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Aim To assess the prognostic meaning of HRR during dipyridamole stress echocardiography (DSE) in patients with abnormal chronotropic response to exercise. Methods 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] Results 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 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. Funding Acknowledgement Type of funding sources: None.

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

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 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.

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; p0.0001), 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 (p0.0001). 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.

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 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: NCT 03049995.

Background Left ventricular contractile reserve (LVCR), coronary flow velocity reserve (CFVR), and heart rate reserve (HRR) have recognized independent impact on outcome in heart failure (HF). They all can be simultaneously measured during dipyridamole stress echocardiography (DSE). Aim To assess the value of comprehensive DSE in patients with non-ischemic heart failure. Methods We evaluated 613 patients with HF, no history of coronary artery disease and no inducible regional wall motion abnormalities: 270 patients with preserved (≥50%) ejection fraction; 147 with mid-range (40–49%) ejection fraction; 196 with HF and reduced ( Results Abnormal CFVR, LVCR and HRR occurred in 29%, 44% and 46% of patients, respectively. After a median follow-up time of 20 months (interquartile range 12–32 months), 41 patients died. Annual mortality rate was lowest in patients (n=200) with normal response, and >10-fold higher in patients (n=96) with 3 abnormal criteria: see figure. At multivariable analysis, a reduced HRR (Hazard Ratio = 3.402, 95% Confidence Intervals 1.530–7.565, p=0.003) was the strongest SE independent predictor of all-cause death. Conclusion Abnormal LVCR, CFVR and HRR can be frequently observed during vasodilator SE in HF patients. They target different pathophysiological vulnerabilities (myocardial function, coronary microcirculation and cardiac autonomic system) and are useful for outcome prediction. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Consiglio nazionale delle ricerche - Institute of Clinical Physiology Figure 1

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).

espanolIntroduccion: Existen diversos softwares especializados en el mercado para el almacenamiento electivo de datos de eco estres (EE). El EE de ultima generacion incorpora nuevos parametros ademas de la motilidad parietal. Objetivo: Desarrollar un nuevo software para el almacenamiento de datos e informe de EE. Metodos: Desarrollamos el prototipo de Software Integral de EE (SIEE) con un conjunto minimo de datos que permite la eventual recoleccion estandarizada de datos. El software corre en computadoras con capacidad de trabajo mediana-baja y con los sistemas operativos mas usados (Windows, MAC OS y Linux). Las funciones de exportacion hacia formatos altamente aceptados permiten compartir los datos facilmente. 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 paginas principales se concentran en las 5 fases ABCDE del EE: fase A (motilidad parietal regional); fase B (lineas B con escaneo simplificado de 4 sitios); fase C (reserva contractil con fuerza derivada de la presion arterial sistolica y volumen de fin de sistole; fase D (Doppler de reserva coronaria de la arteria descendente anterior); y fase E (reserva cronotropica derivada del electrocardiograma medida como la razon de frecuencia cardiaca pico/reposo). La ultima pagina resume la informacion ABCDE en un modelo de prediccion de riesgo (tasa de muerte cardiovascular anual, abarcando desde riesgo bajo 3%. Conclusion: El SIEE puede proporcionar una infraestructura adecuada para una aplicacion clinica y de investigacion avanzada, con un formato grafico simple y opcion de informe satisfactoria. Puede representar una solucion intermedia entre la informacion exhaustiva requerida por los estandares cientificos y la prioridad de un flujo de trabajo fluido de actividades relacionadas a la clinica con gran volumen de pacientes. Su validacion en gran escala y la adaptacion de acuerdo a la opinion de los usuarios es necesaria antes de su difusion a demanda. EnglishBackground: Several specialized softwares are commercially available for the elective storage of stress echo (SE) data. State-of-theart 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 values formats. Results: The program prototype data entry requires 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 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.

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.

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) &lt, 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 &lt, 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.

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

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

Background and aims Mitochondrial DNA copy number (mtDNA-CN) depletion has been recently associated with an increased cardiovascular risk. However, the integrity of mtDNA is another key aspect of the energy metabolism and mitochondrial function. We investigated the prognostic role of peripheral blood common mitochondrial deletion (mtDNA4977) and mtDNA-CN on long-term major adverse cardiac events (MACEs) and all-cause mortality in a cohort of patients with coronary artery disease (CAD). Methods Within the Italian GENOCOR (Genetic Mapping for Assessment of Cardiovascular Risk) cohort, we studied 515 patients (450 males, 65 ± 8 years) with known or suspected stable CAD. mtDNA4977 deletion and mtDNA-CN were assessed in peripheral blood using qRT-PCR. Results During a mean follow-up of 4.5 ± 1.1 years, 78 (15%) patients had MACEs (15 cardiac deaths, 17 nonfatal myocardial infarction and 46 coronary revascularizations) and 28 patients died for non-cardiac causes. Patients with high levels of mtDNA4977 deletion (>75th) had increased risk of MACEs (log rank = 7.2, p=0.007) and all-cause mortality (log rank = 5.7, p=0.01) compared with patients with low mtDNA4977 deletion (≤75th). Multivariate Cox regression analysis showed that log mtDNA4977 was a significant predictor of MACEs (HR = 2.17; 95% CI, 1.31–3.59; p=0.003) and all-cause mortality (HR = 2.03; 95% CI: 1.13–3.65, p=0.02). Log mtDNA-CN was not significantly associated with MACEs or all-cause mortality. However, patients with high mtDNA4977 deletion (>75th) and low mtDNA-CN ( Conclusions Mitochondria DNA damage was associated with an increased risk of MACEs and all-cause mortality in patients with stable CAD, confirming the critical role of mitochondrial dysfunction in atherosclerosis.

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.

Various lung ultrasound (LUS) scanning modalities have been proposed for the detection of B-lines, also referred to as ultrasound lung comets , which are an important indication of extravascular lung water at rest and after exercise stress echo (ESE). The aim of our study was to assess the lung water spatial distribution ( comet map ) at rest and after ESE. We performed LUS at rest and immediately after semi-supine ESE in 135 patients (45 women, 90 men; age 62 ± 12 y, resting left ventricular ejection fraction = 41 ± 13%) with known or suspected heart failure or coronary artery disease. B-lines were measured by scanning 28 intercostal spaces (ISs) on the antero-lateral chest, 2nd–5th IS, along with the midaxillary (MA), anterior axillary (AA), mid-clavicular (MC) and parasternal (PS) lines. Complete 28-region, 16-region (3rd and 4th IS), 8-region (3rd IS), 4-region (3rd IS, only AA and MA) and 1-region (left 3rd IS, MA) scans were analyzed. In each space, the B-lines were counted from 0 = black lung to 10 = white lung. Interpretable images were obtained in all spaces (feasibility = 100 %). B-lines (>0 in at least 1 space) were present at ESE in 93 patients (69%) and absent in 42. More B-lines were found in the 3rd IS and along AA and MA lines. The B-line cumulative distribution was symmetric at rest (right/left = 1.10) and asymmetric with left lung predominance during stress (right/left = 0.67). The correlation of per-patient B-line number between 28-S and 16-S (R 2 = 0.9478), 8-S (R 2 = 0.9478) and 4-S scan (R 2 = 0.9146) was excellent, but only good with 1-S (R 2 = 0.8101). The average imaging and online analysis time were 5 s per space. In conclusion, during ESE, the comet map of lung water accumulation follows a predictable spatial pattern with wet spots preferentially aligned with the third IS and along the AA and MA lines. The time-saving 4-region scan is especially convenient during stress, simply dismissing dry regions and focusing on wet regions alone.

Background Stroke volume response during stress is a major determinant of functional status in heart failure and can be measured by two-dimensional (2-D) volumetric stress echocardiography (SE). The present study hypothesis is that SE may identify mechanisms underlying the change in stroke volume by measuring preload reserve through end-diastolic volume (EDV) and left ventricular contractile reserve (LVCR) with systolic blood pressure and end-systolic volume (ESV). Methods We enrolled 4,735 patients (age 63.6 ± 11.3 yrs, 2800 male) referred to SE for known or suspected coronary artery disease (CAD) and/or heart failure (HF) in 21 SE laboratories in 8 countries. In addition to regional wall motion abnormalities (RWMA), force was measured at rest and peak stress as the ratio of systolic blood pressure by cuff sphygmomanometer/ESV by 2D with Simpson's or linear method. Abnormal values of LVCR (peak/rest) based on force were ≤1.10 for dipyridamole (n=1,992 patients) and adenosine (n=18); ≤2.0 for exercise (n=2,087) or dobutamine (n=638). Results Force-based LVCR was obtained in all 4,735 pts. Lack of stroke volume increase during stress was due to either abnormal LVCR and/or blunted preload reserve, and 57 % of patients with abnormal LVCR nevertheless showed increase in stroke volume. Conclusions Volumetric SE is highly feasible with all stresses, and more frequently impaired in presence of ischemic RWMA, absence of viability and reduced coronary flow velocity reserve. It identifies an altered stroke volume response due to reduced preload and/or contractile reserve.

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

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

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

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

OnBehalf Stress Echo 2020 study group of the Italian Society of Cardiovascular Imaging Background Stress echo (SE) risk stratification is based on regional wall motion abnormalities (RWMA). The assessment of global left ventricular contractile reserve (LVCR) based on load-independent Force may refine prognosis. Aim To assess the value of LVCR during SE in predicting outcome Methods From September 2016 to December 2018, we prospectively enrolled 1848 patients (age 63 ± 11 years; 1121 males, 60%) with known or suspected coronary artery disease and/or heart failure evaluated with SE (exercise in 543, dipyridamole in 1184, adenosine in 10, dobutamine in 43) in 9 quality-controlled centers of 6 countries. Force was measured at rest and peak stress as the ratio of systolic blood pressure by cuff sphygmomanometer/end-systolic volume by 2D and biplane Simpson method of disks. When Simpson method was not feasible, apical single plane or linear parasternal methods were used to calculate volumes. Abnormal values of LVCR (peak/ rest) based on force were ≤1.10 for dipyridamole and adenosine; ≤1.61 for exercise or dobutamine. All patients were followed-up for a median of 16 months. Results RWMA and Force-based LVCR were obtained in all pts. Force was 4.24 ± 1.88 mmHg/ml at rest and increased during stress (7.07 ± 4.60 mmHg/ml, p 3 months from SE) myocardial revascularizations. At multivariable analysis, stress-induced RWMA (Hazard Ratio, HR, 2.899, 95% Confidence Intervals, CI: 2.032-4.137, p Conclusion LVCR based on Force is a useful adjunct to RWMA for risk stratification with SE. Abstract P329 Figure. Survival curves and LVCR

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

Background A blunted heart rate (HR) response during dipyridamole myocardial perfusion imaging have been associated with a poor outcome. Aim To assess the value of HR response in patients undergoing high dose dipyridamole stress echocardiography (SE). Methods We retrospectively selected a consecutive sample of 1,622 patients (none with pacemakers or atrial fibrillation), mean age 66±12 years, 431 (27%) on beta-blockers. All underwent high dose (0.84 mg/kg) dipyridamole SE for known or suspected coronary artery disease and/or heart failure from January 1988 to January 2018 in our Cardiology Division. 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. The composite end-point was made of all cause-death, non-fatal myocardial infarction and late (>3 months) symptoms-driven myocardial revascularizations. Results SE was positive for regional wall motion abnormalities (RWMA) in 192 patients (12%). HR increased (rest=70±11 beats/min vs stress= 92±17 beats/min, p Survival curve Conclusion A blunted HRR is a useful non-imaging predictor of adverse events during high dose dipyridamole-SE. It is additive over resting or inducible regional wall motion abnormalities, and unmasks a prognostically meaningful autonomic unbalance. Chronotropic incompetence during dipyridamole SE is a negative prognostic finding, equally important than RWMA.

Background Stress echocardiography (SE) relies on regional wall motion and left ventricular contractile reserve (LVCR) based on force (systolic blood pressure/end-systolic volume). An additional non-imaging parameter based on EKG is the blunted heart rate reserve (HRR) which is a simple marker of altered autonomic balance and is associated with worse prognosis independently of ischemia. Aim To assess the relationship between HRR and LVCR in patients undergoing SE. Methods We enrolled 4707 patients (age 63.6±11.3 yrs, 2800 males) referred to SE for known or suspected coronary artery disease (CAD) and/or heart failure (HF) in 21 SE laboratories in 8 countries. The employed stress was exercise (n=2062), dipyridamole (n=2007) or dobutamine (n=638). We assessed LVCR (stress/rest ratio of force=systolic blood pressure/end-systolic volume, ESV). Stress-specific abnormal cutoff value of LVCR were Results HRR was related to LVCR at cumulative (n=4707; r=0.351; p Conclusion A blunted HRR is a useful non-imaging predictor of abnormal LVCR response during exercise or pharmacological SE. HRR is a simple biomarker of autonomic unbalance of physiologic and potentially prognostic meaning. A “slow heart” during stress (with blunted HRR) is more often a “weak heart”, with blunted increase in force.

Background Current guidelines recommend the use of exercise stress echocardiography (ESE) in patients with unexplained dyspnoea. The methodological standard of ESE was recently reshaped with the quadruple imaging protocol, mainly tested in patients with chest pain. Aim of this study was to define the ESE pattern of response in patients with dyspnoea as the main symptom Methods From the initial population on a 1-year cohort of 604 patients referred in a single center for clinically-driven semi-supine ESE, we selected a subset of 93 consecutive patients (age 63±9 years, 52 females, resting Ejection fraction = 64±7%) with exertional dyspnea (shortness of breath, exertional fatigue or poor exercise capacity). All underwent quadruple imaging ESE: 1- Regional wall motion abnormalities (RWMA, step A) assessment (with wall motion score index, WMSI); 2- B-lines (step B) with simplified 4-site scan, each space scored from 0 = black, to 10= white (positivity criterion: stress score > rest for at least 2 points); 3- Left ventricle contractile reserve (LVCR, step C) assessment with stress/rest ratio of LV force measured as systolic blood pressure/end-systolic volume (positivity criterion: Results Feasibility was 100% for steps A, B and C, and 82% for step D. RWMA were present in 56 patients (60%). Of them, 27 underwent coronary angiography verification, showing significant coronary artery disease in 81%. B-lines positivity occurred in 35 patients (38%), an abnormal LVCR in 63 patients (68%), and a reduced CFVR in 44 pts (55%). At least one positivity criterion was observed in 80 patients (86%). Conclusions Patients with unexplained dyspnea are a reason of referral to ESE, accounting for 15% of contemporary testing. Quadruple imaging is useful to document the origin of dyspnoea as an ischemic equivalent (A positivity) and/or its cardiogenic origin for acute backward failure with pulmonary congestion (B positivity), myocardial function abnormalities (C positivity), and reduction of CFVR of microvascular-epicardial-myocardial origin (D positivity). Dyspnoea of unexplained origin is a multifactorial problem, and a more comprehensive assessment of these patients during ESE expands the clinical potential of the method.

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; χ 2 , 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 P =0.001), diabetes mellitus (HR, 1.78; 95% CI, 1.34–2.37; P 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.

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.

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, p0.0001), either off- or on-β 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.

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 (&lt, 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 &lt, 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. Conclusion: 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.

Background Previous studies have suggested a decline in positivity of stress cardiac imaging, suggesting the need for developing better strategies for test selection to achieve acceptable cost-effectiveness balance. The aim of this retrospective study was to assess the rate of positivity of stress echocardiography (SE) over 27 consecutive years. Methods We assessed the rate of SE positivity in 2007 patients without previous myocardial infarction or coronary revascularization who performed SE in a tertiary care referral center from 1983 to 2009. SE was performed with dipyridamole (1427), dobutamine (136) or exercise (444). Results There was a progressive decline over time in the rate of SE positivity from 42% (1983–1991) to 22% (2001–2009), with a relative increase of patients with low pre-test probability of disease (from 5% to 27%). The percentage of patients studied with SE under anti-ischemic therapy increased markedly (from 8% in the first to 61% in the last nine years). Conclusion Over 27 consecutive years, we observed a steady decline in SE positivity rate (with >5-fold increase of low probability patients), with almost 8-fold increase in anti-ischemic therapy at testing. We probably need refined criteria of referral for testing and/or better ways to titrate the negative response beyond wall motion abnormalities during SE.

Aim: To assess gender differences in uric acid (UA) as predictor for hard events (HE, mortality and nonfatal myocardial infarction) in a large cohort of patients referred for coronary angiography. Design & patients: 3020 inpatients (2177 males, age: 68 ± 9 years, mean ± SD) were retrospectively studied, collecting data from the Institute electronic databank which included demographic, clinical, instrumental and follow-up data. Results: Although the Kaplan–Meier survival estimates showed a significantly worst outcome in female patients, high UA did not remained a significant predictor for HE after adjustment. Moreover, UA correlated with antioxidant capacity in both sexes. Conclusion: Hyperuricemia was not an independent risk for HE, and being correlated with antioxidant capacity, its elevation appears more likely compensatory than causative for HE.

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 ± 9 years) with angiographically documented CAD. A total of 443 healthy controls (262 males, 56 ± 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.