Citations

Abstract Introduction Transthoracic echocardiography (TTE) identifies a hypercontractile phenotype (HP) in chronic coronary syndromes (CCS), characterized by elevated resting left ventricular (LV) elastance (force = systolic blood pressure/end-systolic volume). To evaluate the prognostic significance and functional correlates of HP. Methods In a prospective multicentre study, 10 677 patients with CCS underwent resting TTE to assess LV ejection fraction (EF), stroke volume, and force by quantitative volumetric echocardiography. All patients were followed for the endpoint of all-cause mortality. In a subset of 5834 patients, stress echocardiography (exercise or dobutamine) was performed for LV contractile reserve and heart rate reserve. Results Patients were stratified into Force quintiles (Q1–Q5). Patients with hypercontractile phenotype exhibited lower stroke volume at rest (Q5 = 34.8 ± 12.3 vs Q1–Q4 = 57.4 ± 19.1 mL; P < .01) and higher EF at rest (Q5 = 64.8 ± 6.9% vs Q1–Q4 = 58.1 ± 8.7%, P < .01). During a median follow-up of 24 months (interquartile range = 12–40 months), 509 deaths occurred. The exposure-adjusted death rate was lowest in Q3 (3.53–4.51 mmHg/mL; 1.03 per 100 person/years) and higher in Q1 (≤2.62 mmHg/mL, 2.88), Q2 (2.63–3.52 mmHg/mL, 1.86), Q4 (4.52–6.11 mmHg/mL, 1.56), and Q5 (HP, >6.11 mmHg/mL; 1.88; P < .0001 vs Q1 and Q3). Multivariable analysis identified HP (Q5; HR 1.531 vs Q3, 95% CI 1.116–2.099; P = .006) and EF (HR 0.963, 95% CI 0.953–0.972; P < .0001) as independent predictors of death. During exercise or dobutamine stress, HP showed reduced LV contractile reserve (ΔEF: Q5 = 4.3 ± 9.4% vs Q1–Q4 = 7.0 ± 9.3%; P < .001) and blunted heart rate reserve (Q5 = 1.77 ± 0.33 vs Q1–Q4 = 1.85 ± 0.39; P < .01). All patients with force-based LV contractile reserve >4.1 (present in 185, 3.2% of the population) survived. Conclusion Patients with CCS with HP assessed by resting TTE demonstrate higher mortality and multilayered functional impairment, including reduced LV contractile and chronotropic reserves. Hypercontractile phenotype improved the prediction of mortality by EF. A ‘stronger’ heart is, in fact, functionally and prognostically weaker.

Abstract Background Exercise stress echocardiography (ESE) is recommended in patients with mitral regurgitation (MR) when resting echocardiographic findings and symptoms do not align. However, the role of MR assessment in patients undergoing ESE for any indication remains uncertain. Purpose This study aimed to investigate whether the assessment of MR during ESE provides prognostic value beyond the evaluation of inducible regional wall motion abnormalities (RWMA) in patients undergoing ESE for any clinical indication, including suspected coronary artery disease (CAD). Methods Data were analyzed from a large multicenter and multinational prospective study. Current analysis included patients who underwent ESE for any indication and had MR (from 0= absent, to 3= severe) assessed at rest and peak exercise with an integrated qualitative, semi-quantitative, and (in selected cases) quantitative assessment. The primary endpoint was all-cause mortality. Results Of 1,351 included patients (age 56±16 years; 66% women; 30% with known CAD). MR score increased during exercise (rest=0.74±0.7 vs. peak=0.89±0.8, p<0.001), with severe MR present in 2% of patients at rest and 7% at peak ESE. Patients with severe MR during exercise (n=96, Group 1) compared to those with non-severe MR during exercise (n=1255, Group 2) showed more B-lines, lower left ventricular contractile and chronotropic reserve, and trend (p=0.09) to more frequent decrease in ejection fraction during ESE (Table 1). After a median follow-up of 2.1 years (IQR 1.0–6.9), 99 patients (7%) had died. Severe MR at rest was associated with increased mortality (log-rank p<0.001). Patients with severe MR at peak ESE had a higher risk of death compared to the other patients (log-rank p 0.035) (Figure 1). After adjusting for age, CAD, and inducible RWMA, severe MR with exercise remained strongly associated with an increased risk of death (adjusted-HR: 2.2, 95%CI 1.3-3.8, p=0.002). Similar results were seen with further adjustment for rest MR severity (adjusted-HR:1.9, 95%CI 1.02-3.5, p=0.004). Conclusion Patients, with and without CAD, with severe MR during ESE have greater functional impairment expressed by more pulmonary congestion, blunted heart rate reserve, and lower left ventricular contractile reserve. The assessment of MR during ESE provides significant prognostic information, independent of resting RWMA or inducible ischemia. Incorporating MR evaluation into routine ESE protocols may improve clinical decision-making and patient outcomes.Fig 1 Survival by MR at peak exercise Table 1

Abstract Background Inducible ST-segment depression during stress echocardiography (SE) is associated with a higher risk in patients with inducible regional wall motion abnormality (RWMA). Objective To assess ST segment elevation's prevalence and functional correlates during SE. Methods ECG response was analyzed in 1712 patients (age 63±12 years; 1011 men, 59%) undergoing SE for chronic coronary syndromes (CCS) prospectively recruited at 39 laboratories. Among the patients analyzed, 1286 (75%) performed SE with exercise, 306 (18%) with dobutamine and 120 (7%) with a vasodilator. ECG response was considered abnormal in case of ST-segment shift >1.0 mm from baseline at 80 ms from the J point developed in ≥2 contiguous leads during SE. The stress to rest (∆) change in the wall motion score index (WMSI) was assessed in all patients. Coronary angiography was available in 765 patients. Major adverse cardiac events (MACE) were the outcome measure in 746 patients with follow-up information. Results No significant ST segment shift was observed in 1000 patients (58%, Group 1), ST-segment depression occurred in 609 patients (35.5%, Group 2), and ST-segment elevation in 103 patients (6%, Group 3). ST-segment elevation occurred in 66/1286 patients (5.2%) with exercise, 30/306 with dobutamine (10%), and 7/120 with vasodilators (6%, p = ns vs. exercise and p<0.01 vs. dobutamine). The prevalence of stress-induced RMWA was higher in Group 2 (38.1%) compared to Group 3 (33%) and Group 1 (11.9%. P< 0.001 vs. Groups 2 and 3); however, the ΔWMSI was more pronounced in Group 3 compared to Group 2 and Group 1 (p = ns vs. Group 2 and p<0.001 vs. Group 1). (Figure, left panel). Non-significant CAD (defined as coronary stenosis <50% on coronary angiography) was more prevalent in Group 1 (36%) and 3 (40%) compared to Group 2 (17.5%, p<0.01 vs. Group 1 and 3). . During a median follow-up of 387 days (IQ range 314-603 days), 150 events occurred in 112 patients: 14 all-cause deaths, 39 acute myocardial infarctions, 19 atrial fibrillations, 34 late coronary revascularizations, and 44 acute heart failure hospitalizations. The exposure-adjusted event rate was the lowest in Group 1 compared to Groups 2 and 3 (Figure, right panel). Conclusion In all-comers with CCS, the electrocardiographic pattern of ST-segment elevation is not rare, more frequent with dobutamine, associated with more stress-to-rest change in RWMA and more events despite less extensive underlying anatomic CAD. The paradox of more ischemia with less coronary stenosis is consistent with a coronary vasospastic origin as an important yet frequently overlooked cause of stress-induced ST segment elevation.Figure

Abstract Background Ischemic mitral regurgitation (IMR) is a common complication of coronary artery disease (CAD), often occurring after myocardial infarction (MI). Even when moderate in severity, IMR is associated with adverse outcomes, including a twofold increase in mortality rates. Aim To assess the functional correlates of resting IMR during stress echocardiography (SE) in patients with CAD. Methods This prospective multicenter study included 192 patients with CAD (143 males; mean age 65 ± 10 years) from eight cardiology institutions. Exclusion criteria included a history of coronary artery bypass surgery, more than moderate IMR, and other significant valvular diseases. Patients were divided into two groups based on semiquantitative- quantitative assessment at rest based on EACVI-ASE criteria: Group 1: Patients with moderate IMR, Group 2: Patients without IMR or with trivial IMR. All patients underwent stress echocardiography (SE) using the ABCE protocol. Patients underwent exercise tests, if execise echocardiography was not possible, dobutamine stress tests were performed. At rest and peak SE, we assessed: Left atrial volume index (LAVi), Left ventricular end-diastolic (LV EDV) and end-systolic volumes (LV ESV), ejection fraction (EF), wall motion score index (WMSI), global longitudinal strain (GLS), B-lines (4-site simplified scan), tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary artery pressure (SPAP), LV contractile reserve (LVCR) and heart rate reserve (HRR). Results Despite similar EF at rest, Group 1 patients showed more pronounced functional impairment at rest, which increased during stress. Stress-induced functional worsening affected indices of MR (more frequently becoming severe), ischemic burden (WMSI), diastolic function (LAVI and LVEDV dilation), LV systolic function (LVCR), pulmonary congestion (B-lines), cardiac sympathetic reserve (reduced HRR) and right ventricular/pulmonary artery coupling (reduced TAPSE/SPAP): table 1. Conclusion Compared to CAD patients with absent-to-trivial resting IMR, patients with moderate IMR at rest show a constellation of functional vulnerabilities during SE involving more frequent exercise-induced worsening of MR, blunted LV diastolic and systolic reserve, more pulmonary congestion, impaired cardiac autonomic reserve, and worse right ventricular-pulmonary artery coupling. The individual patient's functional response heterogeneity can be identified with comprehensive exercise SE, possibly a roadmap to personalized and targeted therapeutic interventions.

Abstract Aims Chronotropic incompetence (CI) is a biomarker of cardiac autonomic dysfunction. The aim of the study is to assess the risk stratification value of CI during exercise or pharmacological stress echocardiography in patients with chronic coronary syndromes. Methods and results In a prospective, multicenter, international, observational study, we enrolled 13 445 patients with known or suspected chronic coronary syndromes who underwent stress echocardiography in 19 clinical sites from 10 countries using either exercise (n = 2594), dobutamine (n = 2440), or dipyridamole (n = 8411). Heart rate was automatically measured from the 1-lead ECG in the echocardiography monitor. We considered CI as failure to reach 85% of the maximal predicted (220-age) heart rate for exercise and dobutamine, and heart rate reserve (peak/rest heart rate) ≤ 1.22 (≤1.17 if in permanent atrial fibrillation) for dipyridamole stress. The primary outcome was all-cause death. CI was observed in 5045 patients (38%) and stress-induced regional wall motion abnormalities in 1648 (13%). Over a median follow-up time of 3.4 years (interquartile range, 1.6–9.1 years), there were 2426 (18%) deaths. The 10-year mortality was 39% in patients with and 21% in patients without CI (P < 0.0001). CI was associated with a significant increase in 10-year mortality in all age groups ranging from ≤54 years to ≥75 years (P < 0.0001). In addition, it was associated with increased mortality (P < 0.0001) irrespective of β-blocker use. Cox multivariable analysis revealed that CI was an independent predictor of mortality (HR: 1.60, 95% confidence interval: 1.47–1.74; P < 0.0001) together with age, male sex, diabetes mellitus, left ventricular ejection fraction, and resting heart rate. Conclusion In patients with chronic coronary syndromes, CI during exercise or pharmacological stress is a simple and objective predictor of survival.

Over the past decade, stress echocardiography has evolved from a test for assessing epicardial artery stenosis to a comprehensive functional test, targeting multiple cardiovascular parameters. The new approach includes several structured steps: (a) evaluating regional wall motion abnormalities to detect epicardial artery stenosis or vasospasm; (b) assessing pulmonary congestion and diastolic function via B-lines with lung ultrasound; (c) gauging preload and contractile reserve with volumetric echocardiography; (d) measuring coronary microvascular reserve using Doppler-based coronary flow velocity in the middistal left anterior descending artery; and (e) determining cardiac sympathetic reserve by tracking heart rate reserve on an ECG. This evolution was supported extensively by the Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI), which played a key role in five areas: (1) developing the initial, curiosity-driven project; (2) disseminating protocols and results at national and international conferences, supporting logistic infrastructure and publication expenses; (3) establishing a digital platform (customized Redcap) for data entry and storage; (4) facilitating patient recruitment across 19 Italian centers; and (5) offering formal endorsement through six presidencies, adding credibility and reach beyond any single institution. The protocol quickly advanced from concept to high-impact publications, earning inclusion in 2024 specialty guidelines. Initially Italian-led, the study now includes 50 centers across 20 countries (e.g. USA and China). Beyond the 50 peer-reviewed papers published in 2016–2024, this study offers a novel, sustainable approach to cardiac stress testing, providing more information at lower costs, with zero radiation and minimal environmental impact. SIECVI’s endorsement was instrumental in amplifying the study’s rigor and outreach.

Abstract Background Guidelines recognize the role of exercise stress testing in evaluating functional capacity in patients with asymptomatic severe aortic stenosis (AS). The study aimed to identify the prognostic role of exercise stress echocardiography (ESE) in asymptomatic severe AS. Methods We enrolled 153 asymptomatic patients (70±13 years; 88 male, 57%) with severe AS, aortic valve area (AVA) <1.0 cm2, mean aortic gradient ≥ 40 mmHg, ejection fraction (EF) ≥55%. All were referred for ESE in 7 quality-controlled centers from 5 countries. Rest and ESE assessment also included global longitudinal strain (GLS) and left atrial volume index (LAVI). B-lines were assessed by LUS with the 4-site simplified scan of the third intercostal space. A 4-point ESE score was based on 4 parameters (0 for normal, 1 for abnormal), with the following pre-determined cutoffs of abnormality: ∆-maximal aortic gradient (MAG) ≥20 mmHg; GLS at peak ≤ 19%, according to receiver operating characteristics curve analysis, stress B-lines ≥2; stress LAVI ≥ 34 mL/m2. Follow-up was completed in 142/153 patients (92%). Results At rest, AVA was 0.85±0.14 cm2, maximal aortic gradient: 79±14 mmHg, and peak aortic velocity: 4.42 ± 0.41 m/s. Mean EF at rest: 63.4±5.3% During a median follow-up of 1802 days (IQ range 651-2302), 41 events occurred in 39 patients: 15 all-cause deaths, 17 acute HF, 1 stroke, 1 myocardial infarction, and 7 coronary revascularization. Patients experiencing events displayed a greater increase in MAG during peak ESE, more B-lines with exercise, greater degree of LAVI dilation with exercise and slightly lower GLS compared to those without events (Table). Increase in ESE score was associated with a significant rise (p=0.001) in event incidence from score 0 (n=0/13, 0%) to score 1 (n=2/21, 9.5%), score 2 (n=10/42, 23.8%), and ≥3 (n=27/66, 40.9%), see figure. Conclusions In asymptomatic severe AS cases with preserved LV EF, comprehensive ESE provides early marker of potential cardiac decompensation at follow-up. The composite ESE index, including MAG, GLS, LAVI, and B-lines, holds promise as a prognostic predictor.TableFigure

Abstract Background/Introduction Cardiac stress tests are carried out in populations with a low probability of ischemic heart disease (IHD) much more frequently than in the past. Stress ECG remains a frequently used modality for the diagnosis of IHD in vast areas of the world with limited facilities. Purpose To assess the diagnostic value of stress ECG for diagnosing IHD using inducible regional wall motion abnormalities (RWMA) on stress echocardiography (SE) as the gold standard method of diagnosis. Methods The 12-lead ECG response was retrospectively analyzed in 4317 patients (age 64±13 years, 59.6% males) undergoing SE for chronic coronary syndromes who were prospectively recruited from 39 cardiac centers between March 2021 and February 2024. Exclusion criteria were left bundle branch block or pacemaker rhythm. ECG response was considered ischemic according to standard criteria (if ST-segment deviated >1.0 mm from baseline in ≥2 contiguous leads at 80 ms from J point) during an exercise (n=2980, 69.8%), dobutamine (n = 766, 18.0%), or vasodilator (n=519, 12.2%) SE. All patients underwent a comprehensive SE protocol with an assessment of wall motion score index (WMSI), B-lines (4-site simplified score), left ventricular contractile reserve (LVCR) based on force, coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending artery (LAD), and heart rate reserve (HRR). Results ECG changes occurred in 641 patients (14.8%, Group 1) for the overall studied population. Compared to patients without ECG changes (Group 2, n=3676, 85.2%), patients with ECG changes showed higher values of peak WMSI and lower values of CFVR and LVCR (see table).Amongst patients without inducible RWMA (n=3553), there were 392 (11%) patients with an ischemic ECG at stress (89% specificity). Of 764 patients with inducible RWMA during SE, 249 had an ischemic ECG trace (sensitivity 33%). In patients without inducible RWMA, those with ischemic ECG changes showed similar abnormal stress B-lines (23% vs. 21%, p=0.719), LVCR (61% vs. 63%, p=0.602), CFVR (31% vs 33%, p=0.607) and HRR (37% vs 41%, p=0.097) compared to those without ECG changes. Amongst patients with inducible RWMA and ECG changes, CFVR was significantly lower in patients with ECG changes (39.2% and 60.8%, respectively, p<0.001). Conclusions Simple standard stress ECG diagnostic value in the current era in populations with a low probability of IHD seems to be low. However, during SE, stress-induced ischemic ECG changes are associated with more extensive RWMA and blunted global LVCR, with reduced CFVR in the LAD. Therefore, analysis of ST segment changes during stress imaging studies can offer additional, significant information.

Abstract Background Guidelines recognize the role of exercise stress testing in evaluating functional capacity in patients with asymptomatic severe aortic stenosis (AS). Exercise stress echocardiography (ESE) allows the detection of pulmonary congestion with B-lines by lung ultrasound (LUS). Aim To identify the prevalence, determinants, and functional correlates of B-lines during ESE in asymptomatic severe AS. Methods We enrolled 35 asymptomatic patients (age= 69±16 years, 69% male) with severe AS, aortic valve area (AVA) <0.6 cm2/m2, mean aortic gradient (MAG) ≥ 40 mmHg, left ventricular ejection fraction ≥55%. All patients were referred for ESE (treadmill in 1, bicycle in 34 patients) in 7 experienced centers from 4 countries between 2021-2022. ESE assessment at rest and peak stress included global longitudinal strain (GLS), left atrial volume index (LAVI) and cardiac output (CO). B-lines were assessed by simplified LUS from 4 lung zones across the third intercostal space (2 on each side). Heart rate reserve (HRR) was measured as the peak/rest heart rate. CO reserve was calculated as the difference between peak stress CO and rest CO. Results B-lines (≥2) were present in 2 patients at rest and in 15 patients during ESE (6% vs 43%, p<0.001). When compared to patients without B-lines during ESE (Group 1, n=20), patients with B-lines during ESE (Group 2, n=15) were older (Group 1= 64±18 vs Group 2=75±8 years, p=0.030) had larger LAVI, higher logNT-pro-BNP and a trend to higher systolic pulmonary artery pressures (SPAP), see Table. The 2 groups showed similar values of resting AVA (Group 1= 0.52±0.11 vs Group 2=0.47±0.15 cm2/m2, p=0.311), stress AVA (Group 1= 0.45±0.09 vs Group 2=0.49±0.13 cm2/m2, p=0.663), resting MAG (Group 1= 45±15 vs Group 2=46±10 mm Hg, p=0.491), and stress MAG (Group 1= 59±19 vs Group 2=58±11 mm Hg, p=0.665). Patients with B-lines during ESE showed lower HRR and CO reserve, with a trend towards lower peak GLS, see Table. Conclusions Exercise-induced pulmonary congestion as evidenced by development of sonographic B- lines on LUS were present commonly (43%) among patients with "asymptomatic" severe AS undergoing ESE. Patients with exercise-induced B-lines have larger resting LAVI, higher NT-pro-BNP levels, lower CO reserve, and blunted HRR. Exercise-induced B-lines might provide an early sign of cardiac decompensation in "asymptomatic" patients with severe AS, which is an important factor to consider in the decision to intervene.TableFigure