Arbucci, Rosina

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 Chronotropic incompetence (CI) is a biomarker of cardiac autonomic dysfunction. Aim To assess the risk stratification value of CI during physical or pharmacological stress echocardiography in patients with chronic coronary syndromes. Methods In a prospective, multicenter, international, observational study design, we enrolled 13,445 patients with known or suspected chronic coronary syndromes who underwent stress echo in 19 sites from 10 countries using either exercise (n=2,594), dobutamine (n=2,440), or dipyridamole (n=8,411). Heart rate was automatically measured from the 1-lead ECG in the echo 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 in permanent atrial fibrillation) for dipyridamole. All-cause death was the outcome measure. Results Heart rate reserve was available in all patients; there was no extra imaging or analysis time, and no intra- and inter-observer variability. CI was observed in 5,045 patients (38%); abnormal regional wall motion abnormality in 1,648 (13%). Over a median follow-up time of 3.5 years, there were 2,426 (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 (p<0.0001) increase in 10-year mortality in all age groups ranging from <54 years to >75 years. In addition, it was associated with increased mortality (p<0.0001) irrespective of β-blocker use (Figure). Cox multivariable analysis revealed that CI was a significant predictor of mortality (HR 1.60, 95% confidence interval 1.47-1.74; p<0.0001) together with age, male sex, diabetes mellitus, ejection fraction, and resting heart rate. Conclusion In patients with chronic coronary syndromes, CI during physical or pharmacological stress is a simple, inexpensive, quantitative, and objective predictor of survival.

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 Obese patients often exhibit a clustering of cardiovascular risk factors and are frequently referred for noninvasive cardiac imaging. Coronary microvascular dysfunction (CMD) represents an early indicator of cardiovascular disease that can be noninvasively diagnosed using coronary flow velocity reserve (CFVR) measurements obtained during stress echocardiography (SE) in patients without evidence of obstructive coronary artery disease (CAD). Purpose This study aimed to evaluate the prognostic significance of CFVR in overweight and obese patients within a prospective multicenter cohort. Methods 2273 patients (mean age 65 ± 11 years; 51% women) classified as overweight or obese (for definition see Table) were included in 27 sites from 11 countries. All patients had normal left ventricular ejection fraction (EF ≥ 50%), no prior history of CAD, and underwent exercise or pharmacological SE, which was negative for inducible ischemia. CFVR of the left anterior descending coronary artery was assessed, with CMD defined as CFVR >2.0. Patients were divided into two groups based on the presence (Group 1) or absence (Group 2) of CMD. The primary endpoint was overall mortality. Results CMD was identified in 492 patients (22%), with a mean CFVR of 2.3 ± 0.5 across the study population. Group 1 patients (CMD) were older, with a greater prevalence of diabetes and metabolic syndrome compared to group 2 (no CMD) (Table). During a median follow-up period of 2.1 years (IQR: 1.2-3.7 years), 103 patients (5%) died. Patients with CMD had significantly worse late survival compared to those without CMD (3-year survival: 96 ± 1% vs. 96 ± 1%, p=ns; 6-year survival: 79 ± 4% vs. 93 ± 1%, p < 0.0001): see Figure. Multivariate analysis adjusting for age, sex, EF, body mass index, smoking habits, diabetes, dyslipidemia, arterial hypertension, and type of stress confirmed CMD as an independent predictor of mortality (hazard ratio: 1.8 [95% CI: 1.1–2.8], p = 0.01). Conclusions CMD, assessed via CFVR during SE, was a robust and independent prognostic marker of long-term mortality in obese patients with preserved EF and no evidence of inducible ischemia. These findings underscore the pivotal role of noninvasive assessment of CMD in refining risk stratification and guiding clinical decision-making in this high-risk population.

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 Atrial fibrillation (AF) is the most prevalent atrial tachyarrhythmia, affecting an estimated 2-4% of adults worldwide. AF is a well-recognized and treatable risk factor for stroke, but it often remains asymptomatic or subclinical, leading to underdiagnosis. This study aimed to identify distinguishing signs during exercise stress echocardiography (ESE) among patients in sinus rhythm (SR), with and without history of paroxysmal/persistent AF (PAF). Methods An international prospective cohort comprising 1035 consecutive patients was initially considered from 12 cardiology institutions. These patients were referred for clinically-driven ESE as part of the Stress Echo 2020-2030 study network. All patients underwent comprehensive ESE with the ABCDE protocol, which included assessment of B-lines, left ventricle contractile reserve (LVCR), ECG-based heart rate reserve (HRR), LV ejection fraction (EF), LV end-diastolic volume, E/e’, pulmonary artery systolic pressure estimation, tricuspid annular plane sytolic excursion (TAPSE), left atrium volume index (LAVi) and left atrium reservoir phase strain (LASr) at rest and with exercise. Results After excluding 89 patients who were in AF during the ESE, 946 patients in SR were included as the main study cohort (101 with and 845 without a history of PAF). A scoring system was then constructed using all independent variables that differentiate the two groups (those with and without history of PAF). Presence of systemic hypertension, rest LAVI>31ml/m2, rest |LASr|< 21%, stress LAVI >29 ml/m2, stress |LASr| <24%, stress E/e’ >7, ∆TAPSE <4.5 mm, HRR<1.87, and LVCR<1.6 were identified as the discriminators between patients with and without PAF. The composite score, summing all 9 items (with a total score range from 0 to 9), yielded a score of >4 as the best balance between sensitivity (87%) and specificity (60%) in predicting those with PAF. The receiver operating characteristic curve analysis of the scoring model showed an AUC of 0.79 (p-value <0.0001), Figure. Conclusion ESE evaluation can be a valuable adjunct for identifying patients in SR with history of PAF. This multifaceted approach enhances the potential for more accurate detection and clinical management of individuals in SR at risk for AF, who could be considered for aggressive monitoring programs to prevent the development of new onset AF and subsequent increase in cardiovascular risk.