Pulmonary Congestion During Exercise Stress Echocardiography in Ischemic and Heart Failure Patients.

BACKGROUND: Lung ultrasound detects pulmonary congestion as B-lines at rest, and more frequently, during exercise stress echocardiography (ESE). METHODS: We performed ESE plus lung ultrasound (4-site simplified scan) in 4392 subjects referred for semi-supine bike ESE in 24 certified centers in 9 countries. B-line score ranged from 0 (normal) to 40 (severely abnormal). Five different populations were evaluated: control subjects (n=103); chronic coronary syndromes (n=3701); heart failure with reduced ejection fraction (n=395); heart failure with preserved ejection fraction (n=70); ischemic mitral regurgitation ≥ moderate at rest (n=123). In a subset of 2478 patients, follow-up information was available. RESULTS: During ESE, B-lines increased in all study groups except controls. Age, hypertension, abnormal ejection fraction, peak wall motion score index, and abnormal heart rate reserve were associated with B-lines in multivariable regression analysis. Stress B lines (hazard ratio, 2.179 [95% CI, 1.015-4.680]; P=0.046) and ejection fraction <50% (hazard ratio, 2.942 [95% CI, 1.268-6.822]; P=0.012) were independent predictors of all-cause death (n=29 after a median follow-up of 29 months). CONCLUSIONS: B-lines identify the pulmonary congestion phenotype at rest, and more frequently, during ESE in ischemic and heart failure patients. Stress B-lines may help to refine risk stratification in these patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03049995.

Additional prognostic value of heart rate reserve over left ventricular contractile reserve and coronary flow velocity reserve in diabetic patients with negative vasodilator stress echocardiography by regional wall motion criteria.

AIMS: In diabetic patients, a blunted left ventricular contractile reserve (LVCR) and/or a reduced coronary flow velocity reserve (CFVR) identify patients at higher risk in spite of stress echocardiography (SE) negative for ischaemia. Cardiac autonomic dysfunction contributes to risk profile independently of inducible ischaemia and can be assessed with heart rate reserve (HRR). We sought to assess the added prognostic value of HRR to LVCR and CFVR in diabetic patients with non-ischaemic SE. METHODS AND RESULTS: Six-hundred and thirty-six diabetic patients (age 68 ± 9 years, 396 men, ejection fraction 58 ± 10%) with sinus rhythm on resting electrocardiogram underwent dipyridamole SE in a two-centre prospective study with assessment of wall motion, force-based LVCR (stress/rest ratio, normal value > 1.1), CFVR of the left anterior descending coronary artery (stress/rest ratio, normal value >2.0), and HRR (stress/rest ratio, normal value >1.22). All-cause death was the only considered endpoint. During a median follow-up of 39 months, 94 (15%) patients died. Independent predictors of death were abnormal CFVR [hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.0-2.52, P = 0.05], reduced LVCR (HR 1.76, 95% CI 1.15-2.69, P = 0.009), and blunted HRR (HR 1.92, 95% CI 1.24-2.96, P = 0.003). Eight-year death rate was 9% for patients with triple negativity (n = 252; 40%), 18% for those with single positivity (n = 216; 34%), 36% with double positivity (n = 124; 19%), and 64% for triple positivity (n = 44; 7%) (P < 0.0001). CONCLUSION: Diabetic patients with dipyridamole SE negative for ischaemia still may have a significant risk in presence of an abnormal LVCR and/or CFVR and/or HRR, which assess the underlying myocardial, microvascular, and cardiac autonomic dysfunction. CLINICAL TRIALS: Gov Identifier NCT 030.49995.

Prognostic value of stress echocardiography assessed by the ABCDE protocol.

AIM: The aim of this study was to assess the prognostic value of ABCDE-SE in a prospective, large scale, multicentre, international, effectiveness study. Stress echocardiography (SE) was recently upgraded to the ABCDE protocol: step A, regional wall motion abnormalities; step B, B lines; step C, left ventricular contractile reserve; step D, Doppler-based coronary flow velocity reserve in left anterior descending coronary artery; and step E, electrocardiogram-based heart rate reserve. METHODS AND RESULTS: From July 2016 to November 2020, we enrolled 3574 all-comers (age 65 ± 11 years, 2070 males, 58%; ejection fraction 60 ± 10%) with known or suspected chronic coronary syndromes referred from 13 certified laboratories. All patients underwent clinically indicated ABCDE-SE. The employed stress modality was exercise (n = 952, with semi-supine bike, n = 887, or treadmill, n = 65 with adenosine for step D) or pharmacological stress (n = 2622, with vasodilator, n = 2151; or dobutamine, n = 471). SE response ranged from score 0 (all steps normal) to score 5 (all steps abnormal). All-cause death was the only endpoint. Rate of abnormal results was 16% for A, 30% for B, 36% for C, 28% for D, and 37% for E steps. During a median follow-up of 21 months (interquartile range: 13-36), 73 deaths occurred. Global X2 was 49.5 considering clinical variables, 50.7 after step A only (P = NS (not significant)) and 80.6 after B-E steps (P < 0.001 vs. step A). Annual mortality rate ranged from 0.4% person-year for score 0 up to 2.7% person-year for score 5. CONCLUSION: ABCDE-SE allows an effective prediction of survival in patients with chronic coronary syndromes.

Coronary Flow, Left Ventricular Contractile and Heart Rate Reserve in Non-Ischemic Heart Failure.

Background: Left ventricular contractile reserve (LVCR), coronary flow velocity reserve (CFVR), and heart rate reserve (HRR) affect outcome in heart failure (HF). They can be simultaneously measured during dipyridamole stress echocardiography (DSE). Aim: To assess the value of comprehensive DSE in patients with non-ischemic HF. Methods: We evaluated 610 patients with HF, no history of coronary artery disease, and no inducible regional wall motion abnormalities: 270 patients with preserved ejection fraction (≥50%), 146 patients with mid-range ejection fraction (40-49%), and 194 patients with reduced ejection fraction (<40%). All underwent DSE (0.84 mg/kg in 6') in 7 accredited laboratories. We measured LVCR (abnormal value ≤ 1.1), CFVR in left anterior descending artery (abnormal value: ≤2.0), and HRR (peak/rest heart rate; abnormal value: ≤1.22). All patients were followed up. Results: Abnormal CFVR, LVCR, and HRR occurred in 29%, 45%, and 47% of patients, respectively (p < 0.001). After a median follow-up time of 20 months (interquartile range: 12-32 months), 113 hard events occurred in 105 patients with 41 deaths, 8 myocardial infarctions, 61 admissions for acute HF, and 3 strokes. The annual mortality rates were 0.8% in 200 patients with none abnormal criteria, 1.8% in 184 patients with 1 abnormal criterion, 7.1% in 130 patients with 2 abnormal criteria, 7.5% in 96 patients with 3 abnormal criteria. Conclusions: Abnormal LVCR, CFVR, and HRR were frequent during DSE in non-ischemic HF patients. They target different pathophysiological vulnerabilities (myocardial function, coronary microcirculation, and cardiac autonomic balance) and are useful for outcome prediction.

Hemodynamic Heterogeneity of Reduced Cardiac Reserve Unmasked by Volumetric Exercise Echocardiography.

BACKGROUND: Two-dimensional volumetric exercise stress echocardiography (ESE) provides an integrated view of left ventricular (LV) preload reserve through end-diastolic volume (EDV) and LV contractile reserve (LVCR) through end-systolic volume (ESV) changes. PURPOSE: To assess the dependence of cardiac reserve upon LVCR, EDV, and heart rate (HR) during ESE. METHODS: We prospectively performed semi-supine bicycle or treadmill ESE in 1344 patients (age 59.8 ± 11.4 years; ejection fraction = 63 ± 8%) referred for known or suspected coronary artery disease. All patients had negative ESE by wall motion criteria. EDV and ESV were measured by biplane Simpson rule with 2-dimensional echocardiography. Cardiac index reserve was identified by peak-rest value. LVCR was the stress-rest ratio of force (systolic blood pressure by cuff sphygmomanometer/ESV, abnormal values ≤2.0). Preload reserve was defined by an increase in EDV. Cardiac index was calculated as stroke volume index * HR (by EKG). HR reserve (stress/rest ratio) <1.85 identified chronotropic incompetence. RESULTS: Of the 1344 patients, 448 were in the lowest tertile of cardiac index reserve with stress. Of them, 303 (67.6%) achieved HR reserve <1.85; 252 (56.3%) had an abnormal LVCR and 341 (76.1%) a reduction of preload reserve, with 446 patients (99.6%) showing ≥1 abnormality. At binary logistic regression analysis, reduced preload reserve (odds ratio [OR]: 5.610; 95% confidence intervals [CI]: 4.025 to 7.821), chronotropic incompetence (OR: 3.923, 95% CI: 2.915 to 5.279), and abnormal LVCR (OR: 1.579; 95% CI: 1.105 to 2.259) were independently associated with lowest tertile of cardiac index reserve at peak stress. CONCLUSIONS: Heart rate assessment and volumetric echocardiography during ESE identify the heterogeneity of hemodynamic phenotypes of impaired chronotropic, preload or LVCR underlying a reduced cardiac reserve.

Prognostic Value of Heart Rate Reserve during Dipyridamole Stress Echocardiography in Patients With Abnormal Chronotropic Response to Exercise.

Heart rate reserve (HRR) during physical or pharmacological stress is a sign of cardiac autonomic function and sympathetic reserve, but it can be reduced during exercise for confounders such as poor motivation, drugs or physical fitness. In this study we sought to assess the prognostic meaning of HRR during dipyridamole stress echocardiography (DSE) in patients with abnormal chronotropic response to exercise. From 2004 to 2019, we prospectively acquired and retrospectively analyzed 379 patients (age 62 ± 11 years; ejection fraction 60 ± 5%) with suspected (n = 243) or known (n = 136) chronic coronary syndromes, referred to DSE for chronotropic incompetence during upright bicycle exercise-electrocardiography test defined as HRR used [(peak HR - rest HR) / (220 - age) - rest HR] ≤80% in patients off and ≤62% in patients on beta-blockers. All patients were in sinus rhythm and underwent DSE (0.84 mg/kg) within 3 months of exercise testing. During DSE, age-independent HRR (peak/rest HR) ≤1.22 was considered abnormal. All patients were followed-up. All-cause death was the only outcome measure. HRR during DSE was normal in 275 (73%) and abnormal in 104 patients (27%). During a follow-up of 9.0 ± 4.2 years, 67 patients (18%) died. The 15-year mortality rate was 23% in patients with normal and 61% in patients with abnormal HRR (p < 0.0001). At multivariable analysis a blunted HRR during DSE was an independent predictor of outcome (hazard ratio 2.01, 95% confidence intervals 1.23-3.29; p = 0.005) with age and diabetes, while neither inducible ischemia nor ongoing beta-blocker therapy were significant predictors. In conclusion, a blunted HRR during DSE predicts a worse survival in patients with chronotropic incompetence during exercise test. HRR during DSE is an appealingly simple biomarker of cardiac autonomic dysfunction independent of imaging, exercise and beta-blocker therapy.

Prognostic Value of Reduced Heart Rate Reserve during Exercise in Hypertrophic Cardiomyopathy.

BACKGROUND: Sympathetic dysfunction can be evaluated by heart rate reserve (HRR) with exercise test. OBJECTIVES: To determine the value of HRR in predicting outcome of patients with hypertrophic cardiomyopathy (HCM). METHODS: We enrolled 917 HCM patients (age = 49 ± 15 years, 516 men) assessed with exercise stress echocardiography (ESE) in 11 centres. ESE modality was semi-supine bicycle in 51 patients (6%), upright bicycle in 476 (52%), and treadmill in 390 (42%). During ESE, we assessed left ventricular outflow tract obstruction (LVOTO), stress-induced new regional wall motion abnormalities (RWMA), and HRR (peak/rest heart rate, HR). By selection, all patients completed the follow-up. Mortality was the predetermined outcome measure Results: During ESE, RWMA occurred in 22 patients (2.4%) and LVOTO (≥50 mmHg) in 281 (30.4%). HRR was 1.90 ± 0.40 (lowest quartile ≤ 1.61, highest quartile > 2.13). Higher resting heart rate (odds ratio 1.027, 95% CI: 1.018-1.036, p < 0.001), older age (odds ratio 1.021, 95% CI: 1.009-1.033, p < 0.001), lower exercise tolerance (mets, odds ratio 0.761, 95% CI: 0.708-0.817, p < 0.001) and resting LVOTO (odds ratio 1.504, 95% CI: 1.043-2.170, p = 0.029) predicted a reduced HRR. During a median follow-up of 89 months (interquartile range: 36-145 months), 90 all-cause deaths occurred. At multivariable analysis, lowest quartile HRR (Hazard ratio 2.354, 95% CI 1.116-4.968 p = 0.025) and RWMA (Hazard ratio 3.279, 95% CI 1.441-7.461 p = 0.004) independently predicted death, in addition to age (Hazard ratio 1.064, 95% CI 1.043-1.085 p < 0.001) and maximal wall thickness (Hazard ratio 1.081, 95% CI 1.037-1.128, p < 0.001). CONCLUSIONS: A blunted HRR during ESE predicts survival independently of RWMA in HCM patients.

Reduced Sympathetic Reserve Detectable by Heart Rate Response after Dipyridamole in Anginal Patients with Normal Coronary Arteries.

Background. Patients with ischemia and normal coronary arteries (INOCA) may show abnormal cardiac sympathetic function, which could be unmasked as a reduced heart rate reserve (HRR) during dipyridamole stress echocardiography (SE). Objectives. To assess whether HRR during dipyridamole SE predicts outcome. Methods. Dipyridamole SE was performed in 292 patients with INOCA. HRR was measured as peak/rest heart rate and considered abnormal when ≤1.22 (≤1.17 in presence of permanent atrial fibrillation). All-cause death was the only endpoint. Results. HRR during SE was normal in 183 (63%) and abnormal in 109 patients (37%). During a follow-up of 10.4 ± 5.5 years, 89 patients (30%) died. The 15-year mortality rate was 27% in patients with normal and 54% in those with abnormal HRR (p < 0.0001). In a multivariable analysis, a blunted HRR during SE was an independent predictor of outcome (hazard ratio 1.86, 95% confidence intervals 1.20-2.88; p = 0.006) outperforming inducible ischemia. Conclusions. A blunted HRR during dipyridamole SE predicts a worse survival in INOCA patients, independent of inducible ischemia.

Feasibility and functional correlates of left atrial volume changes during stress echocardiography in chronic coronary syndromes.

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

Prognostic Value of Heart Rate Reserve in Patients with Permanent Atrial Fibrillation during Dipyridamole Stress Echocardiography.

In patients in sinus rhythm, a blunted heart rate reserve (HRR) during dipyridamole stress echocardiography (SE) is a prognostically unfavorable sign of cardiac autonomic dysfunction. In this study we sought to assess the prognostic meaning of HRR in patients with permanent atrial fibrillation (AF). The study population was made by 301 patients (176 men, age 73 ± 8 years) with suspected (n = 200) or known (n = 101) coronary artery disease and permanent AF who underwent high-dose dipyridamole SE. HRR was calculated on an average of 5 consecutive beats as the peak/rest ratio of HR from 12-lead EKG. During a median follow-up time of 77 months (first quartile 44, third quartile 115 months), 111 (37%) patients died. Receiver operating characteristics analysis identified HRR ≤1.17 as the best predictor of mortality. At multivariable analysis, HRR ≤1.17 (HR 1.75, 95% CI 1.17 to 2.62; p = 0.006) independently predicted mortality together with age (HR 1.09, 95% CI 1.06 to 1.13; p <0.0001), rest wall motion score index (HR 1.69, 95% CI 1.01 to 2.83; p = 0.04), and systemic hypertension (HR 1.76, 95% CI 1.06 to 3.00; p = 0.04). The annual mortality was 5.1% in the overall population, 7.0% in the 140 (46%) patients with abnormal HRR and 3.5% in the 161 (54%) patients with normal HRR. The 8-year mortality was 48% in patients with abnormal HRR and 18% in those with normal HRR (p <0.0001). In conclusion, patients with suspected or known coronary artery disease with permanent AF with a blunted HRR have an increased mortality. HRR outweighs inducible ischemia for prediction of survival. The assessment of HRR should become an integral part of dipyridamole SE reading also in AF.

Prognostic value of heart rate reserve is additive to coronary flow velocity reserve during dipyridamole stress echocardiography.

BACKGROUND: During dipyridamole stress echocardiography (SE), a blunted heart rate reserve (HRR) is a prognostically unfavourable sign of cardiac autonomic dysfunction. AIM: To assess the prognostic meaning of HRR and coronary flow velocity reserve (CFVR). METHODS: The study group comprised 2149 patients (1236 men; mean age 66±12 years) with suspected (n=1280) or known (n=869) coronary artery disease and without inducible regional wall motion abnormalities (RWMA) during dipyridamole SE (0.84mg/kg in 6min). We assessed CFVR of the left anterior descending artery with pulsed-wave Doppler as the ratio between hyperaemic peak and basal peak diastolic flow velocities (abnormal value≤2.0). HRR was calculated as the peak/resting ratio of heart rate from a 12-lead electrocardiogram (abnormal value≤1.22). All patients were followed up. RESULTS: CFVR and HRR were abnormal in 520 (24%) and 670 (31%) patients, respectively. There was a positive linear correlation between CFVR and HRR (r=0.30; P<0.0001). During a median follow-up of 22 months (1st quartile 12 months, 3rd quartile 35 months), 75 (6%) patients died. The annual mortality was 1.6% in the overall population, 0.5% in the 1224 (57%) patients with normal CFVR and HRR, 1.7% in the 405 (19%) patients with abnormal HRR only, 3.6% in the 255 (12%) patients with abnormal CFVR only, and 6.2% in the 265 (12%) patients with abnormal CFVR and HRR. CONCLUSIONS: HRR is weakly related to CFVR, and a blunted HRR usefully complements RWMA and CFVR for prediction of outcome with dipyridamole SE. The patient without inducible RWMA is still at intermediate risk, but the risk is low with concomitant preserved CFVR, and very low with concomitant normal HRR.

Exercise stress echocardiography with ABCDE protocol in unexplained dyspnoea.

Current guidelines recommend the use of exercise stress echocardiography (ESE) in patients with unexplained dyspnoea. SE was recently reshaped with the ABCDE protocol: A for asynergy, B for B-lines (4-site simplified scan), C for contractile reserve based on force, D for Doppler-based coronary flow velocity reserve (CFVR) in left anterior descending coronary artery; and E for EKG-based heart rate reserve (HRR, defined as peak/rest HR < 1.62). Aim of the study was to define the ESE response in patients with dyspnoea as the main symptom. From the initial population of patients referred in 2018 in a single center for semi-supine ESE, we selected two groups (without history of previous myocardial infarction or coronary revascularization) on the basis of the main presenting symptom: dyspnoea (Group 1, n = 100, 62 men, 63 ± 10 years) or chest pain (Group 2, n = 100, 58 men, age 61 ± 8 years). All underwent ESE with ABCDE protocol. Success rate was 100% for steps A, B, C, E, and 88% for step D. Positivity for A criterion occurred in 56 patients of Group 1 and 24 of Group 2 (p < 0.0001). B-lines positivity (stress > rest for ≥ 2 points) occurred in 40 patients of Group 1 and 28 of Group 2 (p = 0.07). LVCR positivity (< 2.0) occurred in 60 patients of Group 1 and 42 of Group 2 (p < 0.05). A reduced CFVR occurred in 56 of Group 1 and 22 of Group 2 (p < 0.0001). A blunted HRR was present in 44 patients of Group 1 and 22 of Group 2 (p < 0.001). In conclusion, in patients with unexplained dyspnoea, SE with ABCDE protocol is useful to document the cardiac origin of dyspnoea with a comprehensive assessment focused not only on ischemia (A) but also pulmonary congestion (B), myocardial scar or necrosis (C), coronary microvascular dysfunction (D) or chronotropic incompetence (E).

Anatomical and functional coronary imaging to predict long-term outcome in patients with suspected coronary artery disease: the EVINCI-outcome study.

AIMS: To investigate the prognostic relevance of coronary anatomy, coronary function, and early revascularization in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: From March 2009 to June 2012, 430 patients with suspected CAD (61 ± 9 years, 62% men) underwent coronary anatomical imaging by computed tomography coronary angiography (CTCA) and coronary functional imaging followed by invasive coronary angiography (ICA) if at least one non-invasive test was abnormal. Obstructive CAD was documented by ICA in 119 patients and 90 were revascularized within 90 days of enrolment. Core laboratory analysis showed that 134 patients had obstructive CAD by CTCA (>50% stenosis in major coronary vessels) and 79 significant ischaemia by functional imaging [>10% left ventricular (LV) myocardium]. Over mean follow-up of 4.4 years, major adverse events (AEs) (all-cause death, non-fatal myocardial infarction, or hospital admission for unstable angina or heart failure) or AEs plus late revascularization (LR) occurred in 40 (9.3%) and 58 (13.5%) patients, respectively. Obstructive CAD at CTCA was the only independent imaging predictor of AEs [hazard ratio (HR) 3.2, 95% confidence interval (CI) 1.10-9.30; P = 0.033] and AEs plus LR (HR 4.3, 95% CI 1.56-11.81; P = 0.005). Patients with CAD in whom early revascularization was performed in the presence of ischaemia and deferred in its absence had fewer AEs, similar to patients without CAD (HR 2.0, 95% CI 0.71-5.51; P = 0.195). CONCLUSION: Obstructive CAD imaged by CTCA is an independent predictor of clinical outcome. Early management of CAD targeted to the combined anatomical and functional disease phenotype improves clinical outcome.

Functional, Anatomical, and Prognostic Correlates of Coronary Flow Velocity Reserve During Stress Echocardiography.

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

Software integral de eco estrés para protocolo ABCDE de última generación / Stress Echo Comprehensive Software (SECS) for State-of-the-art ABCDE Protocol

RESUMEN Introducción: Existen diversos softwares especializados en el mercado para el almacenamiento electivo de datos de eco estrés (EE). El EE de última generación incorpora nuevos parámetros además de la motilidad parietal. Objetivo: Desarrollar un nuevo software para el almacenamiento de datos e informe de EE. Métodos: Desarrollamos el prototipo de Software Integral de EE (SIEE) con un conjunto mínimo de datos que permite la eventual recolección estandarizada de datos. El software corre en computadoras con capacidad de trabajo mediana-baja y con los sistemas operativos más usados (Windows, MAC OS y Linux). Las funciones de exportación hacia formatos altamente aceptados permiten compartir los datos fácilmente. El software es capaz de generar un informe personalizado que se puede expandir en PDF y en formatos de valores separados por comas. Resultados: El ingreso de datos en el programa prototipo requiere menos de 2 minutos por estudio. Las páginas principales se concentran en las 5 fases ABCDE del EE: fase A (motilidad parietal regional); fase B (líneas B con escaneo simplificado de 4 sitios); fase C (reserva contráctil con fuerza derivada de la presión arterial sistólica y volumen de fin de sístole; fase D (Doppler de reserva coronaria de la arteria descendente anterior); y fase E (reserva cronotrópica derivada del electrocardiograma medida como la razón de frecuencia cardíaca pico/reposo). La última página resume la información ABCDE en un modelo de predicción de riesgo (tasa de muerte cardiovascular anual, abarcando desde riesgo bajo <1% hasta riego alto >3%. Conclusión: El SIEE puede proporcionar una infraestructura adecuada para una aplicación clínica y de investigación avanzada, con un formato gráfico simple y opción de informe satisfactoria. Puede representar una solución intermedia entre la información exhaustiva requerida por los estándares científicos y la prioridad de un flujo de trabajo fluido de actividades relacionadas a la clínica con gran volumen de pacientes. Su validación en gran escala y la adaptación de acuerdo a la opinión de los usuarios es necesaria antes de su difusión a demanda.

ABSTRACT Background: Several specialized softwares are commercially available for the elective storage of stress echo (SE) data. State-of-the-art SE is based upon novel parameters in addition to regional wall motion. Objective: To develop a novel software for SE data storage and reporting. Methods: We developed the prototype of a SE Comprehensive Software (SECS) with a minimum data set eventually allowing standardized collection of data. The software runs with medium-low performance computers as well as with the most popular operating systems (Windows, MAC OS and Linux). The export functions towards widely accepted formats allow easy data sharing. The software is able to generate a customized report which can be expanded in PDF and comma-separated value formats. Results: The program prototype data entry requires <2 min per study. The main pages focus on the 5 steps of ABCDE-SE: step A (regional wall motion); step B (B-lines with 4-site simplified scan); step C (contractile reserve with force derived from systolic blood pressure and end-systolic volume); step D (Doppler-based coronary flow velocity reserve in left anterior descending coronary artery); step E (EKG-based chronotropic reserve measured as peak/rest heart rate). The final page graphically summarizes the ABCDE information in a risk prediction model (cardiac death rate per year, from low risk <1% to high risk >3 %). Conclusion: SECS may provide a suitable infrastructure for an advanced clinical and research application, with simple graphic format and convenient reporting option. It may represent a trade-off between exhaustive information required by scientific standards and smooth workflow priority of busy, high volume, clinically-driven activities. Large scale validation and adaptation from users' feedback is necessary prior to dissemination on demand.

Usefulness of Blunted Heart Rate Reserve as an Imaging-Independent Prognostic Predictor During Dipyridamole Stress Echocardiography.

A blunted heart rate (HR) response during dipyridamole myocardial perfusion imaging has been associated with a poor outcome. To assess the value of HR response in patients who underwent high-dose dipyridamole stress echocardiography (SE), we retrospectively selected a sample of 3,059 patients (none with pacemakers or atrial fibrillation; mean age 66 ± 11 years). All underwent high-dose (0.84 mg/kg) dipyridamole SE for evaluation of known or suspected coronary artery disease and/or heart failure in 2 laboratories of Pisa-IFC and Lucca. HR (with 12-lead ECG) was obtained each minute and recorded at rest and peak stress. HR reserve (HRR) was calculated as the peak/rest HR ratio. All patients were followed up. Patients were randomly divided into the modeling and validation group of equal size. During a median follow-up time of 1,004 days, 321 hard events occurred: 231 deaths and 90 nonfatal myocardial infarctions. HRR ≤ 1.22 identified by receiver operating characteristic analysis in the modeling group was an independent predictor of infarction-free survival in the modeling (hazard ratio 1.83, 95% confidence interval [CI] 1.30 to 2.60, p = 0.001), in the validation (hazard ratio 1.47, 95% CI 1.08 to 2.01, p = 0.02), and in the overall group (hazard ratio 1.60, 95% CI 1.27 to 2.02, p <0.0001), either off- or on-ß blockers. Five-year event rate increased from 8% to 24 % from the highest (≥1.41) to the lowest (≤1.14) HRR quartile. In conclusion, blunted HRR is a useful nonimaging predictor of adverse events during high-dose dipyridamole SE, independent of inducible ischemia, and beta-blocker therapy.

Influence of genetic polymorphisms in DICER and XPO5 genes on the risk of coronary artery disease and circulating levels of vascular miRNAs.

INTRODUCTION: Single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) machinery genes may affect the regulatory capacity of miRNAs by impacting their biogenesis. The aim of the study was to analyze the association between SNPs in two key genes (DICER rs1057035T>C and XPO5 rs11077A>C) and coronary artery disease (CAD) risk as well as to examine their effects on circulating levels of vascular miRNAs. MATERIALS AND METHODS: Within the Italian GENOCOR cohort, we studied a cohort of 557 patients (502 males, 57 ±â€¯9 years) with angiographically documented CAD. A total of 443 healthy controls (262 males, 56 ±â€¯12 years) was also enrolled. Genotyping was determined by using a TaqMan®SNP genotyping assay. Analysis of miR-132 and miR-140-3p was assessed in a subset of 70 CAD patients by using qRT-PCR. RESULTS: There were statistically significant differences between CAD patients and healthy controls in the distribution of both DICER and XPO5 genotypes (p = 0.03 and p = 0.02, respectively). Multivariate analysis showed a significantly decreased risk of CAD by 50% in patients with DICER rs105703CC genotype as compared to TC heterozygote and TT homozygote patients (ORadjusted = 0.50; CI: 0.30-0.83, p = 0.007). In a recessive model, the XPO5 rs11077CC genotype was associated with a 32% reduced risk of CAD (ORadjusted = 0.68; CI: 0.30-0.99 p = 0.047). XPO5 rs11077CC genotype was significantly associated with higher levels of both miRNA-132 (p = 0.04) and miRNA-140-3p (p = 0.03). CONCLUSIONS: Genetic polymorphisms in DICER and XPO5 genes are associated with a decreased risk of CAD, probably by impacting expression levels of vascular and cardiac-specific miRNAs. Further studies are needed to better elucidate the biological relevance of both variants in CAD development.

Apparent Declining Prognostic Value of a Negative Stress Echocardiography Based on Regional Wall Motion Abnormalities in Patients With Normal Resting Left Ventricular Function Due to the Changing Referral Profile of the Population Under Study.

Background Cardiology guidelines identify the low-risk response during stress echocardiography as the absence of regional wall motion abnormalities. Methods From 1983 to 2016, we enrolled 5817 patients (age 63±12 years; 2830 males) with suspected coronary artery disease, normal regional, and global left ventricular function at rest and during stress (exercise in 692, dipyridamole in 4291, and dobutamine in 834). Based on timing of enrollment, 4 groups were identified in chronological order of recruitment: years 1983 to 1989, group 1 (n=211); years 1990 to 1999, group 2 (n=1491); years 2000 to 2009, group 3 (n=3285); and years 2010 to 2016, group 4 (n=830). Results There were 240 (4%) events (119 deaths and 121 infarctions) in the follow-up. At 1-year follow-up, the event rate was 0.5% (95% CI, 0.05-0.95), 1.5% (95% CI, -1.18 to 1.82), 1.9% (95% CI, 1.63-2.17), and 1.7% (95% CI, 1.01-2.39; χ2, 9.0; P=0.03) in groups 1 to 4, respectively. At multivariable Cox analysis, independent predictors of future events were age (hazard ratio (HR), 1.05; 95% CI, 1.04-1.07; P<0.0001), male sex (HR, 1.57; 95% CI, 1.20-2.04; P=0.001), diabetes mellitus (HR, 1.78; 95% CI, 1.34-2.37; P<0.0001), smoking habit (HR, 1.40; 95% CI, 1.05-1.85; P=0.02), and ongoing anti-ischemic therapy (HR, 1.50; 95% CI, 1.15-1.97; P=0.003) Conclusions Over the past 3 decades, we observed a progressive decline in the prognostic value of a negative test based on regional wall motion abnormalities, likely reflecting both an increase in risk in patients, as well as a potential decrease in test performance due to concomitant anti-ischemic therapy.

Entrenamiento por etapas basado en la web: el camino hacia el Eco Estrés 2020 / Multi-step Web-based Training: the Road to Stress Echo 2020

RESUMEN Introducción: Una plataforma de entrenamiento estandarizada ayuda a armonizar la lectura de la ecocardiografía de estrés (EE) más allá de las anormalidades en la motilidad parietal regional (AMPR) Objetivo: Armonizar los criterios de lectura del EE a través de diferentes laboratorios. Métodos: El laboratorio central preparó para los lectores de ecocardiografía un módulo obligatorio de 5 parámetros basado en la web de 2 horas de duración: AMPR; líneas B, reserva de la velocidad de flujo coronario (RVFC) evaluada mediante la velocidad pico del flujo diastólico en la arteria coronaria descendente anterior; reserva contráctil ventricular izquierda (RCVI, evaluada a partir de mediciones crudas del volumen de fin de sístole, VFS); y presión sistólica de la arteria pulmonar (basada en mediciones crudas de la velocidad del jet de regurgitación tricuspídea, VRT). La prueba de control de calidad consistió en 20 casos seleccionados por el centro coordinador. El umbral de aprobación determinado a priori fue de 18/20 (> 90%) con un coeficiente de correlación intraclase entre el laboratorio coordinador y el lector periférico > 0.90. Resultados: Ochenta y cuatro lectores completaron la certificación para las AMPR, 65 para las líneas B, 30 para la RVFC, 24 para el VFS y 20 para la VRT. El tiempo de lectura medio por intento fue más corto para la VRT (9 ± 4 min), la RVFC (13 ± 6 min) y las líneas B (17 ± 3 min), intermedio para el VFS (24 ± 7 min), y más prolongado para las AMPR (29 ± 12 min, p < 0.01). La tasa de acierto del primer intento fue más alta para la RVFC (85%), intermedia para la VRT (75%) y las líneas B (43%), menor para el VFS (35%) y más baja para las AMPR (28%, p < 0.01). Conclusiones: La plataforma de aprendizaje basada en la web mejora las habilidades de interpretación de imágenes sin necesidad de un equipamiento de imágenes costoso o de estudiar un paciente. El camino hacia la certificación es más largo para las AMPR, intermedio para el VFS y más corto para la VRT, la RVFC y las líneas B.

ABSTRACT Background: A standardized training platform helps to achieve reading harmonization in stress echocardiography (SE) beyond regional wall motion abnormalities (RWMA). Objective: To harmonize SE reading criteria across different laboratories. Methods: The core lab prepared for readers an obligatory 2-hour web-based learning module for 5 parameters: RWMA; B-lines; coronary flow velocity reserve (CFVR) based on peak diastolic flow velocity on the left anterior descending coronary artery; left ventricular contractile reserve (LVCR, from raw measurementis of end-systolic volume, ESV); systolic arterial pulmonary pressure (from raw measurementis of peak tricuspid regurgitant jet velocity, TRV). The quality control test consisted of 20 cases selected by the coordinating center. The a priori determined pass threshold was 18/20 (>90%) with intra-class correla-tion coefficient between the coordinating lab and the peripheral reader >0.90. Resultis: The certification was completed by 84 readers for RWMA, 65 for B-lines, 30 for CFVR, 24 for ESV and 20 for TRV The mean reading time per attempt was shorter for TRV (9±4 min), CFVR (13±6 min) and B-lines (17±3 min), intermedi-ate for ESV (24±7 min), and longer for RWMA (29±12 min, p <0.01). The success rate of the first attempt was higher for CFVR (85%), intermediate for TRV (75%) and B-lines (43 %), lower for ESV (35%) and lowest for RWMA (28 %, p <0.01). Conclusions: A web-based learning platform improves image interpretation skills without need for expensive imaging equip-ment or a patient to scan. The road to certification is longer for RWMA, intermediate for ESV, and shorter for TRV, CFVR and B-lines.