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Since the 2009 publication of the stress echocardiography expert consensus of the European Association of Echocardiography, and after the 2016 advice of the American Society of Echocardiography-European Association of Cardiovascular Imaging for applications beyond coronary artery disease, new information has become available regarding stress echo. Until recently, the assessment of regional wall motion abnormality was the only universally practiced step of stress echo. In the state-of-the-art ABCDE protocol, regional wall motion abnormality remains the main step A, but at the same time, regional perfusion using ultrasound-contrast agents may be assessed. Diastolic function and pulmonary B-lines are assessed in step B; left ventricular contractile and preload reserve with volumetric echocardiography in step C; Doppler-based coronary flow velocity reserve in the left anterior descending coronary artery in step D; and ECG-based heart rate reserve in non-imaging step E. These five biomarkers converge, conceptually and methodologically, in the ABCDE protocol allowing comprehensive risk stratification of the vulnerable patient with chronic coronary syndromes. The present document summarizes current practice guidelines recommendations and training requirements and harmonizes the clinical guidelines of the European Society of Cardiology in many diverse cardiac conditions, from chronic coronary syndromes to valvular heart disease. The continuous refinement of imaging technology and the diffusion of ultrasound-contrast agents improve image quality, feasibility, and reader accuracy in assessing wall motion and perfusion, left ventricular volumes, and coronary flow velocity. Carotid imaging detects pre-obstructive atherosclerosis and improves risk prediction similarly to coronary atherosclerosis. The revolutionary impact of artificial intelligence on echocardiographic image acquisition and analysis makes stress echo more operator-independent and objective. Stress echo has unique features of low cost, versatility, and universal availability. It does not need ionizing radiation exposure and has near-zero carbon dioxide emissions. Stress echo is a convenient and sustainable choice for functional testing within and beyond coronary artery disease., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Current cardiology guidelines assign a class of recommendation 1 for the diagnosis of chest pain to five imaging techniques based on either anatomic (coronary computed tomography angiography) or functional approaches, such as stress single-photon emission tomography, stress positron emission tomography, stress cardiovascular magnetic resonance, and stress echocardiography. The choice is left to the prescribing physician, based on local availability and expertise. However, the five techniques differ substantially in their cost, applicability based on patient characteristics, long-term risk, and environmental impact. The average European immediate cost ranges from 50 to 1000 euros. The radiation exposure ranges from 0 to 500 chest x-rays. The environmental footprint ranges from 3 to 300 kg of carbon dioxide emissions equivalent. The ethical code of the World Medical Association 2021 recommends the responsible use of healthcare money by doctors, with the minimization of potential damage to patients and the environment. The Euratom law 2013/directive 59 reinforces the justification principle and the optimization principle for medical radiation exposures, with the legal responsibility of both the referrer and the practitioner. A small cost, a minimal long-term risk, and a modest carbon emission per examination multiplied by billions of tests per year become an unaffordable economic burden in the short-term, significant population damage to public health over the years, and impacts on climate change in decades. The cardiology community may wish to adopt a more sustainable practice with affordable, radiation-optimized, and carbon-neutral practices for the benefit of patients, physicians, payers, and the planet., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Functional testing with stress echocardiography is based on the detection of regional wall motion abnormality with two-dimensional echocardiography and is embedded in clinical guidelines. Yet, it under-uses the unique versatility of the technique, ideally suited to describe the different functional abnormalities underlying the same wall motion response during stress. Five parameters converge conceptually and methodologically in the state-of-the-art ABCDE protocol, assessing multiple vulnerabilities of the ischemic patient. The five steps of the ABCDE protocol are (1) step A : regional wall motion; (2) step B : B-lines by lung ultrasound assessing extravascular lung water; (3) step C : left ventricular contractile reserve by volumetric two-dimensional echocardiography; (4) step D : coronary flow velocity reserve in mid-distal left anterior descending coronary with pulsed-wave Doppler; and (5) step E : assessment of heart rate reserve with a one-lead electrocardiogram. ABCDE stress echo offers insight into five functional reserves: epicardial flow (A); diastolic (B), contractile (C), coronary microcirculatory (D), and chronotropic reserve (E). The new format is more comprehensive and allows better functional characterization, risk stratification, and personalized tailoring of therapy. ABCDE protocol is an 'ecumenic' and 'omnivorous' functional test, suitable for all stresses and all patients also beyond coronary artery disease. It fits the need for sustainability of the current era in healthcare, since it requires universally available technology, and is low-cost, radiation-free, and nearly carbon-neutral., Competing Interests: Conflict of interest: The authors have no conflicts of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The real effects of the chronic consumption of anabolic-androgenic steroids (AASs) on cardiovascular structures are subjects of intense debate. The aim of the study was to detect by speckle tracking echocardiography (STE) right ventricular (RV) and left ventricular (LV) dysfunction at rest and during exercise stress echocardiography (ESE) in athletes abusing AAS., Methods and Results: One hundred and fifteen top-level competitive bodybuilders were selected (70 males), including 65 athletes misusing AAS for at least 5 years (users), 50 anabolic-free bodybuilders (non-users), compared to 50 age- and sex-matched healthy sedentary controls. Standard Doppler echocardiography, STE analysis, and lung ultrasound at rest and at peak supine-bicycle ESE were performed. Athletes showed increased LV mass index, wall thickness, and RV diameters compared with controls, whereas LV ejection fraction was comparable within the groups. left atrial volume index, LV and RV strain, and LV E/Em were significantly higher in AAS users. Users showed more B-lines during stress (median 4.4 vs. 1.25 in controls and 1.3 in non-users, P < 0.01 vs. users). By multivariable analyses, LV E/Ea (beta coefficient = 0.35, P < 0.01), pulmonary artery systolic pressure (beta = 0.43, P < 0.001) at peak effort and number of weeks of AAS use per year (beta = 0.45, P < 0.001) emerged as the only independent determinants of resting RV lateral wall peak systolic two-dimensional strain. In addition, a close association between resting RV myocardial function and VO2 peak during ESE was evidenced (P < 0.001), with a powerful incremental value with respect to clinical and standard echocardiographic data., Conclusions: In athletes abusing steroids, STE analysis showed an impaired RV systolic deformation, closely associated with reduced functional capacity during physical effort, and-during exercise-more pulmonary congestion., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Coronary collateral circulation exerts protective effects on myocardial ischaemia due to coronary artery disease and can be promoted by exercise with heparin co-administration. Whether this arteriogenetic effect is accompanied by functional improvement of left ventricle during stress and lessening of angina symptoms remains unknown., Aims: To evaluate the anti-ischaemic efficacy of heparin plus exercise in coronary artery disease., Methods: In a prospective, single-centre, randomized, double-blind study we recruited 32 'no-option' patients (27 males; mean age 61 ± 8 years) with stable angina, exercise-induced ischaemia and coronary artery disease not suitable for revascularization. All underwent a two-week cycle of exercise (two exercise sessions per day, five days per week) and were randomized (n = 16 per group) to intravenous placebo (0.9% saline) versus unfractionated heparin (5.000 IU intravenously), 10 min prior to exercise. We assessed Canadian Cardiovascular Society angina class, stress electrocardiogram and echo parameters (wall motion score index) and computed tomography angiography for collaterals., Results: After two-week cycle, Canadian Cardiovascular Society class statistically decreased in both groups (heparin plus exercise group: 2.6 ± 0.7 to 1.9 ± 0.7, p < 0.001, exercise group: 2.4 ± 0.7 to 2.1 ± 0.9, p = 0.046). Only the heparin plus exercise group improved time-to-ST segment depression (before 270, 228-327 s vs. after 339, 280-360 s, p = 0.012) and wall motion score index (before 1.38 ± 0.25 vs. after 1.28 ± 0.18, p = 0.005). By multi-slice computed tomography angiography, collaterals improved in 12/15 (80%) in the heparin plus exercise group versus 2/16 (12.5%) in the exercise group (p < 0.001)., Conclusion: A two-week, 10-test cycle of heparin plus exercise is better than exercise in improving angina class, myocardial ischaemia and collaterals by computed tomography angiography., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Echocardiography can estimate pulmonary arterial pressure (PAP) from tricuspid regurgitation velocity (TRV) or acceleration time (ACT) of pulmonary flow. We assessed the feasibility of TRV and ACT measurements during exercise stress echocardiography (ESE) and their correlation in all stages of ESE., Methods and Results: We performed ESE in 102 subjects [mean age 49 ± 17 years, 50 females, 39 healthy, 30 with cardiovascular risk factors, and 33 with pulmonary hypertension (PH)] referred for the assessment of exercise tolerance and ischaemia exclusion. ESE was performed on cycloergometer with the load increasing by 25 W for each 2 min. Assessment of TRV with continuous wave and ACT with pulsed Doppler were attempted in 306 time points: at rest, peak exercise, and recovery. In 20 PH patients we evaluated the correlations of TRV and ACT with invasively measured PAP. The success rate was 183/306 for TRV and 304/306 for ACT (feasibility: 60 vs. 99%, P < 0.0001). There was a close correlation between TRV and ACT: r = 0.787, P < 0.001 and ACT at peak ≤67 ms showed 94% specificity for elevated systolic PAP detection. Moreover, TRV and ACT at peak exercise reflected better that resting data the invasive systolic PAP and mean PAP with r = 0.76, P = 0.0004 and r = -0.67, P = 0.0018, respectively., Conclusion: ACT is closely correlated with and substantially more feasible than TRV during ESE and inclusion of both parameters (TRACT approach) expands the possibility of PAP assessment, especially at exercise when TRV feasibility is the lowest but correlation with invasive PAP seems to increase., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: Ionizing radiation may lead to mitochondrial DNA (mtDNA) mutations and changes in mtDNA content in cells, major driving mechanisms for carcinogenesis, vascular aging and neurodegeneration. The aim of this study was to investigate the possible induction of common mitochondrial deletion (mtDNA4977) and mtDNA copy number (mtDNA-CN) changes in peripheral blood of personnel working in high-volume cardiac catheterization laboratories (Cath Labs)., Methods: A group of 147 Cath Lab workers (median individual effective dose = 16.8 mSv, for the 41 with lifetime dosimetric record) and 74 unexposed individuals were evaluated. The occupational radiological risk score was computed for each subject on the basis of the length of employment, individual caseload and proximity to the radiation source. mtDNA4977 deletion and mtDNA-CN were assessed by using quantitative real-time polymerase chain reaction., Results: Increased levels of mtDNA4977 deletion were observed in high-exposure Cath Lab workers compared with unexposed individuals ( p < 0.0001). Conversely, mtDNA-CN was significantly greater in the low-exposure workers ( p = 0.003). Occupational radiological risk score was positively correlated with mtDNA4977 deletion (Spearman's r = 0.172, p = 0.03) and inversely correlated with mtDNA-CN (Spearman's r = -0.202, p = 0.01). In multiple regression model, occupational radiological risk score emerged as significant predictor of high levels of mtDNA4977 deletion (ß coefficient = 0.236, p = 0.04)., Conclusion: mtDNA4977 deletion is significantly high in Cath Lab personnel. Beyond the well-recognized nuclear DNA, mtDNA damage might deserve attention as a pathogenetic molecular pathway and a potential therapeutic target of ionizing radiation damage.

Within the framework of the LUST trial (LUng water by Ultra-Sound guided Treatment to prevent death and cardiovascular events in high-risk end-stage renal disease patients), the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis Transplant Association established a central core lab aimed at training and certifying nephrologists and cardiologists participating in this trial. All participants were trained by an expert trainer with an entirely web-based programme. Thirty nephrologists and 14 cardiologists successfully completed the training. At the end of training, a set of 47 lung ultrasound (US) videos was provided to trainees who were asked to estimate the number of B-lines in each video. The intraclass correlation coefficient (ICC) for the whole series of 47 videos between each trainee and the expert trainer was high (average 0.81 ± 0.21) and >0.70 in all but five cases. After further training, the five underperforming trainees achieved satisfactory agreement with the expert trainer (average post-retraining ICC 0.74 ± 0.14). The Bland-Altman plot showed virtually no bias (difference between the mean 0.03) and strict 95% limits of agreement lines (-1.52 and 1.45 US B-lines). Only four cases overlapped but did not exceed the same limits. Likewise, the Spearman correlation coefficient applied to the same data series was very high (r = 0.979, P < 0.0001). Nephrologists and cardiologists can be effectively trained to measure lung congestion by an entirely web-based programme. This web-based training programme ensures high-quality standardization of US B-line measurements and represents a simple, costless and effective preparatory step for clinical trials targeting lung congestion., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

A unique and highly versatile technique, stress echocardiography (SE) is increasingly recognized for its utility in the evaluation of non-ischaemic heart disease. SE allows for simultaneous assessment of myocardial function and haemodynamics under physiological or pharmacological conditions. Due to its diagnostic and prognostic value, SE has become widely implemented to assess various conditions other than ischaemic heart disease. It has thus become essential to establish guidance for its applications and performance in the area of non-ischaemic heart disease. This paper summarizes these recommendations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: Aim of this study was to compare a minimally fluoroscopic radiofrequency catheter ablation with conventional fluoroscopy-guided ablation for supraventricular tachycardias (SVTs) in terms of ionizing radiation exposure for patient and operator and to estimate patients' lifetime attributable risks associated with such exposure., Methods and Results: We performed a prospective, multicentre, randomized controlled trial in six electrophysiology (EP) laboratories in Italy. A total of 262 patients undergoing EP studies for SVT were randomized to perform a minimally fluoroscopic approach (MFA) procedure with the EnSite TM NavX TM navigation system or a conventional approach (ConvA) procedure. The MFA was associated with a significant reduction in patients' radiation dose (0 mSv, iqr 0-0.08 vs. 8.87 mSv, iqr 3.67-22.01; P < 0.00001), total fluoroscopy time (0 s, iqr 0-12 vs. 859 s, iqr 545-1346; P < 0.00001), and operator radiation dose (1.55 vs. 25.33 µS per procedure; P < 0.001). In the MFA group, X-ray was not used at all in 72% (96/134) of cases. The acute success and complication rates were not different between the two groups (P = ns). The reduction in patients' exposure shows a 96% reduction in the estimated risks of cancer incidence and mortality and an important reduction in estimated years of life lost and years of life affected. Based on economic considerations, the benefits of MFA for patients and professionals are likely to justify its additional costs., Conclusion: This is the first multicentre randomized trial showing that a MFA in the ablation of SVTs dramatically reduces patients' exposure, risks of cancer incidence and mortality, and years of life affected and lost, keeping safety and efficacy., Trial Registration: clinicaltrials.gov Identifier: NCT01132274., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Extravascular lung water (EVLW) is a key variable in heart failure management and prognosis, but its objective assessment remains elusive. Lung imaging has been traditionally considered off-limits for ultrasound techniques due to the acoustic barrier of high-impedance air wall. In pulmonary congestion however, the presence of both air and water creates a peculiar echo fingerprint. Lung ultrasound shows B-lines, comet-like signals arising from a hyper-echoic pleural line with a to-and-fro movement synchronized with respiration. Increasing EVLW accumulation changes the normal, no-echo signal (black lung, no EVLW) into a black-and-white pattern (interstitial sub-pleural oedema with multiple B-lines) or a white lung pattern (alveolar pulmonary oedema) with coalescing B-lines. The number and spatial extent of B-lines on the antero-lateral chest allows a semi-quantitative estimation of EVLW (from absent, ≤5, to severe pulmonary oedema, >30 B-lines). Wet B-lines are made by water and decreased by diuretics, which cannot modify dry B-lines made by connective tissue. B-lines can be evaluated anywhere (including extreme environmental conditions with pocket size instruments to detect high-altitude pulmonary oedema), anytime (during dialysis to titrate intervention), by anyone (even a novice sonographer after 1 h training), and on anybody (since the chest acoustic window usually remains patent when echocardiography is not feasible). Cardiologists can achieve much diagnostic gain with little investment of technology, training, and time. B-lines represent 'the shape of lung water'. They allow non-invasive detection, in real time, of even sub-clinical forms of pulmonary oedema with a low cost, radiation-free approach., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Doppler-derived coronary flow velocity reserve (CFVR) of left anterior descending (LAD) artery is an effective tool to predict overall mortality. The aim was to investigate the capability of CFVR to predict outcome in an unselected cohort of patients older than 80 years having stress echo negative by wall motion criteria., Methods and Results: The study group refers to 369 patients aged > 80 years (156 men; mean age 83 ± 2 years) who had undergone dipyridamole stress echocardiography with CFVR assessment of LAD artery of known (n = 144) or suspected (n = 225) coronary artery disease. Stress echocardiography was negative for wall motion criteria in all cases. Mean CFVR was 2.07 ± 0.53. During a median follow-up of 21 months, there were 62 major adverse cardiac events (MACEs; 45 deaths and 17 non-fatal myocardial infarctions). With a receiver operating characteristic analysis, a CFVR of ≤ 1.93 was the best cut-off for predicting mortality and MACE. At individual patient analysis, 152 (41%) subjects had a CFVR of < 1.93. Annual mortality was 9.8% in patients with CFVR <1.93 and 3.7% in those with CFVR > 1.93 (P = 0.001); an annual MACE rate was 14.8% in the former and 4.5% in the latter (P < 0.0001). Of 15 clinical and echocardiographic parameters analysed, CFVR ≤ 1.93 [hazard ratio (HR) = 2.17, 95% CI 1.14-4.10] and resting wall motion abnormality (RWMA; HR = 2.60; 95% CI 1.35-5.00) were multivariable indicators of mortality. Moreover, CFVR ≤ 1.93 (HR = 2.69, 95% CI 1.56-4.67), and RWMA (HR = 2.38; 95% CI 1.31-4.33) were also strong independent predictors of MACEs. At incremental analysis, CFR ≤ 1.93 added prognostic information over clinical evaluation and RWMA when both mortality and MACE were taken as clinical end points., Conclusions: A reduced CFVR of LAD artery is a strong and independent indicator of both mortality and MACE, adding prognostic information over clinical evaluation and RWMA. Conversely, a preserved CFVR predicts a favourable outcome particularly in subjects with no RWMA., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Systemic sclerosis (SSc) may induce cardiac fibrosis and systo-diastolic dysfunction. Cardiovascular magnetic resonance (CMR) can detect replacement myocardial fibrosis with late gadolinium enhancement (LGE) and interstitial myocardial fibrosis with T1 mapping techniques. The aim of the study was to detect subclinical cardiac involvement with CMR in paucisymptomatic SSc patients with no previous history of myocardial disease, comparing it with skeletal muscle remodelling., Methods and Results: Thirty consecutive SSc patients (mean age: 51 ± 12 years, all women) and 10 healthy controls (mean age: 48 ± 15 years, all women) underwent clinical, biohumoral assessment, and CMR. Extracellular volume fraction (ECV) was calculated from pre- and post-contrast T1 values in the myocardium and skeletal muscle. Seventeen patients (57%) were asymptomatic, 13 (43%) paucisymptomatic (effort dyspnoea). All patients had normal biventricular volumes and systolic function, while LGE was present in seven patients (23%). Myocardial ECV was significantly increased in patients with SSc (30 ± 4%) than controls (28 ± 4%, P = 0.03), as was skeletal muscle ECV (23 ± 6% vs. 18 ± 4%, P < 0.01). Myocardial ECV did not differ between patients with and without LGE (P = NS) and showed no significant correlations with clinical data, biventricular volumes, systolic, or diastolic function. Overall, myocardial ECV showed a significant correlation with skeletal muscle ECV (R = 0.58, P < 0.001)., Conclusion: SSc is associated not only with myocardial replacement fibrosis, as detected by LGE, but also with interstitial remodelling of the myocardium and skeletal muscles, as detected by an increased ECV also in patients with normal biventricular function, with potential diagnostic, prognostic, and therapeutic clinical implications., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Despite the advent of non-fluoroscopic technology, fluoroscopy remains the cornerstone of imaging in most interventional electrophysiological procedures, from diagnostic studies over ablation interventions to device implantation. Moreover, many patients receive additional X-ray imaging, such as cardiac computed tomography and others. More and more complex procedures have the risk to increase the radiation exposure, both for the patients and the operators. The professional lifetime attributable excess cancer risk may be around 1 in 100 for the operators, the same as for a patient undergoing repetitive complex procedures. Moreover, recent reports have also hinted at an excess risk of brain tumours among interventional cardiologists. Apart from evaluating the need for and justifying the use of radiation to assist their procedures, physicians have to continuously explore ways to reduce the radiation exposure. After an introduction on how to quantify the radiation exposure and defining its current magnitude in electrophysiology compared with the other sources of radiation, this position paper wants to offer some very practical advice on how to reduce exposure to patients and staff. The text describes how customization of the X-ray system, workflow adaptations, and shielding measures can be implemented in the cath lab. The potential and the pitfalls of different non-fluoroscopic guiding technologies are discussed. Finally, we suggest further improvements that can be implemented by both the physicians and the industry in the future. We are confident that these suggestions are able to reduce patient and operator exposure by more than an order of magnitude, and therefore think that these recommendations are worth reading and implementing by any electrophysiological operator in the field., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Stress echocardiography is an established method for the diagnosis and prognostic stratification of coronary artery disease. In the last few years, the tremendous technological and conceptual versatility of this technique has been increasingly applied in challenging diagnostic fields. Today, in the echocardiography laboratory we can detect not only ischaemia from coronary artery stenosis, but can also recognize abnormalities of the coronary microvessels, myocardium, heart valves, pulmonary circulation, alveolar-capillary barrier, and right ventricle. Therefore, we evaluate coronary arteries as well as coronary microvascular disease (associated with diabetes and hypertension), suspected or overt dilated cardiomyopathy, systolic and diastolic heart failure, hypertrophic cardiomyopathy, athletes' hearts, valvular heart disease, congenital heart disease, incipient or overt pulmonary hypertension, and heart transplant patients for early detection of chronic or acute rejection as well as potential donors for better selection of suitable donor hearts. From a stress echo era with a one-fits-all approach (wall motion by 2D-echo in the patient with known or suspected coronary artery disease) now we have moved on to an omnivorous, next-generation laboratory employing a variety of technologies (from M-Mode to 2D and pulsed, continuous and colour Doppler, to lung ultrasound and real-time 3D echo, 2D speckle tracking and myocardial contrast echo) on patients covering the entire spectrum of severity (from elite athletes to patients with end-stage heart failure) and ages (from children with congenital heart disease to the elderly with low-flow, low-gradient aortic stenosis). For each patient, we can tailor a dedicated stress protocol with a specific method to address a particular diagnostic question. Provided that the acoustic window is acceptable and the necessary expertise available, stress echocardiography is useful and convenient in many situations, from valvular to congenital heart disease, and whenever there is a mismatch between symptoms during stress and findings at rest. Increasing societal concern regarding cost, environment and radiation risks of medical imaging will lead to a preferential application of ultrasound over competing techniques, due to its unsurpassed versatility, portability, absence of radiation, and low cost.

The benefits of cardiac imaging are immense, and modern medicine requires the extensive and versatile use of a variety of cardiac imaging techniques. Cardiologists are responsible for a large part of the radiation exposures every person gets per year from all medical sources. Therefore, they have a particular responsibility to avoid unjustified and non-optimized use of radiation, but sometimes are imperfectly aware of the radiological dose of the examination they prescribe or practice. This position paper aims to summarize the current knowledge on radiation effective doses (and risks) related to cardiac imaging procedures. We have reviewed the literature on radiation doses, which can range from the equivalent of 1-60 milliSievert (mSv) around a reference dose average of 15 mSv (corresponding to 750 chest X-rays) for a percutaneous coronary intervention, a cardiac radiofrequency ablation, a multidetector coronary angiography, or a myocardial perfusion imaging scintigraphy. We provide a European perspective on the best way to play an active role in implementing into clinical practice the key principle of radiation protection that: 'each patient should get the right imaging exam, at the right time, with the right radiation dose'.

Aims: Myocardial ischaemia during pharmacological stress echocardiography is a strong prognostic predictor in patients with a left bundle branch block (LBBB). However, the additive value of Doppler-derived coronary flow reserve (CFR) during pharmacological stress testing remains to be investigated in this subset of patients., Methods and Results: The study group consisted of 324 LBBB patients (187 men; age 68 ± 10 years) with known (n = 74) or suspected (n = 250) coronary artery disease who had undergone dipyridamole (up to 0.84 mg/kg over 6') stress echocardiography with CFR assessment of left anterior descending (LAD) by Doppler. A value of CFR ≤ 2.0 was considered abnormal. The median duration of follow-up was 15 months (first to third quartile: 8-34 months). Of the 324 patients, 52 (16%) had ischaemia at stress echo by wall motion criteria, and 139 (43%) had a CFR ≤ 2. During follow-up, 51 (16%) events occurred: 37 deaths and 14 myocardial infarctions (MIs). Age (HR: 1.09, 95% CI: 1.04-1.15, P < 0.0001), resting wall motion score index (HR: 5.29, 95% CI: 2.36-11.89, P < 0.0001), smoking habit (HR: 4.38, 95% CI: 1.93-9.91, P < 0.0001), and CFR ≤ 2 (4.69, 95% CI: 1.96-11.19, P = 0.001) were independently correlated with mortality, while CFR ≤ 2 (HR: 3.91, 95% CI: 1.90-8.04, P < 0.0001), age (HR: 1.06, 95% CI: 1.02-1.10, P = 0.001), smoking habit (HR: 2.25, 95% CI: 1.18-4.30, P = 0.01), ischaemia at stress echo (HR: 2.30, 95% CI: 1.11-4.77, P = 0.02), and resting wall motion score index (HR: 2.17, 95% CI: 1.11-4.25, P = 0.02) were independently correlated with death or MI. Four-year mortality and 4-year hard event rate were markedly higher in patients with CFR ≤ 2 than in those with CFR >2 (49 vs. 6% and 56 vs. 8%, respectively; P < 0.0001 for both). A CFR of ≤ 2 was associated with a significantly higher annual hard event rate independently of age, sex, ejection fraction, history of coronary artery disease, diabetes, and hypertension. Moreover, it was correlated with an increased (P < 0.0001) yearly mortality and event rate in patients with non-ischaemic stress echo conducted on therapy. At incremental analysis, a CFR of ≤ 2 added prognostic value to clinical findings, resting wall motion score index, ongoing anti-ischaemic therapy, and ischaemia at stress echo when both death and death or MI were the clinical endpoints., Conclusions: Abnormal CFR on LAD is a strong and independent indicator of mortality and death or MI in patients with LBBB, and is associated with markedly increased risk also in the subset of patients with stress echo negative for ischaemia on therapy.

Aims: Dobutamine stress echocardiography (DSE) is widely used to evaluate myocardial contractile reserve in patients with heart failure (HF). The aim of the study was to assess the relationship between the tissue Doppler (TD) mitral annulus systolic velocity (Sm) change during DSE, contractile reserve, and aerobic exercise capacity in HF patients., Methods and Results: Sixty-four HF patients (age 67 ± 9 years, 58% with an ischaemic aetiology, and a mean value of the ejection fraction 29 ± 7%) underwent high-dose DSE. The mean value of the TD mitral annulus septal-lateral Sm change was analysed at rest and at peak DSE. All patients underwent also the cardiopulmonary exercise test. With a receiver operating characteristic analysis, a value of 2.02 cm/s obtained as a stress-rest difference in a mean value of the peak systolic velocity of the mitral annulus (Sm) was the best value for diagnosing the myocardial contractile reserve [area under the curve 0.69 (95% CI 0.56-0.80), sensitivity 69% (95% CI 54-81), specificity 80% (95% CI 45-97)]. The patient population was divided into two groups: with rest-stress Sm change during DSE ≤ 2.02 cm/s and with rest-stress Sm change >2.02 cm/s. Patients with Sm rest-stress >2.02 change during DSE, compared with patients with rest-stress change ≤2.02, showed a lower incidence of severe diastolic dysfunction at rest (16 vs. 46%, P= 0.039) and lower E/Ea values (11 ± 5 vs. 15 ± 6, P = 0.005), similar ejection fraction at rest but higher ejection fraction at peak DSE (53 ± 14 vs. 41 ± 12%, P = 0.001), better myocardial contractile reserve assessed by a pressure-volume relationship (1.89 ± 2.01 vs. 0.58 ± 1.38 mmHg/mL/m(2), P = 0.004), with a lower end-systolic volume (-46 ± 20 vs. -24 ± 19%, P< 0.001), a higher increase in the ejection fraction (23 ± 10 vs. 12 ± 10%, P = 0.001) during DSE, and better peak oxygen consumption (16 ± 4 vs. 13 ± 2 mL/kg/min, P = 0.01)., Conclusion: In patients with HF, the rest-stress variation of mitral annulus systolic velocities during DSE predicts the presence of myocardial contractile reserve and exercise tolerance.

Modern US equipment allows rheumatologists to directly visualize vascular, musculoskeletal, dermal and internal organ structure. In multisystemic and challenging diseases such as vasculitides and scleroderma, where new outcome measures are required in both clinical practice and trials, US measures promise reproducible and objective scores of disease activity and extension. US reveals early pathognonomic abnormalities and may help start early treatment.

Objectives: The present study investigates early clinical and haemodynamic results with the Freedom SOLO bioprosthesis (FSB) for aortic valve replacement (AVR) in eight Italian institutions., Methods: From 2004 to 2008, a total of 229 patients [139 females (60.7%); mean age 74 ± 8 years, left ventricular (LV) ejection fraction >40%] underwent AVR with FSB. One hundred and four patients underwent preoperatively, at 1-3 and at 12 months after AVR resting transthoracic echocardiography with the effective orifice area index (EOAi) assessment, peak and mean transvalvular pressure gradients and the LV mass index (LVMi) measurement. A subset of 34 patients underwent exercise stress echocardiography at a mean of 9.6 months after AVR., Results: Post-operative mortality was 3.1%. At 1-3 months, FSB showed a significant increase in the EOAi (0.39 ± 0.17 to 1.04 ± 0.17 cm(2)/m(2); P < 0.0001), a reduction in the mean gradient (43.2 ± 16.9 to 4.3 ± 2.3 mmHg; P < 0.0001) and a significant regression of the LVMi (147.6 ± 30.5 to 121.6 ± 27.4 g/m(2); P < 0.0001). During exercise stress echocardiography, the mean aortic gradients increased from 4.4 ± 1.7 at rest to 7.0 ± 2.7 mmHg at peak stress (P < 0.001). The EOA increased from 1.74 ± 0.33 to 1.80 ± 0.36 cm(2) (P = 0.0291). Mean gradients at peak stress had better correlation with resting EOAi (r = -0.74; P < 0.001) than with the prosthesis size (r = 0.43; P = 0.01)., Conclusions: The supra-annular implantation of FSB offers excellent haemodynamic performance both at rest and during exercise and is associated with the rapid regression of the LV.

Professional exposure of interventional cardiologist to low-dose radiation prompts cellular changes that may protect from harm.

Aims Invasive cardiologists are the most exposed to ionizing radiation among health professionals and show an increased rate of somatic DNA damage. To evaluate the effects of chronic low-dose exposure to ionizing radiation on redox state and apoptotic activation. Methods and results We enrolled 10 healthy exposed professionals (all interventional cardiologists, Group II, exposed: age = 38 ± 5 years) and 10 age- and gender-matched unexposed controls (Group I, non-exposed). Exposed subjects had a median exposure of 4 mSv/year (range 1-8) by film badge dosimetry (below lead apron). We measured reduced glutathione (GSH, a marker of antioxidant response) in erythrocytes and plasma generation of hydrogen peroxide (a marker of oxyradical stress) by ferrous oxidation-xylenol orange assay in plasma. In both groups, lymphocytes were isolated and caspase-3 activity (a marker of apoptotic response) measured at baseline and following 2 Gy in vitro irradiation. Exposed subjects showed a three-fold increase in hydrogen peroxide (Group I = 2.21 ± 1.03 vs. II = 6.51 ± 1.55 μM H(2)O(2) equivalents) and a 1.7-fold increase in GSH (I = 12.37 ± 1.22 vs. II = 20.61 ± 2.16 mM). Exposed subjects also showed higher values of caspase-3 activity, both at baseline and-more strikingly-following high-dose radiation challenge. Conclusion In interventional cardiologists, chronic exposure to low-dose radiation is associated with an altered redox balance mirrored by an increase in hydrogen peroxide and with two possibly adaptive cellular responses: (i) an enhanced antioxidant defence (increase in GSH, counteracting increased oxyradical stress) and (ii) an increased susceptibility to apoptotic induction which might efficiently remove genetically damaged cells.

Aims To compare the prognostic implication of stress echocardiography (SE) in a large cohort of hypertensive and normotensive patients with known or suspected coronary artery disease (CAD). The relative prognostic meaning of the SE result in hypertensive and normotensive patients remains to be addressed. Methods and results The study group was formed by 11 542 patients (6214 hypertensive patients; 5328 normotensive patients) who underwent exercise (n= 686), dobutamine (n= 2524), or dipyridamole (n= 8332) SE for evaluation of known (n= 4563) or suspected (n= 6979) CAD. Patients were followed up for a median of 25 months (1st quartile, 7; 3rd quartile, 57). Ischaemia on SE (new wall motion abnormality) was detected in 3209 (28%) patients. During follow-up, 1587 events (924 deaths, 663 non-fatal infarctions) occurred. Patients (n= 2764) undergoing revascularization were censored. The annual event rate was 7.0% in hypertensive and 5.7% in normotensive patients (P = 0.02) with known CAD, and 3.7% in hypertensive and 2.4% in normotensive patients (P< 0.0001) with suspected CAD. Ischaemia on stress echo, resting wall motion abnormality (RWMA), age, male sex, and diabetes mellitus were multivariable prognostic predictors in both patient groups. Analysing data according to the interaction of prognostically important echocardiographic covariates, such as ischaemia on SE and RWMA, an effective risk assessment was obtained in hypertensive as well as normotensive patients. The annual event rate was markedly higher in hypertensive than in normotensive patients with no ischaemia and no RWMA (2.5 and 1.7%, P = 0.0001). Finally, the incremental prognostic value of inducible ischaemia over clinical evaluation and resting left ventricular function was greater in hypertensive than in normotensive patients both with known and suspected CAD. Conclusion The SE result allows an effective prognostication in hypertensive and normotensive patients. However, a non-ischaemic test predicts better survival in normotensive than in hypertensive patients with no RWMA.

Obesity and metabolic syndrome (MetS) are serious and growing health care problems worldwide, leading an increased risk for type 2 diabetes (T2D) and cardiovascular disease (CVD). Over the past decade, emerging evidence has shown that an increased chromosomal damage, as determined by the cytokinesis-block micronucleus (CBMN) assay, is correlated to the pathogenesis of metabolic and CVD. An increased micronuclei (MN) frequency has been demonstrated in peripheral blood lymphocytes of patients with polycystic ovary syndrome, a common condition in reproductive-aged women associated with impaired glucose tolerance, T2D mellitus and the MetS. High levels of MN have been detected to be significantly correlated with T2D as well as with the occurrence and the severity of coronary artery disease (CAD). Long-term follow-up studies have shown that an increased MN frequency is a predictive biomarker of cardiovascular mortality within a population of healthy subjects as well as of major adverse cardiovascular events in patients with known CAD. Overall, these findings support the hypothesis that CBMN assay may provide an useful tool for screening of the MetS and its progression to diabetes and CVD in adults as well in children. Large population-based cohorts are needed in order to compare the MN frequencies as well as to better define whether MN is a biomarker or a mediator of cardiometabolic diseases.

Objective: To assess the correlation between ultrasound lung comets (ULCs, a recently described echographic sign of interstitial lung fibrosis) and the current undisputed gold-standard high-resolution CT (HRCT) to detect pulmonary fibrosis in patients with SSc., Methods: We enrolled 33 consecutive SSc patients (mean age 54 +/- 13 years, 30 females) in the Rheumatology Clinic of the University of Pisa. We assessed ULCs and chest HRCT within 1 week independently in all the patients. ULC score was obtained by summing the number of lung comets on the anterior and posterior chest. Pulmonary fibrosis was quantified by HRCT with a previously described 30-point Warrick score., Results: Presence of ULCs (defined as a total number more than 10) was observed in 17 (51%) SSc patients. Mean ULC score was 37 +/- 50, higher in the diffuse than in the limited form (73 +/- 66 vs 21 +/- 35; P < 0.05). A significant positive linear correlation was found between ULCs and Warrick scores (r = 0.72; P < 0.001)., Conclusions: ULCs are often found in SSc, are more frequent in the diffuse than the limited form and are reasonably well correlated with HRCT-derived assessment of lung fibrosis. They represent a simple, bedside, radiation-free hallmark of pulmonary fibrosis of potential diagnostic and prognostic value.

Aims: The aim of the study was to evaluate the prognostic value of Doppler echocardiographic-derived coronary flow reserve (CFR) over regional wall motion in patients with known or suspected coronary artery disease (CAD) undergoing dipyridamole echocardiography test (DET)., Methods and Results: In a prospective, multicentre, observational study, we evaluated 1145 patients (702 males; 64 +/- 11 years) who underwent high-dose dipyridamole (0.84 mg/kg over 6 min) stress echo with CFR evaluation of LAD by Doppler. DET was positive for regional wall motion abnormalities in 291 (25%) and negative in 854 (74%) patients. Mean CFR was 2.2 +/- 0.5. At individual patient analysis 702 patients had normal (CFR > 2.0) and 443 had abnormal CFR on LAD. During a median follow-up of 27 months, 109 events occurred: 16 deaths, 17 non-fatal myocardial infarctions, 76 re-hospitalizations for unstable angina. The 30 months infarction-free survival showed the best outcome for those patients with negative DET by wall motion criteria and normal CFR and the worst outcome for patients with positive DET by wall motion and abnormal CFR (99 vs. 68%, P < 0.001). At multivariable analysis, CFR on LAD [hazard ratio (HR) 2.4, 95% CI 1.1-5.4, P = 0.030], medical therapy at time of testing (HR 2.8, 95% CI 1.2-6.6, P = 0.022), DET positivity for regional wall motion abnormalities (HR 3.6, 95% CI 1.5-8.7, P = 0.000), and angina on effort (HR 6.3, 95% CI 2.7-14.8, P = 0.000) were independent prognostic predictors of hard cardiac events., Conclusion: In patients with known or suspected CAD, DET result by wall motion criteria and CFR are additive and complementary for the identification of patients at risk of experiencing hard events.

Background: Ultrasound lung comets (ULCs) are an echographic sign of extravascular lung water, that originate from water-thickened interlobular septa., Aim: To establish the echocardiographic correlates of ULCs., Methods: 340 in-hospital patients (68 +/- 12years, 115 females) admitted to adult cardiology department underwent upon admission a separate evaluation of chest ULCs and a comprehensive 2D and Doppler echocardiography assessment, including the degree of left ventricular diastolic dysfunction (from 0 = normal to 3 = restrictive pattern). A patient ULC score has been obtained by summing the number of ULCs from each of the scanning spaces in the anterior right and left chest, from second to fifth intercostal space., Results: Multivariate linear regression analysis identified New York Heart Association (NYHA) class (OR = 2.1, CI = 1.4-2.9), ejection fraction (OR 0.954, CI = 0.928-0.981) and degree of diastolic dysfunction (OR = 2.438, CI = 1.418-4.190) as the only parameters independently associated to the number of ULCs., Conclusion: ULCs are a simple echographic sign of extravascular lung water, more frequently associated with left ventricular diastolic and/or systolic dysfunction. ULCs can usefully integrate the clinical and pathophysiological information provided by conventional 2D and Doppler echocardiography, in patients with known or suspected heart failure and dyspnoea as a presenting symptom.

Aims: We evaluated whether radiation exposure during interventional cardiovascular procedures can induce damage to deoxyribonucleic acid (DNA)., Methods and Results: Micronucleus assay (MN) was performed as biomarker of chromosomal damage and intermediate endpoint in carcinogenesis. Seventy-two patients (54 males, age = 63.8 +/- 10.5 years) undergoing a wide range of radiation exposure during invasive cardiovascular procedures (coronary angiography, n = 9; percutaneous coronary intervention, n = 9; peripheral transluminal angioplasty, n = 37; and cardiac resynchronization therapy, n = 17) were enrolled. MN frequency was evaluated before, 2, and 24 h after the radiation exposure. Dose-area product (DAP; Gy cm(2)) was assessed as physical measure of radiation load. DAP value was 96.0 +/- 63.9 Gy cm(2). MN frequency was 15.1 +/- 7.1 per thousand at baseline and showed a significant rise at 2 h (17.5 +/- 6.5 per thousand, P = 0.03) and 24 h (18.5 +/- 7.3 per thousand, P = 0.004) after procedures., Conclusion: Our results corroborate the current radioprotection assumption that even modest radiation load can damage the DNA of the cell and induce chromosome alterations which are early predictors of increased cancer risk.

Aims: Medical radiological exposure is associated with an additional risk of cancer. Children with repaired congenital heart disease (CHD) are theoretically at a relatively greater cancer risk as the radiological exposure can be intensive in these patients. Chromosomal aberrations test (CA) and micronucleus assay (MN) in peripheral blood lymphocytes are biomarkers of chromosomal damage and intermediate endpoints in carcinogenesis., Methods and Results: The frequency of CA and MN was assessed in three groups of patients: Group I, 32 exposed patients (17 males, age=15.5+/-8.3 years) who underwent cardiac procedures employing ionizing radiation (mostly cardiac catheterization) for CHD between 1965 and 2000; Group II, 32 healthy age- and sex-matched subjects (17 males, age=14.1+/-12.3 years), and Group III, 10 newborn non-exposed patients (7 males) with CHD. Exposed patients of Group I had a mean value of 2.9+/-1.4 cardiac catheterization (range 1-5) procedures per person. The mean frequency of CA was higher in the exposed patients (Group I=2.8+/-1.9% vs. Group II=0.7+/-0.7%; vs. Group III=0.8+/-0.8%; P<0.0001). Similarly, the mean values of MN were higher in the exposed patients (Group I =12.3+/-5.1 per thousand vs. Group II=6.0+/-3.8 per thousand; vs. Group III=4.4+/-1.4 per thousand; P<0.0001)., Conclusion: Cardiac ionizing procedures are associated with a long-lasting mark in the chromosomal damage of exposed children with CHD.

Aims: Coronary flow-reserve (CFR) can be impaired in non-ischaemic dilated cardiomyopathy (DCM), unmasking a coronary microcirculatory dysfunction of potential prognostic impact. The aim of the present study is to evaluate the prognostic value of Doppler echocardiographic-derived CFR in patients with DCM., Methods and Results: We evaluated 129 DCM patients (85 male; age 62+/-11) by transthoracic dipyridamole (0.84 mg/kg in 10 min) stress echocardiography. All patients had an ejection fraction<40% (mean 32+/-7) and angiographically normal coronary arteries with NYHA class2.0) and 83 had abnormal CFR. During follow-up, 18 patients died and 33 showed worsening of NYHA class. The worse event-free survival was observed in those patients with an abnormal CFR when compared with those having a normal CFR at high dose of dipyridamole (70 vs. 22%, at 75 months of follow-up, P<0.0001). In the multivariable analysis, severity of mitral insufficiency (HR=1.9, 95% CI=1.06-2.87), abnormal CFR (HR=4.0, 95% CI=1.1-15.6), resting wall motion score index (HR=6.9, 95% CI=1.5-30.7) were independent predictors of survival., Conclusion: In DCM patients, CFR is often impaired. A reduced CFR during vasodilator stress is an independent prognostic marker of bad prognosis.

Aims: Left ventricular end-systolic pressure-volume relationship (PVR) provides a robust, relatively load-insensitive evaluation of contractility and can be assessed non-invasively during exercise echo. Dobutamine might provide an exercise-independent alternative approach to assess inotropic reserve. The feasibility of a non-invasive estimation of PVR during dobutamine stress in the echo lab and its relationship with subsequent clinical events was assessed., Methods and Results: We enrolled 137 consecutive patients referred for dobutamine stress echo. To build the PVR, the force was determined at different heart rate increments during stepwise dobutamine infusion as the ratio of the systolic pressure/end-systolic volume index. The PVR at increasing heart rate was flat-biphasic in 65 and up-sloping in 72 patients: 42 patients underwent surgery and 95 patients were treated medically (median follow-up, 18 months; interquartile range, 12-24). Events occurred in 18 patients (death in eight, acute heart failure in 10); a flat-biphasic PVR was independent predictor of events (RR=10.16, P<0.01)., Conclusion: PVR is feasible during dobutamine stress. This index of global contractility is reasonably simple, does not affect the imaging time, and only minimally prolongs the off-line analysis time. It allows unmasking quite different, and heterogeneous, contractility reserve patterns underlying a given ejection fraction at rest. The best survival is observed in patients with up-sloping PVR, whereas flat-biphasic pattern is a strong predictor of cardiac events.

Aims: Patients with normal coronary arteries have a heterogeneous prognosis. Aim of this study was to assess whether dipyridamole stress echocardiography positivity identifies a prognostically less benign subset., Methods and Results: We selected 457 patients (245 males; 56+/-10 years) who underwent stress high-dose dipyridamole echocardiography and had angiographically non-significant (<50% visually assessed) stenosis in any major vessel and preserved left ventricular function. All patients were followed up for a median of 7.1 years (first quartile 5 and third quartile 10.5). Dipyridamole echocardiography test (DET) positivity for regional dysfunction occurred in 43(9%) patients. Kaplan-Meier survival estimates showed a significant better outcome for those patients with negative dipyridamole echocardiography test compared with those with a positive test (90 vs. 75.7%, at 140 months of follow-up, P=0.0018). At multivariable analysis, mild or moderate irregularity on coronary arteriogram (HR=3.3, CI 95%=1.7-6.2), diabetes (HR=3.5, CI 95%=1.4-9.2), and wall motion score index at peak stress (HR=6.7, CI 95%=2.5-17.8) were independent predictors of all-cause death., Conclusion: DET adds incremental value to the prognostic stratification achieved with clinical and angiographic data in the subset of patients with normal or near-normal coronary arteries.

Aims: Risk stratification after uncomplicated acute myocardial infarction is mostly applied by either symptom-limited post discharge exercise electrocardiography or pre-discharge submaximal exercise test. Aim of the present study was to determine if early pharmacological stress echocardiography and discharge within 24 hours of the test in cases without induced myocardial ischemia leads to lower costs and similar clinical outcome during 1 year follow up when compared to clinical evaluation and exercise electrocardiography after discharge., Methods and Results: Four-hundred fifty-eight patients from 10 participating centers with a recent uncomplicated myocardial infarction were randomized to pharmacological stress echocardiography on day 3-5 followed by early discharge in the case of negative test result (early discharge strategy) (n=233) or clinical evaluation with hospital discharge on day 7-9 and symptom-limited post-discharge exercise electrocardiography at 2-4 weeks after myocardial infarction (usual care strategy) (n=225). At 1 year follow up there were 63 events (4 deaths, 9 non fatal reinfarctions, 50 chest pains requiring hospitalization) in patients randomized to early discharge, and 69 events (6 deaths, 13 reinfarctions, 50 chest pains requiring hospitalization) in usual care (p=ns). Total median individual costs calculated on the basis of hospitalizations, investigations and interventions during 1 year follow up were 3561 for early discharge strategy vs 3850 for usual care strategy (p<0.05)., Conclusions: Early pharmacological stress echocardiography followed by early discharge in case of negative test result gives similar clinical outcome and lower costs after uncomplicated myocardial infarction than clinical evaluation and delayed post-discharge symptom-limited exercise electrocardiography.

Background: In the stress imaging era, ECG positivity is regarded as a frequent source of false-positive responses. However, it is known that normal coronary arteries frequently coexist with abnormal endothelial function in patients with chest pain., Aim: To evaluate the anatomical coronary epicardial, and functional systemic endothelial determinants of wall motion and electrocardiographic responses during stress testing., Method: Sixty-eight in-hospital patients with chest pain syndrome, no previous myocardial infarction, and off nitrate therapy at the time of testing underwent, on different days, in random order and within 1 month: (1) stress ECG echo testing (with dipyridamole in 43, dobutamine in 3, and exercise in 22 patients); (2) coronary angiography; (3) endothelium-dependent, flow-mediated dilation of the brachial artery during reactive hyperaemia using high-resolution ultrasound. Criteria of positivity were: ST segment depression >0.1mm in the stress ECG; regional dysfunction >2 segments demonstrated by stress-echo; diameter reduction >50% on coronary angiography; and <5% flow-mediated dilation as revealed by endothelial function., Results: Significant coronary artery disease was present in 39 patients, and was predicted on multivariate analysis by stress-induced wall motion abnormalities (OR=108.8; 95% CI=8.5-1,389.4, P=0.0003), but not by either ST segment depression (P=0.13; OR=0.47; 95% CI=0.7-1.3) or reduced flow-mediated dilation (P=0.81; OR=0.87; 95% CI=0.27-2.8). Abnormal flow-mediated dilation was present in 53 patients (78%), and was predicted by stress-induced ST segment depression (P=0.023; OR=6.2; 95% CI=1.3-30.5), but not by either stress echo positivity (P=0.66; OR=0.77; 95% CI=0.23 to 2.5) or angiographically assessed coronary artery disease. There was no correlation between flow-mediated dilation and extent of coronary artery disease as assessed by the angiographic Duke score (from 0=normal to 100=most severe disease): r=-0.13, P=0.91., Conclusion: Epicardial coronary artery anatomy affects wall motion abnormalities, and systemic endothelial dysfunction affects ST segment depression during stress. However, echocardiographic positivity is unrelated to endothelial dysfunction, and electrocardiographic positivity is an inaccurate predictor of coronary stenosis. An integration of ECG and functional markers is warranted in the stress testing lab.

Aims: The aim of the present study was to assess the relative prognostic value of clinical variables, the exercise electrocardiography test and the pharmacological stress echocardiography test either with dipyridamole or dobutamine early after a first uncomplicated acute myocardial infarction in a large, multicentre, prospective study., Methods and Results: Seven hundred and fifty-nine in-hospital patients (age=56+/-10 years) with a recent and first clinical uncomplicated myocardial infarction, with baseline echocardiographic findings of satisfactory quality, an interpretable ECG and able to exercise underwent a resting 2D echocardiogram, a pharmacological stress test with either dipyridamole or dobutamine and an exercise electrocardiography test at a mean of 10 days from the infarction; they were followed-up for a median of 10 months. During the follow-up, there were 13 deaths, 23 non-fatal myocardial infarctions and 59 re-hospitalizations for unstable angina. When all spontaneous events were considered, with multivariate analysis, the difference between the wall motion score index at rest and peak stress (delta wall motion score index), and exercise duration were independent predictors of future spontaneous events (relative risk 7.2; 95% CI=2.73-19.1; P=0.000; relative risk 1.1, 95% CI=1.02-1.18; P=0.008, respectively). Kaplan-Meier survival estimates showed a better outcome for those patients with a negative pharmacological stress echocardiography test compared to patients with low dose positivity (94.7 vs 74.8%, P=0.000)., Conclusion: Stress echocardiography tests provide stronger information than historical and exercise electrocardiography test variables. Pharmacological echocardiography as well as the exercise ECG is able to predict all spontaneously occurring events when the presence as well as the timing, severity, and extension of stress-induced wall motion abnormalities are considered., (Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.)

Background: Echocardiographic parameters for predicting cardioversion outcome in patients with non-valvular atrial fibrillation are not accurately defined., Objective: To evaluate the role of left atrial appendage flow velocity detected by transoesophageal echocardiography for prediction of cardioversion outcome in patients with non-valvular atrial fibrillation enrolled in a prospective. multicentre, international study., Methods: Four hundred and eight patients (257 males, mean age: 66 +/- 10 years) with non-valvular atrial fibrillation lasting more than 48 h but less than 1 year underwent transthoracic echocardiography and transoesophageal echocardiography before either electrical (n=324) or pharmacological (n=84) cardioversion., Results: Cardioversion was successful in restoring sinus rhythm in 328 (80%) and unsuccessful in 80 patients (20%). Mean left atrial appendage peak emptying flow velocity was significantly higher in patients with successful than in those with unsuccessful cardioversion (32.4 +/- 17.7 vs 23.5 +/- 13.6 cm x s(-1); P<0.0001). At multivariate logistic regression analysis, three parameters proved to be independent predictors of cardioversion success: the atrial fibrillation duration <2 weeks (P=0.011, OR=4.9, CI 95%=1.9-12.7), the mean left atrial appendage flow velocity >31 cm x s(-1) (P=0.0013, OR=2.8, CI 95%=1.5-5.4) and the left atrial diameter <47 mm (P=0.093, OR=2.0, CI 95%=1.2-3.4). These independent predictors of cardioversion success outperformed other univariate predictors such as left ventricular end-diastolic diameter <58 mm, ejection fraction >56% and the absence of left atrial spontaneous echo contrast., Conclusion: In patients with non-valvular atrial fibrillation, measurement of the left atrial appendage flow velocity profile by transoesophageal echocardiography before cardioversion provides valuable information for prediction of cardioversion outcome.

Nitrates act as donors of nitric oxide (NO), a molecule with a recognized potential for genotoxicity. In order to assess whether chronic long-term nitrate therapy may increase genotoxicity, we evaluated chromosomal damage in peripheral lymphocytes of 27 ischaemic patients undergoing chronic nitrate treatment for vertical line4 years (7.9 +/- 3.1, mean +/- SD) and 18 age- and sex-matched subjects without any previous nitrate treatment. At the same time, after treatment in vitro with 0-20 microM sodium nitroprusside as NO donor, micronucleus induction and cell proliferation were also evaluated using blood from six different healthy donors. The results showed that the frequency of structural chromosomal aberrations was not significantly higher in the drug-treated group than the control [2.1 +/- 1.4 versus 1.6 +/- 1.2 (mean +/- SD); P = 0.23]. The frequency of micronucleated lymphocytes was higher in the nitrate group than in the control group (6.5 +/- 4.6 versus 3.5 +/- 2.9, P=0.01). In vitro treatment indicated a dose-dependent increase in the frequency of micronucleated lymphocytes with increasing SNP concentrations. Cytotoxicity and cell cycle delay, with a statistically significant difference with respect to control culture, were also observed. Our results suggest a possible genotoxic activity of nitrate therapy. Further studies focusing on the possible link between nitrate therapy and genotoxicity are warranted at this point.

Background: Oral dipyridamole induces accumulation of endogenous adenosine, which in a hypoxic milieu exerts experimentally an angiogenic effect on coronary collateral circulation. A meta-analysis of 13 randomized placebo-controlled trials published between 1960 and 1992 showed evidence of benefit for dipyridamole in the treatment of angina pectoris, especially with longer duration of treatment. Aim To assess the efficacy and safety of dipyridamole in the treatment of patients with chronic stable angina in a large scale, international, randomized, placebo-controlled, parallel group study., Methods: Four hundred patients with chronic stable angina pectoris and a positive treadmill exercise test were randomized to receive either modified release dipyridamole (200 mg b.i.d. p.o., n=198) or corresponding placebo (n=202), for 24 weeks as an add-on to conventional antianginal therapy and for 4 additional weeks as monotherapy--the latter after withdrawal of standard treatment with calcium antagonists and/or beta-blockers and/or long-acting (prophylactic) nitrates., Results: Of the 198 patients randomized to dipyridamole, 134 completed the add-on and only 12 the monotherapy phase. Of the 202 patients randomized to placebo, 162 reached the add-on and only 12 the monotherapy phase. Serious adverse events occurred in 15 patients with dipyridamole and in 12 with placebo (7.6% vs 6.0, P=0.52). Increase over the baseline treadmill exercise test was similar in the treatment groups at each stage of the trial for all the main efficacy parameters: total treadmill exercise test duration; time to first anginal pain (except for a -13 s difference in favour of placebo at week 24;P=0.040); time to ST segment depression >0.1 mVolt (except for a +21 s difference in favour of dipyridamole at week 8;P=0.024; this latter difference was totally attributable to patients with lower exercise tolerance--Bruce stage II at study entry)., Conclusion: In patients with chronic stable angina treated with regular antianginal background medication, the use of oral dipyridamole is safe and well tolerated. Antianginal and antiischaemic efficacy, as assessed by exercise testing, is comparable to placebo, except for a beneficial effect on time to ischaemia after 2 months, totally attributable to patients with lower exercise tolerance at study entry., (Copyright 2001 The European Society of Cardiology.)

Aims: The aim of this study was to assess the prognostic value of myocardial viability recognized as a contractile response to vasodilator stimulation in patients with left ventricular dysfunction in a large scale, prospective, multicentre, observational study., Methods and Results: Three hundred and seven patients (mean age 60 +/- 10 years) with angiographically proven coronary artery disease, previous (>3 months) myocardial infarction and severe left ventricular dysfunction (ejection fraction <35%; mean ejection fraction: 28 +/- 7%) were enrolled in the study. Each patient underwent low dose dipyridamole echo (0.28 mg x kg(-1) in 4 min). Myocardial viability was identified as an improvement of >0.20 in the wall motion score index. By selection, all patients were followed up for a median of 36 months. One-hundred and twenty-four were revascularized either by coronary artery bypass grafting (n=83) or coronary angioplasty (n=41). The only end-point analysed was cardiac death. In the revascularized group, cardiac death occurred in one of the 41 patients with and in 16 of the 83 patients without a viable myocardium (2.4% vs 19.3%, P<0.01). Outcome, as estimated by Kaplan-Meier survival, was better for patients with, compared to patients without, a viable myocardium, who underwent coronary revascularization (97.6 vs 77.4%, P=0.01). Using a Cox proportional hazards model, the presence of myocardial viability was shown to exert a protective effect on survival (chi-square 4.6, hazard ratio 0.1, 95% CI 0.01-0.8, P<0.03). The survival rate in medically treated patients was lower than in revascularized patients irrespective of the presence of a viable myocardium (79.7% vs 86.2, P=ns)., Conclusion: In severe left ventricular ischaemic dysfunction, myocardial viability, as assessed by low dose dipyridamole echo, is associated with improved survival in revascularized patients.

Aim: To assess whether 'eye education' through short-term, high-intensity joint reading sessions may improve diagnostic accuracy and inter-observer agreement among beginners., Methods and Results: Seventeen cardiologists with absent to minimal (<100 studies performed) previous stress echo experience independently and blindly read 18 stress echo studies, nine at the beginning ('pre-training' set) and nine at the end ('post-training' set) of a 2 day stress echo school which included a joint reading session of 50 tapes. The two sets were balanced as far as type of stress and image quality. The 17 observers had an average accuracy score of 51+/-16.4 before and 64.3+/-8.7% after the training (P<0.005). Concordant (i.e. >14 readers giving the same response) interpretation occurred in three out of nine studies before and in eight out of nine studies after the training (33% vs 88%, P<0.01). Kappa values went from 0.14 (poor) before to 0.39 (fair, close to moderate) after the training., Conclusion: Short-term, high-intensity dedicated training in stress echo, with joint reading sessions and consensus development of reading criteria significantly increased accuracy and markedly reduced the inter-observer variability in the reading of stress echoes by beginners. If there is a Shakespearean madness in stress echo reading, 'yet there is a method in't' (Hamlet, II, II, 205-206)., (Copyright 1999 The European Society of Cardiology.)