Stress Echo 2030: the Novel ABCDE-(FGLPR) Protocol to Define the Future of Imaging

Study Overview
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Brief Summary
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With stress echo (SE) 2020 study, a new standard of practice in stress imaging was developed and disseminated: the ABCDE protocol for functional testing within and beyond CAD. ABCDE protocol was the fruit of SE 2020, and is the seed of SE 2030, which is articulated in 12 projects: 1-SE in coronary artery disease (SECAD); 2- SE in diastolic heart failure (SEDIA); 3-SE in hypertrophic cardiomyopathy (SEHCA); 4- SE post-chest radiotherapy and chemotherapy (SERA); 5- Artificial intelligence SE evaluation (AI-SEE); 6- Environmental stress echocardiography and air pollution (ESTER); 7- SE in repaired Tetralogy of Fallot (SETOF) ; 8- SE in post-COVID-19 (SECOV); 9: Recovery by stress echo of conventionally unfit donor good hearts (RESURGE); 10- SE for mitral ischemic regurgitation (SEMIR); 11- SE in valvular heart disease (SEVA); 12- SE for coronary vasospasm (SESPASM). The study aims to recruit in the next 5 years (2021-2025) ≥10 000 patients followed for ≥5 years (up to 2030) from ≥20 quality-controlled laboratories from ≥10 countries. In this COVID-19 era of sustainable health care delivery, SE2030 will provide the evidence to finally recommend SE as the optimal and versatile imaging modality for functional testing anywhere, any time and in any patient.

Detailed Description
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Stress echo (SE) 2020 is an international, multicenter, prospective, effectiveness study started in 2016 that conceptualized, disseminated and validated a new approach for functional testing within and beyond coronary artery disease (CAD). As originally planned, the study created the cultural, informatic and scientific infrastructure connecting high-volume, accredited SE labs, sharing common criteria of indication, execution, reporting and archiving SE. This approach allowed acquisition of original safety, feasibility, and outcome data in evidence-poor diagnostic fields, beyond the established core application of SE in CAD based on regional wall motion abnormality (RWMA) assessment. SE2020 standardized procedures, validated emerging signs, and integrated new information with established knowledge, helping to build a next-generation SE lab adopting the ABCDE protocol. Each and every step of ABCDE-SE provides independent and incremental prognostic information building on the prior steps and identifies distinct patient phenotypes and vulnerabilities possibly outlining different therapeutic targets: myocardial ischemia in step A, pulmonary congestion with B-lines in step B, preload reserve and left ventricular contractile reserve (LVCR) in step C, coronary microcirculation with coronary flow velocity reserve (CFVR) or real-time myocardial contrast echocardiography in step D, and cardiac autonomic balance with heart rate reserve (HRR) in step E. This shared practice can now be used as a new standard of care and a suitable platform for the next wave of studies converging towards SE 2030 and sharing with the older SE2020 study some distinct features: effectiveness study, performed in the real world with real doctors facing real clinical problems in real consecutive patients; upstream quality control of reading and direct entering of data from peripheral centers in the data bank so that evidence is obtained inside and outside highly specialized academic centers; identification of simple yet innovative objectives relevant to change the clinical practice. These features are completely different from efficacy studies, as when highly specialized centers recruit highly selected patients, the resulting data may be difficult to translate in clinical practice. For these reasons, the American Society of Echocardiography has identified already in 2013 as a top research need the development of a registry of echocardiographic information (and eventually images) that can serve as a platform for quality improvement and clinical research. Such registry data would be accessible to the research community facilitating a broad range of clinical research on the effectiveness of echocardiography for the improvement of patient management and outcome. SE2030 will establish the platform of evidence to build the perfect SE test, suitable for all patients, anywhere, anytime, also quantitative and operator independent. The need for such an ideal test is especially vital in our times, when the economic crisis, the increased awareness of cancer and non-cancer radiation damage, the pressing need for climate-neutral choices in health care, and the unavoidable trend to externalize health care are potent propelling forces, boosted by COVID pandemics, for the diffusion of a low cost, radiation-free, climate-friendly, and portable technique such as cardiovascular ultrasound. Methodology. Five important aspects will be shared by SE2030 in full continuity with SE2020, with minor adaptations and implementations. Upstream quality control. The study is a prospective registry but it is necessary to have an upstream quality control with a certified reader from each center. A mandatory quality control is necessary for conventional and innovative parameters, since the volume of activity is necessary but not sufficient to ensure the quality of reading. Peripheral reading and inclusivity. Once the reader has been certified, the peripheral reading will be directly entered in the data bank via the Redcap program property of the Italian Society of Echocardiography and Cardiovascular Imaging. This will allow a more flexible and rapid platform, less error in data inputting and better compliance with new regulations strictly protecting privacy in clinical studies. Another feature of SE2030 is inclusivity, so that any center meeting the selection criteria can be enrolled, allowing centers traditionally outside the editorial stage but producing high quality clinical activity to contribute to generate data relevant for the scientific community. Uniform methodology. Each laboratory will adopt the preferred choice of stress among physical, pharmacologic or pacing stress according to standardized protocol in line with guidelines recommendations. Physical exercise includes semi-supine or upright bicycle exercise, and peak or post-treadmill exercise. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal atrial pacing or with external programming of a permanent pacemaker. Independent of the chosen form of stress, execution, performance, archiving and interpretation of testing will follow a standardized format with the ABCDE protocol. From the technical viewpoint of success rate, a limiting step is step D. Step D is easy and feasible with vasodilator, less easy but still highly feasible with dobutamine, not easy and less feasible with semi-supine exercise, and virtually impossible with (peak or post) treadmill exercise. Therefore, our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages of exercise when most flow increase occurs and feasibility is still high, before it drops at higher levels of exercise. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response. All laboratories will be granted with free artificial intelligence (AI) software and encouraged to use ultrasound enhancing agents when needed to help leading edge technology upgrade and uniformity of methods across all study laboratories . The full spectrum of enrolled patients evaluated for clinically relevant endpoints. The various projects will include patients with known or suspected CAD (project 1), known or suspected heart failure with preserved ejection fraction (project 2), hypertrophic cardiomyopathy (HCM, project 3), status post-chest radiotherapy and chemotherapy (project 4), repaired Tetralogy of Fallot (project 7), cardio-pulmonary involvement post-COVID 19 (project 8), post-ischemic (project 10) and primary valvular heart disease (project 11) and suspected coronary vasospasm, a diagnosis frequently missed but important to recognize as a possible cause of life-threatening disease, which is easy to treat when promptly identified (project 12). The 12 protocols running on the SE-ABCDE platform are spread all over the spectrum of cardiovascular disease, from severe valvular heart disease to suspected CAD in patients with normal LV function. Potential heart donors with brain death will be evaluated to assess the suitability for donation of hearts currently dismissed on the basis of clinical history criteria but in the absence of a cardiac functional evaluation (project 9). The study will exploit and possibly contribute to upgrade the leading edge quantitative and operator-independent technology of AI-SE and cardiac strain (project 5) for image interpretation and data analysis and will also evaluate the results of SE parameters in the context of powerful environmental modulators of stress results and/or long-term outcome such as air pollutants and medical radiation exposure analyzed through big data mining with AI (project 6). The overarching aim of the study is to make SE practice more uniform, versatile, standardized, quantitative and evidence-rich, producing data potentially relevant to change clinical practice. Sponsored by a professional scientific society. The study is investigator-driven and not industry-driven. It is endorsed by an independent-not for profit professional society (Italian Society of Echocardiography and Cardiovascular Imaging) and not sponsored by industry, although some materials useful for project completion such as AI-software will be donated by industrial partners for recruiting centers.

Official Title
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The International Stress Echo Study to to Define the Future of Imaging

Conditions
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Coronary Artery Disease, Heart Failure, Hypertrophic Cardiomyopathy, Congenital Heart Disease, Valvular Heart Disease, Post-chest Radio/Chemiotherapy, Heart Transplantation

Intervention / Treatment
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* Diagnostic Test: ABCDE-Stress Echo
* Diagnostic Test: SE diastolic assessment
* Diagnostic Test: SE Right ventricular function assessment
* Diagnostic Test: SE in heart donors


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Known or suspected coronary artery disease Hypertrofic cardiomiopathy Repaired Tetralogy of Fallot Primary valvular disease Exclusion Criteria: -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| ABCDE-Stress Echo in Coronary Artery Disease (SECAD project)<br>All patients with known or suspected CAD will be evaluated with ABCDE-SE. Patients will be referred according to existing 2020 guidelines indication; status post heart transplant; pediatric patients and congenital heart disease ; peri-partum cardiomyopathy. Information on demographics, lifestyle and other risk factors and ongoing therapy will be collected. Data related to carotid disease and cardiac calcification will be collected. All patients will enter a regular clinical follow-up program with annotation of cardiovascular and non-cardiovascular endpoints, such as cancer or neurodegenerative disease, characterized by endothelial dysfunction (step D positivity) and autonomic dysfunction (step E positivity). A sample size of about 2 430 patients with a 5-year follow-up is required to provide 90% power with an alpha error of 5% to detect a difference for the primary endpoint of all-cause mortality among those with positive versus negative SE also considering a 20% drop-out. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>|
| ABCDE-Stress Echo in Diastolic Heart failure (SEDIA project)<br>Patients with dyspnea and known or suspected heart failure with preserved ejection fraction by 2019 European Society of Cardiology criteria will be enrolled and studied with cycle-ergometer in semi-supine SE (or treadmill). A score of at least 1 according to the criteria proposed by Pieske et al. is required for inclusion. In patients unable to exercise or did not allow sampling of CFVR, pharmacological test (vasodilator or dobutamine) is recommended. Assuming that the hypothesis of proportionality of hazard holds, as required for Cox proportional hazards regression, with a power of 90%, an attrition rate of 10% and a 5-year follow-up period of a sample size of 181 patients is required. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>|
| ABCDE-Stress Echo in Hypertrophic Cardiomyopathy (SEHCA project)<br>The primary aim is to evaluate the feasibility of comprehensive ABCDEFG-SE in the evaluation of HCM. The secondary aim is to assess the value of each of obtaained parameters in predicting response to specific therapy and other interventions. The tertiary aim is to assess the prognostic value of SE indices for prognostic stratification in the medium-long-term. HCM diagnosis will be based on existing guidelines. All patients will be followed-up. In patients and first-degree relatives with genetic characterization different phenotypes will be correlated with specific genotypes. Non-imaging or routine imaging non-ultrasound exams will be collected and analyzed with neural network analysis developed in project 5. We assume that a sample size of 338 patients is required. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>|
| ABCDE-Stress Echo post-Radiotherapy (SERA project)<br>Radiation-induced heart disease is associated with a significantly higher morbidity and mortality in cancer patients. The most frequent forms treated with chest radiation therapy are breast, lung, and esophageal cancers or lymphoma. The chances of developing radiation-induced heart disease increase with higher cumulative doses (>30 Gray) in anterior or left sided irradiation, concomitant chemotherapy, presence of cardiovascular risk factors, and increased distance from time of irradiation. The estimated incidence of major cardiac events related to ischemic heart disease is 30% at 10 years post-treatment in female patients with radiotherapy post-breast cancer. The resulting epicardial artery stenosis, low grade inflammation , myocardial fibrosis, microvascular injury , alterations in autonomic balance, valve leaflets, and accelerated calcification can lead to significant alteration of all SE steps. A sample size of 507 patients is required and will be enrolled. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>|
| ABCDE- Artificial Intelligence Stress echo (AI-SEE)<br>The project have 2 separate aims: AI-SEE images: To make SE reading operator-independent for each of the essential reading steps (from A to E). AI-SEE data: To identify the links between clinical imaging and stress variables and develop a tailored personalized model for risk prediction. For each parameter assessment (positivity versus negativity), the area under the receiver-operating characteristic curve produced by the deep learning algorithm will be compared to that produced by the experienced cardiologist (cross-sectional analysis). AI-SEE images: a set of images from 1 250 patients from at least 10 laboratories will be sufficient to develop the algorithm (modeling set) subsequently prospectively tested on a different set of 1250 patients (validation set). AI-SEE data: a set of data from 2 500 patients from at least 10 laboratories will be sufficient to develop the algorithm (modeling set) subsequently tested on a different set of 2 500 patients (validation set). | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>Diagnostic Test: SE Right ventricular function assessment<br>* Right ventricular function will be assessed at baseline and peak stress with variations of tricuspid annular plane systolic excursion, an index of right ventricular longitudinal function, and right ventricular fractional area change (a load-dependent index of right ventricular inlet function). To distinguish between genuine right ventricular dysfunction and/or pathological increases in pulmonary vascular load, we will combine systolic pulmonary artery pressure and right ventricular end-systolic area to calculate right ventricular end-systolic pressure-area relation. Peak systolic tricuspid annulus velocity and conventional indices of left ventricular systolic and diastolic function will also be measured at baseline and peak stress according to the standard ABCDE-FGLPR protocol. Right ventricular free wall strain combined with interventricular septum strain will be assessed. Left ventricular function, wall motion score index and E/e' at baseline and peak stress.<br>|
| ABCDE- Environmental Stress Echocardiography, air pollution and medical radiation (ESTER project)<br>The primary aim is to assess the inter-patient correlation between SE results and outdoor air pollution levels in patients matched for clinical, coronary anatomy (if available) and resting functional features. Secondary aim is to assess the effects of air quality and cumulative medical radiation exposure in prognostic modeling using traditional risk factors and SE results. All patients enrolled in projects 1 to 4 have information on house residency and work place in the data bank. The air epidemiology unit will obtain same day local air quality data from publicly available data sets from regional authority of environmental protection. For each patient and each test of the same patient, the values of 2 particulate and 4 gaseous pollutants will be collected when available. Data on medical radiation exposure will also be systematically collected. Of the 2 430 tests recruited in protocol 1, at least 600 will have access to geo-referenced air quality data. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>Diagnostic Test: SE Right ventricular function assessment<br>* Right ventricular function will be assessed at baseline and peak stress with variations of tricuspid annular plane systolic excursion, an index of right ventricular longitudinal function, and right ventricular fractional area change (a load-dependent index of right ventricular inlet function). To distinguish between genuine right ventricular dysfunction and/or pathological increases in pulmonary vascular load, we will combine systolic pulmonary artery pressure and right ventricular end-systolic area to calculate right ventricular end-systolic pressure-area relation. Peak systolic tricuspid annulus velocity and conventional indices of left ventricular systolic and diastolic function will also be measured at baseline and peak stress according to the standard ABCDE-FGLPR protocol. Right ventricular free wall strain combined with interventricular septum strain will be assessed. Left ventricular function, wall motion score index and E/e' at baseline and peak stress.<br>|
| SETOF Stress Echo in operated Tetralogy of Fallot.<br>The primary aim is to evaluate the feasibility of right ventricular SE in patients with repaired Tetralogy of Fallot. The secondary aim is to assess the presence and amount of right ventricular contractile reserve and its correlation with indices of functional severity (NYHA class, cardiac natriuretic peptides, peak VO2, 6-min walking test, etc.). The tertiary aim is to assess the prognostic value of SE indices for prognostic stratification in the medium and long-term. Patients with repaired Tetralogy of Fallot or Fallot-like pathology evaluated at least 1 year after the last surgical or percutaneous procedure, will be recruited by regional reference centers for congenital heart disease. Additional inclusion criteria are age>10 years, height>140 cm, NYHA class I or II. Data on medical radiation exposure will also be systematically collected. A sample size of about 250 patients is required to detect a significant stress-induced increase in tricuspid annular plane systolic excursion. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>Diagnostic Test: SE Right ventricular function assessment<br>* Right ventricular function will be assessed at baseline and peak stress with variations of tricuspid annular plane systolic excursion, an index of right ventricular longitudinal function, and right ventricular fractional area change (a load-dependent index of right ventricular inlet function). To distinguish between genuine right ventricular dysfunction and/or pathological increases in pulmonary vascular load, we will combine systolic pulmonary artery pressure and right ventricular end-systolic area to calculate right ventricular end-systolic pressure-area relation. Peak systolic tricuspid annulus velocity and conventional indices of left ventricular systolic and diastolic function will also be measured at baseline and peak stress according to the standard ABCDE-FGLPR protocol. Right ventricular free wall strain combined with interventricular septum strain will be assessed. Left ventricular function, wall motion score index and E/e' at baseline and peak stress.<br>|
| Stress Echo for surveillance post-COVID-19 (SECOV).<br>Cardiovascular abnormalities are observed in half of all COVID-19 patients and may range from RWMA to interstitial lung disease with alveolar capillary distress, global contractile dysfunction, coronary microvascular abnormalities and cardiac autonomic dysfunction. In addition, pulmonary hypertension and valves abnormalities are a possible consequence. The primary aim is to assess the feasibility of an integrated ABCDEFG approach in post-COVID 19 patients. Secondary aim is to prevalence of abnormalities of different SE parameters in populations stratified according to severity of COVID-19. Tertiary aim is to assess the prognostic value of individually considered or combined SE indices in prognostic modeling using traditional risk factors and COVID-19 variables. The relevant parameters related to COVID-19 infection will be collected .SE will be performed from 3 months to 3 years after infection. A sample size of 406 patients is required. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>Diagnostic Test: SE Right ventricular function assessment<br>* Right ventricular function will be assessed at baseline and peak stress with variations of tricuspid annular plane systolic excursion, an index of right ventricular longitudinal function, and right ventricular fractional area change (a load-dependent index of right ventricular inlet function). To distinguish between genuine right ventricular dysfunction and/or pathological increases in pulmonary vascular load, we will combine systolic pulmonary artery pressure and right ventricular end-systolic area to calculate right ventricular end-systolic pressure-area relation. Peak systolic tricuspid annulus velocity and conventional indices of left ventricular systolic and diastolic function will also be measured at baseline and peak stress according to the standard ABCDE-FGLPR protocol. Right ventricular free wall strain combined with interventricular septum strain will be assessed. Left ventricular function, wall motion score index and E/e' at baseline and peak stress.<br>|
| RESURGE: Recovery by stress echo of conventionally unfit donor good hearts.<br>The primary aim is to recruit hearts from donation which are currently excluded by conventional criteria as aged hearts in patients > 55 years and ≤ 55 years with multiple risk factors. Secondary aim is to assess outcome in SE-driven transplantation compared to hearts transplanted in the same cardiac surgery centers on the basis of conventional criteria. Tertiary aim is to assess the additional prognostic value of other signs not used for decision-making. These aspects may include diastolic function, preload reserve, coronary microvascular function, and residual innervation of the intrinsic cardiac autonomic system through assessment of HRR in donor heart. In case of donor with age >55 years o ≤ 55 years but with concomitant ≥ 3 risk factors (diabetes, hypertension, smoking, obesity, hypercholesterolemia) or history of cardiac arrest, the protocol will be applied. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE in heart donors<br>* The examination of the heart starts with a resting transthoracic echocardiography. Exclusion criteria are: resting wall motion score index>1.0; ejection fraction <45%; diastolic dysfunction of grade 2 or more; hemodynamically significant (moderate or higher) valve regurgitation or stenosis; severe left ventricular hypertrophy (left ventricular mass index >175 g/m2). A pharmacological SE with dipyridamole (0.84 mg/kg over 6 minutes) is recommended. The diagnostic end-points are stress-induced RWMA and abnormalities in global LVCR. All images will be analyzed as per guidelines similarly to the other projects, with emphasis on wall motion score index and LVCR based on ejection fraction and force. The hearts excluded from donation for RWMA or abnormal LVCR could however be collected for heart valve preparation and evaluated by coronary angiography and by pathological examination according to local facilities.<br>|
| SEMIR- Stress echo in ischemic mitral regurgitation<br>The value of SE testing as an indicator of outcome will be assessed in patients with resting moderate mitral regurgitation (effective regurgitant orifice 0.2-0.39 cm2, and regurgitant volume 30-59 ml) of ischemic origin and angiographically documented CAD, and will enter a regular clinical follow-up program with annotation of cardiovascular and non-cardiovascular endpoints. Patients undergoing CABG with or without mitral repair or PCI with or without mitral valve intervention will be separately analyzed. A sample size of 173 patients per arm (CABG or PCI) is required. The primary hypothesis is that patients with moderate mitral regurgitation worsening of ≥ 1 grade during exercise have worse outcome on medical therapy and greater benefit from valve correction. The secondary hypothesis is that patients with worse SE pre-surgery parameters will have worse prognosis independent of regurgitation severity and treatment (medical therapy or valve repair). | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>Diagnostic Test: SE Right ventricular function assessment<br>* Right ventricular function will be assessed at baseline and peak stress with variations of tricuspid annular plane systolic excursion, an index of right ventricular longitudinal function, and right ventricular fractional area change (a load-dependent index of right ventricular inlet function). To distinguish between genuine right ventricular dysfunction and/or pathological increases in pulmonary vascular load, we will combine systolic pulmonary artery pressure and right ventricular end-systolic area to calculate right ventricular end-systolic pressure-area relation. Peak systolic tricuspid annulus velocity and conventional indices of left ventricular systolic and diastolic function will also be measured at baseline and peak stress according to the standard ABCDE-FGLPR protocol. Right ventricular free wall strain combined with interventricular septum strain will be assessed. Left ventricular function, wall motion score index and E/e' at baseline and peak stress.<br>|
| SEVA: Stress Echocardiography in Valvular Heart Disease<br>SE is recommended in valvular heart disease in patients characterized by a mismatch between resting transthoracic echocardiography findings and symptoms during exercise or activities of daily living: 1. Severe valve disease without symptoms; 2. Non-severe single- or multi-valve disease with symptoms; and 3. Symptomatic valve disease of indeterminate severity in context of low flow. The primary aim is to evaluate the feasibility of ABCDEFG-SE plus L (left atrium), P (pulmonary vascular reserve) and R (right ventricular function) in these patients. The secondary aim is to assess the correlation of each SE parameter with indices of functional severity (NYHA, cardiac natriuretic peptides, peak oxygen consumption, etc.). The tertiary aim is to assess the prognostic value of SE for prognostic stratification in the long-term. A sample size of about 217 patients per sub-group is required to evaluate the tertiary endpoint with 90% power and an alpha error of 5% . | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>Diagnostic Test: SE Right ventricular function assessment<br>* Right ventricular function will be assessed at baseline and peak stress with variations of tricuspid annular plane systolic excursion, an index of right ventricular longitudinal function, and right ventricular fractional area change (a load-dependent index of right ventricular inlet function). To distinguish between genuine right ventricular dysfunction and/or pathological increases in pulmonary vascular load, we will combine systolic pulmonary artery pressure and right ventricular end-systolic area to calculate right ventricular end-systolic pressure-area relation. Peak systolic tricuspid annulus velocity and conventional indices of left ventricular systolic and diastolic function will also be measured at baseline and peak stress according to the standard ABCDE-FGLPR protocol. Right ventricular free wall strain combined with interventricular septum strain will be assessed. Left ventricular function, wall motion score index and E/e' at baseline and peak stress.<br>|
| SESPASM - SE for coronary vasospasm<br>The primary aim is to evaluate the feasibility and safety of hyperventilation and exercise ABCDE-SE in patients with angiographically normal coronary arteries and an intermediate-to-high pre-test probability of coronary vasospasm of epicardial arteries or microvasculature. The secondary aim is to assess the positivity rate of A and D criteria in these patients, compared to standard ECG criteria. The tertiary aim is to assess the prognostic value of the different responses of SE leading to SE-driven therapies. Only patients with strong (Class 1) indication to vasospasm testing according to the recent guidelines will be initially considered. Patients prepared for exercise testing will undergo vasospasm testing in the morning with hyperventilation. If negative or equivocal at 5 minutes after the end of hyperventilation, the patient will start exercise with the usual protocol. A sample size of 513 patients is required with a 5-year follow-up for the composite endpoint. | Diagnostic Test: ABCDE-Stress Echo<br>* Each laboratory will adopt the preferred Echo stress among physical pharmacologic or pacing stress according to guidelines recommendations. Pharmacologic testing will be with dobutamine or vasodilators (dipyridamole, adenosine or regadenoson) according to physician preferences, patients' contraindications, local availability and cost. Pacing stress can be performed with transesophageal or with external permanent pacemaker. A standardized format with the ABCDE protocol will be followedl. Step D is easy with vasodilator, less easy with dobutamine, not easy and less feasible - impossible with (peak or post) treadmill exercise. Our recommendation is to use semi-supine exercise, capturing coronary flow signal in early or intermediate stages when most flow increases and feasibility is still high. When treadmill is used, step D is skipped; if information is deemed important, a vasodilator test can be performed at 30' after the end of exercise focused on CFVR and heart rate response.<br>Diagnostic Test: SE diastolic assessment<br>* The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation, at intermediate load of exercise and/or 1- 2 min after the end of the exercise. We will also assess, at baseline, intermediate load (50 watts) and peak-post stress: end-diastolic left ventricular volume index; end-systolic left ventricular volume index; ejection fraction and both stroke volume and cardiac output (to assess conventional contractile reserve); mitral regurgitation and left ventricular outflow tract obstruction; pulmonary artery systolic pressure; B-lines; right ventricular free wall strain to assess the presence of right ventricular dysfunction; left atrial volume index; peak atrial longitudinal strain; and mitral inflow E velocity and mitral annulus e' tissue Doppler velocity; global longitudinal strain (GLS).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause death | Death from any cause occurring between 5 years after the time of SE enrollment | 5 years | 
| Cardiac death | Death from cardiac cause occurring between 5 years after the time of SE enrollment | 5 years | 
| Diagnosis of Cancer | Diagnosis of cancer of any type occurring between 5 years after the time of SE enrollment | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnosis of Acute Myocardial Infarction | Diagnosi of hospitalization for acute Myocardial infarction occurring between 5 years after the time of SE enrollment | 5 years | 
| Implantable Cardioverter defibrillator implantation | Implantable Cardioverter defibrillator implantation date occurring between 5 years after the time of SE enrollment | 5 years | 
| Coronary percutaneous revascolarization | Coronary percutaneous revascolarization date occurring between 5 years after the time of SE enrollment | 5 years | 
| CABG surgery | CABG surgery date occurring between 5 years after the time of SE enrollment | 5 years | 
| Miectomy procedure | Miectomy procedure date occurring between 5 years after the time of SE enrollment | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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effectiveness, registry, stress echo, sustainability