Methods and Results This prospective study includes 60 symptomatic patients (45 men, mean age 57±9 years) with MB on the left anterior descending artery and systolic compression ≥50% diameter stenosis. Patients were evaluated by exercise stress‐echocardiography test, and both conventional‐FFR and d‐FFR in the distal segment of left anterior descending artery during intravenous infusion of adenosine (140 μg/kg per minute) and dobutamine (10–50 μg/kg per minute), separately. Exercise–stress‐echocardiography test was positive for myocardial ischemia in 19/60 patients (32%). Conventional‐FFR during adenosine and peak dobutamine had similar values (0.84±0.04 versus 0.84±0.06, P =0.852), but d‐FFR during peak dobutamine was significantly lower than d‐FFR during adenosine (0.76±0.08 versus 0.79±0.08, P =0.018). Diastolic‐FFR during peak dobutamine was significantly lower in the exercise‐stress‐echocardiography test –positive group compared with the exercise‐ stress‐echocardiography test –negative group (0.70±0.07 versus 0.79±0.06, P P =0.613). Among physiological indices, d‐FFR during peak dobutamine was the only independent predictor of functionally significant MB (odds ratio, 0.870; 95% CI, 0.767–0.986, P =0.03). Receiver‐operating characteristics curve analysis identifies the optimal d‐FFR during peak dobutamine cut‐off ≤0.76 (area under curve, 0.927; 95% CI, 0.833–1.000; P Conclusions Diastolic‐FFR, but not conventional‐FFR, during inotropic stimulation with high‐dose dobutamine, in comparison to vasodilatation with adenosine, provides more reliable functional significance of MB in relation to stress‐induced myocardial ischemia.

Funding Acknowledgements Type of funding sources: None. Introduction Since mitral regurgitation (MR) is a very common finding in patients with hypertrophic cardiomyopathy (HCM), the evaluation of the mitral valve anatomy and the degree of MR is of utmost importance in this population. However, data regarding the prognostic value of different degrees of MR in HCM remains scarce. Purpose The aim of this study was to determine whether the presence of a higher degree of MR affects: 1) long term prognosis; 2) clinical and echocardiographic presentation of HCM patients. Material and Methods We included prospectively 102 patients, diagnosed with primary asymmetric HCM. The degree of MR was determined echocardiographicaly according to current recommendations of the American Association of Echocardiography. According to the MR severity, patients were divided into 2 groups: Group 1 (n = 52) with no/trace or mild MR and Group 2 with moderate or moderate to severe MR. All patients had clinical and echocardiographic examination, 24-hour Holter ECG and NT pro BNP analysis performed. The primary outcome was a composite of: 1) HCM related death or sudden death; 2) hospitalization due to acute heart failure; 3) sustained ventricular tachycardia; 4) ischemic stroke. Results Patients with higher MR degree had more frequent chest pain (p = 0.039), syncope (p = 0.041) and NYHA II functional class (p 10), as well as higher levels of NT pro BNP (p = 0.001). By Kaplan-Meier analysis we demonstrated that the event free survival rate during follow up of median 75 (IQR 48-103) months was significantly higher in Group 1 compared to the Group 2 (79% vs. 46%, p Conclusion Presence of moderate, or moderate to severe MR was associated with poor long-term outcome of HCM patients. These results indicate the importance of an adequate MR assessment and detailed evaluation of the mitral valve anatomy in the prediction of complications and adequate treatment of patients with HCM. Abstract Figure.

Background The effectiveness trial “Stress echo (SE) 2020” evaluates novel applications of SE in and beyond coronary artery disease. The core protocol also includes 4-site simplified scan of B-lines by lung ultrasound, useful to assess pulmonary congestion. Purpose To provide web-based upstream quality control and harmonization of B-lines reading criteria. Methods 60 readers (all previously accredited for regional wall motion, 53 B-lines naive) from 52 centers of 16 countries of SE 2020 network read a set of 20 lung ultrasound video-clips selected by the Pisa lab serving as reference standard, after taking an obligatory web-based learning 2-h module ( http://se2020.altervista.org ). Each test clip was scored for B-lines from 0 (black lung, A-lines, no B-lines) to 10 (white lung, coalescing B-lines). The diagnostic gold standard was the concordant assessment of two experienced readers of the Pisa lab. The answer of the reader was considered correct if concordant with reference standard reading ±1 (for instance, reference standard reading of 5 B-lines; correct answer 4, 5, or 6). The a priori determined pass threshold was 18/20 (≥ 90%) with R value (intra-class correlation coefficient) between reference standard and recruiting center) > 0.90. Inter-observer agreement was assessed with intra-class correlation coefficient statistics. Results All 60 readers were successfully accredited: 26 (43%) on first, 24 (40%) on second, and 10 (17%) on third attempt. The average diagnostic accuracy of the 60 accredited readers was 95%, with R value of 0.95 compared to reference standard reading. The 53 B-lines naive scored similarly to the 7 B-lines expert on first attempt (90 versus 95%, p = NS). Compared to the step-1 of quality control for regional wall motion abnormalities, the mean reading time per attempt was shorter (17 ± 3 vs 29 ± 12 min, p

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. Purpose 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. Methods 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. Results 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. Conclusions 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. Funding Acknowledgement Type of funding source: None

Background Patients with ischemia and no obstructive coronary artery disease (INOCA) are a heterogeneous group and an unmet diagnostic challenge. Noninvasive Doppler is a feasible tool to assess coronary flow velocity (CFV) in left anterior descending coronary artery (LAD) during stress echocardiography (SE). Aim To assess CFV response during coronary vasoconstrictor and vasodilator stimuli in INOCA patients. Methods In a prospective single center study, we enrolled 16 INOCA patients (age 60±12 years, 15 females) with previously normal angiograms. All underwent SE testing with hyperventilation (HYP, respiratory rate of 30 per min for 5') followed by supine bicycle exercise (HYP+EXE); and adenosine CFV evaluation (ADO, 0.84 mg/kg in 1 min) on the other day. The ratio of peak/rest changes of CFV during HYP in LAD was taken as an index of vasoconstriction, and CFV reserve was evaluated after EXE. An abnormal response to HYP was a CFV ratio Results The double product increased during HYP, in comparison to rest (13 337 vs 9858, p Conclusion In INOCA patients, HYP+EXE is a more powerful ischemic stress than HYP alone and unmasks abnormalities in regional wall motion and/or CFV response in over one- half of patients, likely unmasking the underlying abnormal coronary vasomotor response of large epicardial and/ or small coronary vessels. INOCA patients show profound heterogeneity of coronary vasomotor responses which can be detected with a combined vasodilator - vasoconstrictor SE approach with CFV assessment. The clarification of underlying coronary microcirculatory heterogeneity is the prerequisite for a personalized treatment, and can be easily extracted from CFV-SE. Normal INOCA hearts are all alike, every abnormal heart is abnormal in its own way. Funding Acknowledgement Type of funding source: None

Background Heart rate reserve (HRR) during exercise evaluates chronotropic incompetence and is a prognostically important marker of cardiac autonomic dysfunction, additive to regional wall motion abnormalities (RWMA) in patients with coronary artery disease. Objectives To assess determinants and prognostic value of HRR in patients with hypertrophic cardiomyopathy (HCM). Methods From 1998 to 2019, we enrolled 774 HCM patients (age = 48.8±15.9 years, 410 men) with exercise stress echocardiography (ESE) in 10 certified centres of the international stress echo network. During ESE we assessed: left ventricular outflow tract obstruction (LVOTO, significant when >50 mmHg); RWMA; HRR (peak/ rest heart rate), 344 in beta-blockers therapy (44.4%). Patients were followed for a median 49 months (IQ range, 25–78 months). The study end-point was all-cause mortality. Results During ESE, we observed stress-induced RWMA in 42 (5.4%) and LVOTO in 248 (33%); HRR was 1.92.±0.41. There were no difference in patients with normal and abnormal HRR with and without beta-blockers therapy (147, 41.1% vs 211, 58.9%, p=0.079). During follow-up, 43 deaths occurred. Beta blockers therapy in univariate analysis did not have prognostic role (HR 1.105, 95% CI 0.602–2.028, p=0.768). The lowest HRR quartile (≤1.62) had a 10-fold higher 6-year death rate (10.9%) than the highest quartile (>2.16, 1.04%): see figure. At multivariable analysis, lowest HRR quartile (HR 2.074, 95% CI 1.082–6.773, p=0.034), age (HR 1.045, 95% CI 1.014–1.077, p=0.004), maximal wall thickness (HR 1.137, 95% CI 1.054–1.226, p=0.001), stress-induced RWMA s(HR 4.289, 95% CI 1.733–10.615, p=0.002) and ≥ moderate mitral regurgitation at rest (HR 3.127, 95% CI 1.507–6.488, p=0.002) predicted death. Conclusions A blunted HRR during ESE predicts adverse outcome independent of inducible RWMA in HCM patients. Autonomic dysfunction deserves consideration as a potential therapeutic target in this disease. Figure 1 Funding Acknowledgement Type of funding source: None

Background Previous studies have shown that left bundle branch block (LBBB), as a relatively common electrocardiographic (ECG) abnormality, represents the condition with often non benign and sometimes adverse outcome. Purpose The Aim of our study was to determine the predictive value of a stress echocardiography test in patients with LBBB. Methods Our study population included 189 patients (88 male, 46.6%, mean age 63.08±9.65) with diagnosed left bundle branch block who performed stress echocardiography (SECHO) according to Bruce protocol. Median follow-up of the patients was 56 months (IQR 48–71 months) for the occurrence of cardiovascular death and non-fatal myocardial infarction, repeat revascularization (coronary artery bypass grafting-CABG or percutaneous coronary intervention-PCI). Results Out of 189 patients, 32 (16.9%) patients had positive, while 157 (83.1%) patients had negative SECHO test. During the follow up period 28 patients had major adverse cardiac event: 1 nonfatal myocardial infarction, 6 heart failure hospitalizations, 5 CABGs, 8 PCIs, while 8 patients had cardiac death. Using the Cox regression analysis, univariate predictors of adverse cardiac events were diabetes mellitus (HR 4.530 [95% CI 1.355–15.141], p=0.014), PCI (HR 4.288 [95% [95% CI 2.010–9.144], p Conclusion Patients with LBBB and negative SEHO test have good prognosis. Patients with history of CAD and diabetes mellitus and LBBB are at increased risk for future events and need periodical reassessment. Funding Acknowledgement Type of funding source: None

Introduction Left anterior descending velocity reserve (LADVR) by transthoracic echocardiography (TTE) has been proposed for cardiovascular risk stratification in observational prospective studies. Aim of the current study was to interrogate the prognostic consistency and coherence of the existing LADVR data by the means of meta-analysis of relevant studies. Methods A systematic research through electronic databases was performed for prospective studies with patients with known or suspected coronary artery disease (CAD) who had LADVR data. The exposure was abnormal values of LADVR as defined in each study and the outcome was the occurrence of cardiovascular event or death (CE-D). Statistical index considered were the risk ratio (RR) for CE-D of patients with abnormal vs. normal LADVR, as obtained from Cox proportional hazard models. A meta-analysis of these studies using random-effects model was performed to evaluate the pooled prognostic value of abnormal LADVR. Results Fifteen studies with 13050 patients (59.7% male; mean age 64.2 years; mean follow-up 25.1 months) were included in this meta-analysis. Every study used adjustments for every established risk factor for CE-D (age, hypertension, diabetes, dyslipidemia, smoking habits, wall motion abnormalities during stress echo). The abnormal value of LADVR was associated with an increased risk of CE-D (RR=3.33, 95% CI: 2.54–4.37, p-value Conclusions Meta-analytic data for the cardiovascular risk stratification based on dichotomous LADVR data provide robust evidence for efficient prognostic yield. The current results support the broader clinical application of the LADVR. LADVR meta-analysis forestplot Funding Acknowledgement Type of funding source: None

Background Exercise and dobutamine stress may induce acute left atrial volume index (LAVI) dilatation in 1 out 10 patients. The effect of vasodilator stress in LAVI remains unknown. Purpose To assess the feasibility and functional correlates of LAVI change during dipyridamole stress echocardiography (SE). Methods We studied 149 patients (99 male, age 66±10 years, ejection fraction 59±8%, 64 with previous myocardial infarction), who underwent dipyridamole ABCDE-SE. LAVI was measured with the biplane disk summation method at rest and peak stress: LAVI-dilators were defined as those with stress-rest increase ≥6.8 ml/m2. Criteria for abnormal response of ABCDE-SE were: stress-induced changes in regional wall motion abnormalities (RWMA) for step A; B-lines at peak stress ≥2 for step B (4-site simplified scan, each site scored from 0= A-lines or black lung to 10= white lung for coalescing B-lines); reduced left ventricular contractile reserve (LVCR, peak/ rest based on force) ≤1.1 for step C; abnormal coronary flow velocity reserve (CFVR) ≤2.0, assessed by pulsed wave Doppler sampling in left anterior descending coronary artery for step D; abnormal heart rate reserve (HRR, peak/rest heart rate) ≤1.22 for step E. Results LAVI dilation occurred in 13 patients (9%). The positivity was for step A: RWMA in 6 pts (4%); step B: presence of peak B-lines in 12 pts (8%); step C: abnormal LCVR in 14 pts (9%); step D: reduced CFVR in 17 pts (11%) and step E: abnormal HRR in 46 pts (31%). LAVI dilators showed significantly higher incidence of positivity of steps A-B-C-D (see figure) compared to patients without LAVI dilatation. Conclusion Evaluation of LAVI change during vasodilator SE is feasible, and LAVI dilatation is more frequently found with ischemic (step A), wet (step B), weak (step C) and cold (step D) heart. Figure 1 Funding Acknowledgement Type of funding source: None

Background The new methodological standard in stress echo (SE) is the comprehensive approach with ABCDE protocol: step A for regional wall motion abnormalities (RWMA); step B for B-lines by lung ultrasound; step C for left ventricular contractile reserve (LVCR); step D for Doppler-based coronary flow velocity reserve (CFVR) in left anterior descending coronary artery; and step E for imaging-independent EKG-based heart rate reserve (HRR). Purpose To assess the feasibility of ABCDE-SE in a prospective, large scale, multicenter, international, effectiveness study. Methods From September 2016 to December 2019, we enrolled 4,585 all-comers patients (age 63±11 years, 2,566 males, 56%; ejection fraction 61±9%) with known or suspected chronic coronary artery disease referred to clinically-driven SE with exercise (n=1,774, 38.7%), dipyridamole (n=2,403, 52.4%), dobutamine (n=375, 8.2%) or adenosine (n=33, 0.7%). Recruitment involved 13-certified laboratories of 7 countries. All patients underwent ABCDE-SE. The same transducer was used for cardiac and lung scan. Criteria for abnormal response were: stress-induced changes in RWMA in 2 contiguous segments for step A; stress-rest increase in B-lines ≥2 for step B (4-site simplified scan, each site scored from 0= A-lines or black lung to 10= white lung for coalescing B-lines); LVCR ≤2.0 for exercise and dobutamine (≤1.1 for vasodilators) for step C; CFVR in LAD ≤2.0 for step D; HRR (peak/rest heart rate) ≤1.80 for exercise and dobutamine (≤1.22 for vasodilators) for step E. Results Success rate was 98%, 100%, 99%, 86% and 100% for A, B, C, D and E steps, respectively. The positivity rate was 19% for A, 27% for B, 35% for C, 27% for D and 37% for E. All 5 parameters were normal in 1,496 patients (32.6%), all 5 were abnormal in 183 patients (4.0%). Most patients had abnormal response of 1 (n=1,356, 29.6%), 2 (n=788, 17.2%), 3 (n=477, 9.7%) or 4 (n=315, 6.9%) criteria (see Figure). Conclusions ABCDE-SE is extremely feasible, user-friendly, with minimal increase in imaging and off-line analysis time. It allows a comprehensive and personalized functional stratification assessing different vulnerabilities: epicardial coronary artery stenosis (step A), pulmonary congestion (step B), global myocardial dysfunction (step C), coronary microcirculatory dysfunction (step D), and cardiac autonomic nervous system imbalance (step E). The SE response is not only black and white with step A but can be effectively titrated from benign green code (all steps negative) to more functionally malignant red code (at least 3 steps positive). Figure 1 Funding Acknowledgement Type of funding source: None

Background Relevant number of all stress echocardiography results are non-diagnostic or inconclusive. Such importance cannot be ignored as previous studies have shown that these patients have higher risk for adverse events. Non-invasive transthoracic Doppler derived coronary flow reserve (CFR) of left anterior descending (LAD) artery, as additional test, is an effective tool to predict adverse cardiac events in various clinical settings. Purpose The aim of this study was to investigate the value of CFR of LAD in predicting outcome. Methods 122 patients, (35,8% with previous MI) with nondiagnostic stress echocardiography results (target heart rate not reached, chest pain without ECG and echo changes) and with inconclusive stress echocardiography results (target heart rate reached, chest pain with ECG changes and without echo changes) were referred for transthoracic Doppler echocardiographic CFR assessment of LAD. CFR was calculated as the ratio between maximal hyperemic and baseline coronary flow velocity. CFR ≤2 was considered abnormal. All patients were followed for major adverse cardiac events (MACE): nonfatal myocardial infarction, hospitalization, revascularization (CABG or PCI) and death. Results Measured values of CFR LAD were in the range 1,52- 4,00 (mean: 2,4±0.44). CFR LAD was abnormal in 22 (18%), and preserved in 100 patients (82%). During median follow-up of 23 months (interquartile range 9–35), 14 patients underwent revascularization (2 had CABG, 12 had PCI). There were no myocardial infarctions, hospitalizations or cardiovascular deaths in the follow-up period. Patients with lower CFR values (CFR≤2) had a higher event rate and shorter event free survival time compared to those with CFR>2, event rate (9/22, 40,9% vs 5/98 5,1%; p Conclusions Preserved CFR of LAD (>2.0) predicts excellent survival in patients with non-diagnostic and inconclusive stress echocardiography. Funding Acknowledgement Type of funding source: None

Background A reduction in coronary flow velocity reserve (CFVR) related to coronary microvascular dysfunction is a major mechanism for ischemia in hypertrophic cardiomyopathy (HCM). Hypothesis To assess the functional correlates and prognostic value of CFVR during stress echocardiography (SE) in HCM. Methods We enrolled 201 HCM patients (age 51±14 years, 105 male, 52%; maximal wall thickness: 18±3 mm) studied with CFVR during exercise (n=33, 16.4%), dipyridamole (n=89, 44.3%) or adenosine (n=79, 39.3%) SE in 6 certified centers. CFVR was assessed using pulsed wave Doppler sampling in left anterior descending coronary artery. All patients completed the clinical follow-up. Results During SE mean value of CFVR was 2.11±0.46. No patients showed regional wall motion abnormalities during stress. LV outflow tract obstruction (LVOTO) was present in 34 (16.9%) patients at rest and in 47 (23.4%) at peak stress. CFVR was inversely related to age (r=−0.229, p=0.001) and maximal wall thickness (r=−0.197, p=0.031). During a median follow-up of 26 months (IQ range: 12–48 months), 75 events in 63 patients occurred: 10 deaths, 33 new hospital admission for acute heart failure, 8 sustained ventricular tachycardias and 24 atrial fibrillations. Patients in the lowest tertile (≤1.88) showed the worse prognosis with higher incidence of follow-up events compared to median tertile (1.89–2.29) and highest tertile (≥2.30) (see figure). At multivariable analysis, NYHA functional class (HR: 2.234, 95% CI: 1.398–3.517, p=0.001), presence of LVOTO at rest (HR: 2.958, 95% CI: 1.074–3.570, p=0.028) and lowest tertile of CFVR (HR: 2.144, 95% CI: 1.126–4.081, p=0.011) were the independent predictors of follow-up events. Conclusions In HCM patients, reduction in CFVR is associated to a clearly worse outcome. The spectrum of prognostic stratification is expanded if the response is titrated according to a continuous scale. Figure 1 Funding Acknowledgement Type of funding source: None

Background 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. Purpose To assess the dependence of stroke volume (SV) and cardiac output (CO) upon LVCR EDV changes and heart rate (HR) during ESE. Methods 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 Results 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 Conclusion 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 Funding Acknowledgement Type of funding source: None

Background Percutaneous coronary intervention of chronic total coronary occlusion (PCI of CTO) is proved to reduce symptoms of angina and long term survival. Purpose This study aimed to assess systolic and diastolic left ventricular function with standard echocardiographic indices. Methods We analyzed total of 46 CTO patients (age 58 ± 9, 73% male). Measures were obtained with the transducer in the apical four-chamber view. Doppler time intervals were measured from mitral inflow and left ventricular outflow Doppler tracings by pulsed wave Doppler. The isovolumetric relaxation time (IVRT) was measured from closure of the aortic valve to opening of the mitral valve. The isovolumetric contraction time (IVCT) was measured from closure of the mitral valve to opening of the aortic valve. Ejection time (ET) was measured from the opening to the closure of the aortic valve on the LV outflow velocity profile. Myocardial performance index (MPI) is simple method for evaluation of overall cardiac function and is independent of heart rate and blood pressure. MPI was equal to the sum of the IVRT and IVCT divided by the ET. Velocity of early mitral filling wave (E) was measured and divided by average peak early diastolic annular velocity (e") which was measured as average value between septal and lateral side of the mitral annulus using Doppler tissue imaging. The E/e’ ratio was calculated to estimate the LV filling pressures Results Six months after PCI of CTO patients showed no change in ejection fraction (EF) (55.69 ± 8.56% vs. 54.83 ± 8.44%, p = 0.10). MPI was significantly decreased (0.676 ± 0.99 vs. 0.632 ± 0.96 p Conclusion PCI of CTO improves overall cardiac function, particularly diastolic function in patients with reduced ejection fraction.

OnBehalf Stress Echo 2020 study group of the Italian Society of Cardiovascular Imaging Background ABCDE-stress echocardiography (SE) may explore different aspects in the heterogeneous entity of known or suspected heart failure (HF). Aim To assess ABCDE-vasodilator SE in non-ischemic HF Methods In a prospective, observational, multicenter study, we recruited 428 patients with angiographically normal coronary arteries: 148 patients with HF and preserved (>50%) ejection fraction (HFpEF, Group 1); 100 with HF and mid-range (40-50%) ejection fraction (HFmrEF, Group 2); 180 with HF and reduced ( Results All positivity criteria, except A, were more prevalent (p Conclusions ABCDE-vasodilator SE can help to identify the profound pathophysiological heterogeneity underlying a similar clinical presentation in patients with known or suspected HF with angiographically normal coronary arteries. These patients rarely show stress-induced regional wall motion abnormalities (A), but may exhibit pulmonary congestion (B), reduced myocardial functional reserve (C), altered coronary microcirculation (D) and cardiac autonomic dysfunction (E). Abstract 1675 Figure. The positivity rate of ABCDE criteria

Background Percutaneous coronary intervention for chronic total occlusion (PCI CTO) is still high risk procedure and it is doubtful will it become standard of care. There is evidence that it can reduce angina but even silent ischemia represent ischemic burden that ultimately lead to left ventricle remodeling and electrical instability. Purpose Our aim was to access effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) on myocardial function. Methods We compared two groups of pts. First patients with percutaneous coronary intervention of chronic total occlusion with optimal medical therapy and second group - patients with only optimal medical therapy (control group). Echocardiographic exam was performed before randomization and after 6 months of follow-up. Doppler intervals- isovolumetric relaxation time (IVRT), isovolumetric contraction time (IVCT) and ejection time (ET) were measured. MPI (Myocardial performance index) is equal to the sum of the IVRT and IVCT divided by the ET. Velocity of early mitral wave (E) was divided by average peak early diastolic annular velocity (e"). Peak longitudinal strain was assessed in 17 left ventricular segments. Time intervals from start Q/R on electrocardiogram to peak negative strain during the cardiac cycle were assessed. Mechanical dispersion was defined as the standard deviation of this time intervals from 17 segments, reflecting myocardial contraction heterogeneity. Results A total of 94 age matched CTO patients (48 in PCI + OMT group and 46 in OMT) were analyzed. Changes in ejection fraction (EF), diastolic function represented by E/e", global cardiac function represented by MPI, global longitudinal strain (GLS) and myocardial dispersion changes were compared between groups. At follow up between groups in there was no significant change in ejection fraction (EF), diastolic function, GLS and mechanical dispersion, but there was improvement in MPI. Conclusion Myocardial performance index is sensitive marker which can detect subtle improvement in global myocardial function after recanalization of chronic total occlusion.. Variable PCI + OMT (n = 46) OMT (n = 48) ΔOMT vs. ΔPCI + OMT p value baseline At 6month follow up P value baseline At 6month follow up P value EF (%) 55.69 ± 8.56 54.83 ± 8.44 0.10 50.22 ± 11.71 51.42 ± 10.45 0.06 0.71 MPI 0.676 ± 0.99 0.632 ± 0.96

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.

OnBehalf Stress Echo 2020 study group of the Italian Society of Cardiovascular Imaging Background Stress echocardiography (SE) based on regional wall motion abnormalities (RWMA) has established risk stratification capabilities, further enhanced by assessment of coronary flow velocity reserve (CFVR) on mid-distal left anterior descending coronary artery which assesses not only epicardial coronary artery stenosis but also coronary microcirculation. Aim To assess the value of CFVR in predicting outcome Methods From September 2016 to December 2018, we enrolled 1848 patients (age 63 ± 11 years; 1121 males, 60%) with known or suspected coronary artery disease and/or heart failure evaluated with SE (exercise in 631, dipyridamole in 1184, adenosine in 10, dobutamine in 43) in 9 quality-controlled centers of 6 countries. CFVR was measured from pulsed wave Doppler as peak/rest ratio of peak diastolic flow. All patients were followed-up for a median of 16 months. Results CFV was 28 ± 10 cm/s at rest and 62 ± 19 cm/s at peak stress (p 3 months from SE) myocardial revascularizations. At multivariable analysis, stress-induced RWMA (Hazard Ratio 3.883, 95% Confidence Intervals: 2.379-6.336, p Conclusion In patients referred to SE, CFVR assessing coronary microvascular dysfunction allows a more accurate prediction of outcome than RWMA which only detect epicardial coronary artery stenoses. Abstract P1792 Figure. CFVR and event-free survival curves

Background Heart rate recovery (HRR) has been shown to predict cardiovascular and all-cause morbidity and mortality in different populations. Recent studies have indicated the CHA2DS2-VASc score can be used as predictor of mortality in patients with coronary artery disease, without atrial fibrillation. However, the relation between these two parameters has not yet been documented. The Aim: The aim of this study was to determine the relation between CHA2DS2-VASc score and impaired heart rate recovery in patients without inducible myocardial ischemia. Methods Our study comprised of 2699 consecutive patients (1319 male, 42.8%, average age 60 ± 11 years) who underwent treadmill exercise testing (stress echocardiography or stress echocardiography) according to Bruce protocol for the assessment of myocardial ischemia. We excluded patients with the systolic heart failure (left ventricle ejection fraction Results Out of 2699 patients, 378 (12.3%) had a positive test and they were excluded from further analysis. Of the remaining 2321 patients, 251 (10.8%) had an impaired HRR, whereas 2070 (89.2%) had normal HRR. Previously known coronary artery disease (previous myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft surgery) had 78 (3.4%) patients. Patients with impaired HRR had significantly higher CHA2DS2-VASc score (3.1 ± 1.3 vs 2.3 ± 1.2, p Conclusion CHA2DS2-VASc score is an independent predictor of impaired HRR in patients without inducible ischemia.

OnBehalf Stress Echo 2020 study group of the Italian Society of Cardiovascular Imaging Background Over the last 3 decades, we observed a progressive decline in the prognostic value of a negative stress echo (SE) test based on regional wall motion abnormalities (RWMA), likely reflecting both an increase in risk in patients (older and more often diabetics) as well as a potential decrease in test performance due to concomitant anti-ischemic therapy. Aim To assess the value of SE in predicting outcome in contemporary populations Methods From September 2016 to December 2018, we enrolled 1848 patients (age 63 ± 11 years; 1121 males, 60%) with known or suspected coronary artery disease and/or heart failure evaluated with SE (exercise in 543, dipyridamole in 1184, adenosine in 10, dobutamine in 43) in 9 quality-controlled centers of 6 countries. Wall motion score index (WMSI) was evaluated at rest and peak stress (17-segment model, from 1 = normal-hyperkinetic to 4 = dyskinetic).All patients were followed-up for a median of 16 months. Results WMSI was 1.09 ± 0.23 at rest and increased during stress (1.17 ± 0.32, p3 months from SE) myocardial revascularizations. Multivariable analysis identified stress-induced RWMA (Hazard Ratio 2.754, 95% Confidence Intervals: 2.053-3.963, p2.0) abnormal peak WMSI: see figure. In patients with negative SE, event-rate was 1.4% per year considering hard events (death and myocardial infarction) and 0.8 % per year considering only death. Conclusion RWMA show risk stratification capability in contemporary patients referred to SE testing. The higher the peak WMSI, and the worse the prognosis. Nevertheless, the positivity rate is low (< 20%) and patients with normal baseline and stress function still have a significant event rate. A more comprehensive risk assessment with other parameters is warranted Abstract P1791 Figure. Survival curves and peak WMSI

OnBehalf Stress Echo 2020 study group of the Italian Society of Cardiovascular Imaging Background Coronary microvascular abnormalities determining a reduction of coronary flow velocity reserve (CFVR) have been described in patients (pts) with non-ischemic heart failure (HF). Aim To assess the prognostic value of CFVR in HF. Methods In a prospective, observational, multicenter study, we recruited 333 pts with angiographically normal coronary arteries: 105 patients with HF and preserved (>50%) ejection fraction (HFpEF); 71 with HF and mid-range (40-50%) ejection fraction (HFmrEF); 157 with HF and reduced ( Results After a median follow-up time of 15 months, 78 events occurred: 36 hospital admissions for acute decompensated heart failure, 23 deaths, 16 worsening in NYHA functional class, 2 stroke and 1 late revascularization. Event-free survival was best in patients with preserved CFVR and LVCR and worst in pts with reduced CFVR and impaired LVCR, with intermediate values for patients with either one (CFVR or LVCR) abnormal results: see figure. A preserved CFVR was associated with a better 24-month event-free survival than reduced CFVR in a subset analysis in pts with HFpEF (HR = 16.2, 95% CI, 1.8-145.1, p = 0.001) and in HFrEF (HR = 3.06, 95% CI, 1.6-5.6, p Conclusions A reduction in CFVR identifies a high risk subset in HF patients, outlining a shared role of coronary microvascular abnormalities as a marker and potential therapeutic target of HF, independently of underlying EF. Abstract P1401 Figure. Event-free survival based on CFVR-LVCR

OnBehalf Stress Echo 2020 study group of the Italian Society of Cardiovascular Imaging Background A blunted heart rate reserve (HRR) during exercise or vasodilator stress echo (SE) has been associated with a poor outcome in retrospective studies. Aim. To assess the prognostic value of HRR in patients undergoing SE in prospective study. Methods We prospectively recruited a sample of 1825 patients (none with pacemakers or atrial fibrillation; mean age 63 ± 11 years; 1099 male, 60%; 1125, 62% on beta-blockers at the time of testing). All underwent SE with either exercise (n= 631, 543 with semi-supine bicycle and 88 with post-treadmill) or vasodilator (n = 1194, 1184 with accelerated high dose dipyridamole and 10 with adenosine) SE for evaluation of known or suspected coronary artery disease and/or heart failure in 7 accredited laboratories of 5 countries. HRR was calculated by ECG as the peak/rest HR ratio. All patients were followed-up. Results During a median follow-up time of 480 days, 211 events occurred: 20 deaths, 22 non-fatal myocardial infarctions, 58 hospital admissions for acute decompensated heart failure and 111 late (> 3 months from SE) myocardial revascularizations. Positivity cutoff for HRR identified by ROC analysis was ≤1.67 (sensitivity 51.0, specificity 63.4) in the exercise group and ≤1.32 (sensitivity 65.0, specificity 48.9) in the vasodilator group. The separation was present both in the exercise (left panel) and the vasodilator (right panel) subsets : see figure. At multivariable analysis, blunted HRR was an independent predictor of event-free survival in the overall group (Hazard Ratio 1.422, 95 % Confidence Intervals: 1.055-1.917, p=.021), independent of beta-blocker therapy. Conclusion A blunted HRR is a useful non-imaging predictor of adverse events during both vasodilator and exercise SE, independent of inducible ischemia and beta-blocker therapy. Abstract P1793 Figure. HRR and event-free survival curves