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

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

An enlarged left atrial volume index (LAVI) at rest mirrors increased LA pressure and/or impairment of LA function. A cardiovascular stress may acutely modify left atrial volume (LAV) within minutes. Aim of this study was to assess the feasibility and functional correlates of LAV-stress echocardiography (SE) Out of 514 subjects referred to 10 quality-controlled labs, LAV-SE was completed in 490 (359 male, age 67 ± 12 years) with suspected or known chronic coronary syndromes (n = 462) or asymptomatic controls (n = 28). The utilized stress was exercise in 177, vasodilator in 167, dobutamine in 146. LAV was measured with the biplane disk summation method. SE was performed with the ABCDE protocol. The intra-observer and inter-observer LAV variability were 5% and 8%, respectively. ∆-LAVI changes (stress-rest) were negatively correlated with resting LAVI (r = - 0.271, p < 0.001) and heart rate reserve (r = -.239, p < 0.001). LAV-dilators were defined as those with stress-rest increase ≥ 6.8 ml/m 2 , 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.

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

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)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In patients in sinus rhythm, a blunted heart rate reserve (HRR) during dipyridamole stress echocardiography (SE) is a prognostically unfavorable sign of cardiac autonomic dysfunction. In this study we sought to assess the prognostic meaning of HRR in patients with permanent atrial fibrillation (AF). The study population was made by 301 patients (176 men, age 73 ± 8 years) with suspected (n = 200) or known (n = 101) coronary artery disease and permanent AF who underwent high-dose dipyridamole SE. HRR was calculated on an average of 5 consecutive beats as the peak/rest ratio of HR from 12-lead EKG. During a median follow-up time of 77 months (first quartile 44, third quartile 115 months), 111 (37%) patients died. Receiver operating characteristics analysis identified HRR ≤1.17 as the best predictor of mortality. At multivariable analysis, HRR ≤1.17 (HR 1.75, 95% CI 1.17 to 2.62; p = 0.006) independently predicted mortality together with age (HR 1.09, 95% CI 1.06 to 1.13; p <0.0001), rest wall motion score index (HR 1.69, 95% CI 1.01 to 2.83; p = 0.04), and systemic hypertension (HR 1.76, 95% CI 1.06 to 3.00; p = 0.04). The annual mortality was 5.1% in the overall population, 7.0% in the 140 (46%) patients with abnormal HRR and 3.5% in the 161 (54%) patients with normal HRR. The 8-year mortality was 48% in patients with abnormal HRR and 18% in those with normal HRR (p <0.0001). In conclusion, patients with suspected or known coronary artery disease with permanent AF with a blunted HRR have an increased mortality. HRR outweighs inducible ischemia for prediction of survival. The assessment of HRR should become an integral part of dipyridamole SE reading also in AF., (Copyright © 2020. Published by Elsevier Inc.)

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).

Background: During dipyridamole stress echocardiography (SE), a blunted heart rate reserve (HRR) is a prognostically unfavourable sign of cardiac autonomic dysfunction., Aim: To assess the prognostic meaning of HRR and coronary flow velocity reserve (CFVR)., Methods: The study group comprised 2149 patients (1236 men; mean age 66±12 years) with suspected (n=1280) or known (n=869) coronary artery disease and without inducible regional wall motion abnormalities (RWMA) during dipyridamole SE (0.84mg/kg in 6min). We assessed CFVR of the left anterior descending artery with pulsed-wave Doppler as the ratio between hyperaemic peak and basal peak diastolic flow velocities (abnormal value≤2.0). HRR was calculated as the peak/resting ratio of heart rate from a 12-lead electrocardiogram (abnormal value≤1.22). All patients were followed up., Results: CFVR and HRR were abnormal in 520 (24%) and 670 (31%) patients, respectively. There was a positive linear correlation between CFVR and HRR (r=0.30; P<0.0001). During a median follow-up of 22 months (1st quartile 12 months, 3rd quartile 35 months), 75 (6%) patients died. The annual mortality was 1.6% in the overall population, 0.5% in the 1224 (57%) patients with normal CFVR and HRR, 1.7% in the 405 (19%) patients with abnormal HRR only, 3.6% in the 255 (12%) patients with abnormal CFVR only, and 6.2% in the 265 (12%) patients with abnormal CFVR and HRR., Conclusions: HRR is weakly related to CFVR, and a blunted HRR usefully complements RWMA and CFVR for prediction of outcome with dipyridamole SE. The patient without inducible RWMA is still at intermediate risk, but the risk is low with concomitant preserved CFVR, and very low with concomitant normal HRR., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

A blunted heart rate (HR) response during dipyridamole myocardial perfusion imaging has been associated with a poor outcome. To assess the value of HR response in patients who underwent high-dose dipyridamole stress echocardiography (SE), we retrospectively selected a sample of 3,059 patients (none with pacemakers or atrial fibrillation; mean age 66 ± 11 years). All underwent high-dose (0.84 mg/kg) dipyridamole SE for evaluation of known or suspected coronary artery disease and/or heart failure in 2 laboratories of Pisa-IFC and Lucca. HR (with 12-lead ECG) was obtained each minute and recorded at rest and peak stress. HR reserve (HRR) was calculated as the peak/rest HR ratio. All patients were followed up. Patients were randomly divided into the modeling and validation group of equal size. During a median follow-up time of 1,004 days, 321 hard events occurred: 231 deaths and 90 nonfatal myocardial infarctions. HRR ≤ 1.22 identified by receiver operating characteristic analysis in the modeling group was an independent predictor of infarction-free survival in the modeling (hazard ratio 1.83, 95% confidence interval [CI] 1.30 to 2.60, p = 0.001), in the validation (hazard ratio 1.47, 95% CI 1.08 to 2.01, p = 0.02), and in the overall group (hazard ratio 1.60, 95% CI 1.27 to 2.02, p <0.0001), either off- or on-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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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 (OR adjusted  = 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 (OR adjusted  = 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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<0.0001), male sex (HR, 1.57; 95% CI, 1.20-2.04; P=0.001), diabetes mellitus (HR, 1.78; 95% CI, 1.34-2.37; P<0.0001), smoking habit (HR, 1.40; 95% CI, 1.05-1.85; P=0.02), and ongoing anti-ischemic therapy (HR, 1.50; 95% CI, 1.15-1.97; P=0.003) Conclusions Over the past 3 decades, we observed a progressive decline in the prognostic value of a negative test based on regional wall motion abnormalities, likely reflecting both an increase in risk in patients, as well as a potential decrease in test performance due to concomitant anti-ischemic therapy.

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk., Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD., Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09)., Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD., Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events., Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints., Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Background: The detection of regional wall motion abnormalities is the cornerstone of stress echocardiography. Today, stress echo shows increasing trends of utilization due to growing concerns for radiation risk, higher cost and stronger environmental impact of competing techniques. However, it has also limitations: underused ability to identify factors of clinical vulnerability outside coronary artery stenosis; operator-dependence; low positivity rate in contemporary populations; intermediate risk associated with a negative test; limited value of wall motion beyond coronary artery disease. Nevertheless, stress echo has potential to adapt to a changing environment and overcome its current limitations., Integrated-Quadruple Stress-Echo: Four parameters now converge conceptually, logistically, and methodologically in the Integrated Quadruple (IQ)-stress echo. They are: 1- regional wall motion abnormalities; 2-B-lines measured by lung ultrasound; 3-left ventricular contractile reserve assessed as the stress/rest ratio of force (systolic arterial pressure by cuff sphygmomanometer/end-systolic volume from 2D); 4- coronary flow velocity reserve on left anterior descending coronary artery (with color-Doppler guided pulsed wave Doppler). IQ-Stress echo allows a synoptic functional assessment of epicardial coronary artery stenosis (wall motion), lung water (B-lines), myocardial function (left ventricular contractile reserve) and coronary small vessels (coronary flow velocity reserve in mid or distal left anterior descending artery). In "ABCD" protocol, A stands for Asynergy (ischemic vs non-ischemic heart); B for B-lines (wet vs dry lung); C for Contractile reserve (weak vs strong heart); D for Doppler flowmetry (warm vs cold heart, since the hyperemic blood flow increases the local temperature of the myocardium). From the technical (acquisition/analysis) viewpoint and required training, B-lines are the kindergarten, left ventricular contractile reserve the primary (for acquisition) and secondary (for analysis) school, wall motion the university, and coronary flow velocity reserve the PhD program of stress echo., Conclusion: Stress echo is changing. As an old landline telephone with only one function, yesterday stress echo used one sign (regional wall motion abnormalities) for one patient with coronary artery disease. As a versatile smart-phone with multiple applications, stress echo today uses many signs for different pathophysiological and clinical targets. Large scale effectiveness studies are now in progress in the Stress Echo2020 project with the omnivorous "ABCD" protocol.

Background: The effectiveness trial "Stress echo (SE) 2020" evaluates novel applications of SE in and beyond coronary artery disease. The core protocol also includes 4-site simplified scan of B-lines by lung ultrasound, useful to assess pulmonary congestion., Purpose: To provide web-based upstream quality control and harmonization of B-lines reading criteria., Methods: 60 readers (all previously accredited for regional wall motion, 53 B-lines naive) from 52 centers of 16 countries of SE 2020 network read a set of 20 lung ultrasound video-clips selected by the Pisa lab serving as reference standard, after taking an obligatory web-based learning 2-h module ( http://se2020.altervista.org ). Each test clip was scored for B-lines from 0 (black lung, A-lines, no B-lines) to 10 (white lung, coalescing B-lines). The diagnostic gold standard was the concordant assessment of two experienced readers of the Pisa lab. The answer of the reader was considered correct if concordant with reference standard reading ±1 (for instance, reference standard reading of 5 B-lines; correct answer 4, 5, or 6). The a priori determined pass threshold was 18/20 (≥ 90%) with R value (intra-class correlation coefficient) between reference standard and recruiting center) > 0.90. Inter-observer agreement was assessed with intra-class correlation coefficient statistics., Results: All 60 readers were successfully accredited: 26 (43%) on first, 24 (40%) on second, and 10 (17%) on third attempt. The average diagnostic accuracy of the 60 accredited readers was 95%, with R value of 0.95 compared to reference standard reading. The 53 B-lines naive scored similarly to the 7 B-lines expert on first attempt (90 versus 95%, p = NS). Compared to the step-1 of quality control for regional wall motion abnormalities, the mean reading time per attempt was shorter (17 ± 3 vs 29 ± 12 min, p < .01), the first attempt success rate was higher (43 vs 28%, p < 0.01), and the drop-out of readers smaller (0 vs 28%, p < .01)., Conclusions: Web-based learning is highly effective for teaching and harmonizing B-lines reading. Echocardiographers without previous experience with B-lines learn quickly.

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 (mtDNA 4977 ) 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. mtDNA 4977 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 mtDNA 4977 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 mtDNA 4977 deletion (≤75th). Multivariate Cox regression analysis showed that log mtDNA 4977 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 mtDNA 4977 deletion (>75th) and low mtDNA-CN (<25th) had significantly increased risk for MACEs (HR: 3.73; 95% CI: 1.79-7.79; p=0.0005)., 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Angina pectoris (AP) and unheralded myocardial infarction (MI) are considered random clinical equivalents of ischemic heart disease (IHD). Aim of the study was to evaluate the long-term progression of AP as opposed to unheralded MI as alternative first clinical presentations of IHD and the effect of sex on prognosis., Methods: The study included 2272 consecutive patients, 1419 MI and 1353 AP, hospitalized from 1995 to 2007 at CNR Clinical Physiology Institute, Pisa, Italy and followed up to December 2013, who fulfilled the following criteria: unheralded MI or AP as first manifestation of IHD; age < = 70 years; known coronary anatomy; at least 10-year follow-up. Fatal and non fatal MI, all-cause, and cardiac deaths were the end-points., Results: Males were predominant in MI (86%) as compared to AP (77%). Females were predominantly affected by AP (61%, MI 39%), and older than men (61 ± 7 vs 59 ± 8 years, p < 0.001). Coronary stenoses were prevalent in MI. During 115 ± 58 months follow-up, 628 deaths (23%) were observed, including 269 cardiac (43%), and 149 cancer deaths (24%). Long-term prognosis was significantly better in AP than MI group. The lowest prevalence of future MI was recorded in female AP (p < 0.001)., Conclusions: MI as first clinical manifestation of IHD implies a more adverse prognosis than AP; future MI is a rare event in AP; sex influences the first presentation of IHD and its course with possible implications for preventive strategy.

Objectives: To assess the value of a simple score integrating non-ischaemia-related variables in expanding the wall motion abnormalities risk power during stress echocardiography (SE)., Methods: Study includes 14 279 patients who underwent SE for evaluation of coronary artery disease. All-cause death was the end point. Patients were randomly divided into the modelling and validation group of equal size. In the modelling group, multivariate analysis was conducted using clinical, rest and SE data, and a score was obtained from the number of non-ischaemia-related independent prognostic predictors. The score prognostic capability was compared in both groups., Results: During a median follow-up of 31 months, 1230 patients died: 622 (9%) in the modelling and 608 (9%) in the validation group (p=0.68). Independent predictors of mortality were ischaemia at SE (HR 1.77, 95% CI 1.49 to 2.12; p<0.0001) and six other parameters: age > 65 years, wall motion at rest, diabetes, left bundle branch block, anti-ischaemic therapy and male sex. Risk score resulted prognostically effective in the modelling and validation groups, both with and without inducible ischaemia subset. When risk score was included in the multivariate analysis, besides ischaemia at SE it was the only independent predictor of mortality in the modelling (HR 1.70, 95% CI 1.60 to 1.82; p<0.0001), in the validation (HR 1.77, 95% CI 1.65 to 1.90; p<0.0001) and in the overall group (HR 1.73, 95% CI 1.66 to 1.82; p<0.0001)., Conclusions: Simple clinical variables may be able to optimise SE risk stratification., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The trial "Stress Echo (SE) 2020" evaluates novel applications of SE beyond coronary artery disease. The aim of the study was control quality and harmonize reading criteria., Methods: One reader from 78 centers of the SE 2020 network asked for credentials to read a set of 20 SE video-clips selected by the core lab. All aspiring centers met the pre-requisite of high-volume and the years of experience in SE ranged from 5 to 31years (mean value 18years). The diagnostic gold standard was a reading by the core lab. The a priori determined pass threshold was 18/20 (≥90%)., Results: Of the initial 78 who started, 57 completed the first attempt: individual readers' score on first attempt ranged from 07/20 to 20/20 (accuracy from 35% to 100%, mean 78.7±13%) and 44 readers passed it. There was a very poor correlation between years of experience and the reader's score on first attempt (r=-0.161, p=0.231). Of the 13 readers who failed the first attempt, 12 took it again after the web-based session and their accuracy improved (74% vs. 96%, p<0.001). The kappa inter-observer agreement before and after web-based training was 0.59 on first attempt and rose to 0.91 on the last attempt., Conclusions: In SE reading, the volume of activity or years of experience is not synonymous with diagnostic quality. Qualitative analysis and operator-dependence can become a limiting weakness in clinical practice, in the absence of strict pathways of learning, credentialing and audit., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Stress echocardiography (SE) predicts cardiac death, but an increasing share of cardiac patients eventually die of cancer. The aim of the study was to assess whether SE positivity predicts cancer death., Methods and Results: In a retrospective analysis of prospectively acquired single-center, observational data, we evaluated 4673 consecutive patients who underwent SE from 1983 to 2009. All patients were cancer-free at index SE and were followed up for a median of 131 months (interquartile range 134). We separately analyzed predetermined end points: cardiovascular, cancer, and noncardiovascular, noncancer death, with and without competing risk. SE was positive in 1757 and negative in 2916 patients; 869 cardiovascular, 418 cancer, and 625 noncardiovascular, noncancer deaths were registered. The 25-year mortality was higher in SE-positive than in SE-negative patients, considering cardiovascular (40% versus 31%; P <0.001) and cancer mortality (26% versus 17%; P <0.01). SE positivity was a strong predictor of cancer (cause-specific hazard ratio 1.19; 95% confidence interval, 1.16-1.73; P =0.05) and cardiovascular mortality (1.18; 95% confidence interval, 1.03-1.35; P =0.02). Fine-Gray analysis to account for competing risk gave similar results. Cancer risk diverged after 15 years, whereas differences were already significant at 5 years for cardiovascular risk., Conclusions: SE results predict cardiovascular and cancer mortality. SE may act as a proxy of the shared risk factor milieu for cancer or cardiovascular death., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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., (Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: The presence of left ventricular contractile reserve (LVCR) during stress echo (SE) may provide favorable response to cardiac resynchronization therapy (CRT) in heart failure patients. The aim of the study was to perform a meta-analysis of available SE data in this set of patients., Methods: From a Pubmed and Advance Google Scholar database web based search scan up to December 2016, we initially identified 5906 records. From this initial set, we removed that did not include SE and duplicate studies. We assessed for eligibility 71 full-text articles assessed for eligibility, and 60 of them did not meet the inclusion criteria as follow: 1) heart failure patients with NYHA class III and IV, depressed ejection fraction (EF <35%) and QRS duration ≥120 ms at study entry; 2) SE with assessment of LVCR; 3) Follow-up data. LVCR during SE was identified as reduction in wall motion score index and/or an increase in EF., Results: Eleven studies with 861 patients (mean age 67 ± 9 years, ejection fraction 25 ± 6%) were included in the meta-analysis. The type of stress was either exercise (n = 2) or dobutamine (n = 9), the latter with low-dose (10 mcg) in two, intermediate-dose (20 mcg) in five, and high-dose (40 mcg) protocol in two studies. LVCR was detected in 555 patients (63%) and CRT-response was present in 584 (66%). The overall odds ratio for LVCR to predict a favorable CRT response was 2.06 (95%, CI 1.70-2-43), Z score: 11.055, p < 0.001., Conclusion: The presence of LVCR during SE with either dobutamine or exercise is associated with a greater chance of response to CRT. This parameter is now ready to be tested in a prospective multicenter trial to select patients more likely to benefit from CRT.

The initial clinical manifestation of ischemic heart disease (IHD) i.e. unheralded myocardial infarction (MI) versus chronic angina pectoris (AP) is statistically associated with adverse or mild disease progression respectively in the long-term follow-up. Here, we subjected AP and MI patients to blood proteomic analysis by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) in order to investigate putative new prognostic biomarkers of IHD manifestation. We found several differentially expressed peaks but four of them (4176, 4475, 14,158m/z and 8922m/z for AP and MI, respectively) were most reliable. Two of them were identified; 14,158m/z peak was the double-charged form of Apolipoprotein A-I and its vasoprotective action accords with prominence in AP. The 4176m/z peak was related to FAM83C protein, while neither the 4475m/z peak nor the MI-linked 8922m/z peak could be identified. We conclude that SELDI-TOF-MS analysis may yield a panel of molecular signals able to retrospectively classify patients according to their clinical and molecular features, exploitable for predicting the natural course of IHD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Patients with coronary artery disease can accumulate significant radiation dose through repeated exposures to coronary computed tomographic angiography, myocardial perfusion imaging with single photon emission computed tomography or positron emission tomography, and to invasive coronary angiography. Aim of the study was to audit radiation doses of coronary computed tomographic angiography, single photon emission computed tomography, positron emission tomography and invasive coronary angiography in patients enrolled in the prospective, randomized, multi-centre European study-EVINCI (Evaluation of Integrated Cardiac Imaging for the Detection and Characterization of Ischemic Heart Disease)., Methods: We reviewed 1070 tests (476 coronary computed tomographic angiographies, 85 positron emission tomographies, 310 single photon emission computed tomographies, 199 invasive coronary angiographies) performed in 476 patients (mean age 60 ± 9 years, 60% males) enrolled in 12 centers of the EVINCI. The effective doses were calculated in milli-Sievert (mSv) as median, interquartile range (IQR) and coefficient of variation of the mean., Results: Coronary computed tomographic angiography (476 exams in 12 centers) median effective dose was 9.6 mSv (IQR = 13.2 mSv); single photon emission computed tomography (310 exams in 9 centers) effective dose was 9.3 (IQR = 2.8); positron emission tomography (85 in 3 centers) effective dose 1.8 (IQR = 1.6) and invasive coronary angiography (199 in 9 centers) effective dose 7.4 (IQR = 7.3). Inter-institutional variability was highest for invasive coronary angiography (100%) and coronary computed tomographic angiography (54%) and lowest for single photon emission computed tomography (20%). Intra-institutional variability was highest for invasive coronary angiography (121%) and coronary computed tomographic angiography (115%) and lowest for single photon emission computed tomography (14%)., Conclusion: Coronary computed tomographic angiography and invasive coronary angiography doses vary substantially between and within centers. The variability in nuclear medicine procedures is substantially lower. The findings highlight the need to audit doses, to track cumulative exposures and to standardize doses for imaging techniques., Trial Registration: The study protocol is available at https://www.clinicaltrials.gov/ (ClinicalTrials.gov Identifier: NCT00979199 ). Information provided on September 16, 2009.

Background: Stress echocardiography (SE) has an established role in evidence-based guidelines, but recently its breadth and variety of applications have extended well beyond coronary artery disease (CAD). We lack a prospective research study of SE applications, in and beyond CAD, also considering a variety of signs in addition to regional wall motion abnormalities., Methods: In a prospective, multicenter, international, observational study design, > 100 certified high-volume SE labs (initially from Italy, Brazil, Hungary, and Serbia) will be networked with an organized system of clinical, laboratory and imaging data collection at the time of physical or pharmacological SE, with structured follow-up information. The study is endorsed by the Italian Society of Cardiovascular Echography and organized in 10 subprojects focusing on: contractile reserve for prediction of cardiac resynchronization or medical therapy response; stress B-lines in heart failure; hypertrophic cardiomyopathy; heart failure with preserved ejection fraction; mitral regurgitation after either transcatheter or surgical aortic valve replacement; outdoor SE in extreme physiology; right ventricular contractile reserve in repaired Tetralogy of Fallot; suspected or initial pulmonary arterial hypertension; coronary flow velocity, left ventricular elastance reserve and B-lines in known or suspected CAD; identification of subclinical familial disease in genotype-positive, phenotype- negative healthy relatives of inherited disease (such as hypertrophic cardiomyopathy)., Results: We expect to recruit about 10,000 patients over a 5-year period (2016-2020), with sample sizes ranging from 5,000 for coronary flow velocity/ left ventricular elastance/ B-lines in CAD to around 250 for hypertrophic cardiomyopathy or repaired Tetralogy of Fallot. This data-base will allow to investigate technical questions such as feasibility and reproducibility of various SE parameters and to assess their prognostic value in different clinical scenarios., Conclusions: The study will create the cultural, informatic and scientific infrastructure connecting high-volume, accredited SE labs, sharing common criteria of indication, execution, reporting and image storage of SE to obtain original safety, feasibility, and outcome data in evidence-poor diagnostic fields, also outside the established core application of SE in CAD based on regional wall motion abnormalities. The study will standardize procedures, validate emerging signs, and integrate the new information with established knowledge, helping to build a next-generation SE lab without inner walls.

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: Hybrid imaging provides a non-invasive assessment of coronary anatomy and myocardial perfusion. We sought to evaluate the added clinical value of hybrid imaging in a multi-centre multi-vendor setting., Methods and Results: Fourteen centres enrolled 252 patients with stable angina and intermediate (20-90%) pre-test likelihood of coronary artery disease (CAD) who underwent myocardial perfusion scintigraphy (MPS), CT coronary angiography (CTCA), and quantitative coronary angiography (QCA) with fractional flow reserve (FFR). Hybrid MPS/CTCA images were obtained by 3D image fusion. Blinded core-lab analyses were performed for CTCA, MPS, QCA and hybrid datasets. Hemodynamically significant CAD was ruled-in non-invasively in the presence of a matched finding (myocardial perfusion defect co-localized with stenosed coronary artery) and ruled-out with normal findings (both CTCA and MPS normal). Overall prevalence of significant CAD on QCA (>70% stenosis or 30-70% with FFR≤0.80) was 37%. Of 1004 pathological myocardial segments on MPS, 246 (25%) were reclassified from their standard coronary distribution to another territory by hybrid imaging. In this respect, in 45/252 (18%) patients, hybrid imaging reassigned an entire perfusion defect to another coronary territory, changing the final diagnosis in 42% of the cases. Hybrid imaging allowed non-invasive CAD rule-out in 41%, and rule-in in 24% of patients, with a negative and positive predictive value of 88% and 87%, respectively., Conclusion: In patients at intermediate risk of CAD, hybrid imaging allows non-invasive co-localization of myocardial perfusion defects and subtending coronary arteries, impacting clinical decision-making in almost one every five subjects., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Every radiological and nuclear medicine examination confers a definite long-term risk of cancer, but most patients undergoing such examinations receive no or inaccurate information about radiation dose and corresponding risk related to the dose received. Informed consent is a procedure to support (not substitute) the physician/patient dialogue and relationship, facilitating a free, informed and aware expression of the patient's will in the principle of patient autonomy. Physicians are responsible for providing patients with all the information on risks, benefits and alternatives useful to the patient to make the decision. In current radiological practice the information on the radiation dose and long-term cancer risks is difficult to find and not easy to understand. The form using plain language should spell-out the type of examination, the effective dose (mSv), the effective dose expressed in number of chest radiographs and the risk of cancer. The current practice clashes against the guidelines and the law.

Background: Although magnesium (Mg) has recognized cardioprotective properties and hypomagnesemia is common in patients with acute myocardial infarction (AMI), data regarding the role of Mg as prognostic factor for adverse events are scarce, as well as there are conflicting results on the use of Mg as adjuvant therapy in AMI., Aim: To evaluate the role of Mg as predictor for hard events (HE, all cause death, and nonfatal myocardial infarction) in AMI patients., Design and Patients: We studied 406 AMI patients (306 males, age: 67 ± 12 years, mean ± SD). Patient data were collected from the Institute electronic databank which saves demographic, clinical, instrumental, therapeutical and follow-up data of all patients admitted to our Coronary Unit., Results: During a mean follow-up period of 21 ± 18 months, the combined endpoint accounted for 63 HE, 44 (11%) deaths (35 cardiac deaths), 19 (5%) nonfatal MI. The multiple regression model identified glycemia as the only independent determinant of Mg in AMI pts. (T value = - 2.8, standard coefficient = - 0.15, p < 0.01). The Kaplan-Meier survival estimates failed to show a significantly worst outcome in patients presenting low Mg (< 0.783 mmol/L, 25th percentile). Aging (> 67 years-50th percentile), and ejection fraction (< 40%) remained as prognostic factors for HE in the adjusted Cox multivariate proportional hazard model (HR = 2.8, 95% CI = 1.6-5, p < 0.001; HR = 3.2, 95% CI = 1.9-5.3 p < 0.001, respectively)., Conclusion: The present findings do not support a significant role of low Mg as predictor for HE in AMI.

Uric acid (UA) is a potent endogenous antioxidant. However, high concentrations of this molecule have been associated with cardiovascular disease (CVD) and renal dysfunction, involving mechanisms that include oxidative stress, inflammatory processes, and endothelial injury. Experimental and in vitro results suggest that this biomarker behaves like other antioxidants, which can shift from the physiological antioxidant action to a pro-oxidizing effect according to their level and to microenvironment conditions. However, data on patients (general population or CAD cohorts) are controversial, so the debate on the role of hyperuricemia as a causative factor for CVD is still ongoing. Increasing evidence indicates UA as more meaningful to assess CVD in women, even though this aspect needs deeper investigation. It will be important to identify thresholds responsible for UA "biological shift" from protective to harmful effects in different pathological conditions, and according to possible gender-related differences. In any case, UA is a low-tech and inexpensive biomarker, generally performed at patient's hospitalization and, therefore, easily accessible information for clinicians. For these reasons, UA might represent a useful additive tool as much as a CV risk marker. Thus, in view of available evidence, progressive UA elevation with levels higher than 6 mg/dL could be considered an "alarm" for increased CV risk.

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.

Background: Low radiation doses from diagnostic and therapeutic procedures may increase cancer incidence after decades in cardiac patients. The aim of the study was to evaluate the long-term outcome and the prognostic effect of radiological exposure., Methods: A retrospective cohort study examined 16,311 Italian cardiac patients without cancer consecutively hospitalized between 1970 and 2009 and followed-up for a median of 10 years. Cumulative estimated effective dose was calculated for the imaging procedures. Main causes of death and primary cancer onset were the end points and their relation with radiation exposure was analyzed by Cox model., Results: Over the years, there was an increasing trend of cancer, a decreasing trend of cardiovascular, with stability of other-causes death. Cumulative estimated effective radiation dose was higher in patients who died for cancer (20 ± 19 mSv) compared to cardiovascular (17 ± 17, P < 0.001) and other-causes deaths (15 ± 17, p < 0.001). The cumulative estimated effective dose adjusted HR was 1.004 (95% CI 1.000-1.009, p = 0.045) for cancer death and 1.008 (95% CI 1.005-1.011, p < 0.001) for (fatal and non-fatal) cancer onset. Radiation effective dose was not predictive of cardiovascular mortality (HR = 0.991), nor it was of other types of deaths (HR = 0.995). Smoking was a predictor for cardiovascular mortality, but it was not of other types of deaths., Conclusions: Non-cardiovascular causes of death are responsible for almost half of later deaths in cardiac patients. The radiological exposure from medical imaging procedures is predictive of cancer risk and cancer death., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: the aim of this study was to report a ten years experience in the electronic medical record (EMR) use. An estimated 80% of healthcare transactions are still paper-based., Methods: an EMR system was built at the end of 1998 in an Italian tertiary care center to achieve total integration among different human and instrumental sources, eliminating paper-based medical records. Physicians and nurses who used EMR system reported their opinions. In particular the hospital activity supported electronically, regarding 4,911 adult patients hospitalized in the 2004- 2008 period, was examined., Results: the final EMR product integrated multimedia document (text, images, signals). EMR presented for the most part advantages and was well adopted by the personnel. Appropriateness evaluation was also possible for some procedures. Some disadvantages were encountered, such as start-up costs, long time required to learn how to use the tool, little to no standardization between systems and the EMR technology., Conclusion: the EMR is a strategic goal for clinical system integration to allow a better health care quality. The advantages of the EMR overcome the disadvantages, yielding a positive return on investment to health care organization.

Background: In patients with chronic angina-like chest pain, the probability of coronary artery disease (CAD) is estimated by symptoms, age, and sex according to the Genders clinical model. We investigated the incremental value of circulating biomarkers over the Genders model to predict functionally significant CAD in patients with chronic chest pain., Methods: In 527 patients (60.4 years, standard deviation, 8.9 years; 61.3% male participants) enrolled in the European Evaluation of Integrated Cardiac Imaging (EVINCI) study, clinical and biohumoral data were collected., Results: Functionally significant CAD-ie, obstructive coronary disease seen at invasive angiography causing myocardial ischemia at stress imaging or associated with reduced fractional flow reserve (FFR < 0.8), or both-was present in 15.2% of patients. High-density lipoprotein (HDL) cholesterol, aspartate aminotransferase (AST) levels, and high-sensitivity C-reactive protein (hs-CRP) were the only independent predictors of disease among 31 biomarkers analyzed. The model integrating these biohumoral markers with clinical variables outperformed the Genders model by receiver operating characteristic curve (ROC) (area under the curve [AUC], 0.70 [standard error (SE), 0.03] vs 0.58 [SE, 0.03], respectively, P < 0.001) and reclassification analysis (net reclassification improvement, 0.15 [SE, 0.07]; P = 0.04). Cross-validation of the ROC analysis confirmed the discrimination ability of the new model (AUC, 0.66). As many as 56% of patients who were assigned to a higher pretest probability by the Genders model were correctly reassigned to a low probability class (< 15%) by the new integrated model., Conclusions: The Genders model has a low accuracy for predicting functionally significant CAD. A new model integrating HDL cholesterol, AST, and hs-CRP levels with common clinical variables has a higher predictive accuracy for functionally significant CAD and allows the reclassification of patients from an intermediate/high to a low pretest likelihood of CAD., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The choice of imaging techniques in patients with suspected coronary artery disease (CAD) varies between countries, regions, and hospitals. This prospective, multicenter, comparative effectiveness study was designed to assess the relative accuracy of commonly used imaging techniques for identifying patients with significant CAD., Methods and Results: A total of 475 patients with stable chest pain and intermediate likelihood of CAD underwent coronary computed tomographic angiography and stress myocardial perfusion imaging by single photon emission computed tomography or positron emission tomography, and ventricular wall motion imaging by stress echocardiography or cardiac magnetic resonance. If ≥1 test was abnormal, patients underwent invasive coronary angiography. Significant CAD was defined by invasive coronary angiography as >50% stenosis of the left main stem, >70% stenosis in a major coronary vessel, or 30% to 70% stenosis with fractional flow reserve ≤0.8. Significant CAD was present in 29% of patients. In a patient-based analysis, coronary computed tomographic angiography had the highest diagnostic accuracy, the area under the receiver operating characteristics curve being 0.91 (95% confidence interval, 0.88-0.94), sensitivity being 91%, and specificity being 92%. Myocardial perfusion imaging had good diagnostic accuracy (area under the curve, 0.74; confidence interval, 0.69-0.78), sensitivity 74%, and specificity 73%. Wall motion imaging had similar accuracy (area under the curve, 0.70; confidence interval, 0.65-0.75) but lower sensitivity (49%, P<0.001) and higher specificity (92%, P<0.001). The diagnostic accuracy of myocardial perfusion imaging and wall motion imaging were lower than that of coronary computed tomographic angiography (P<0.001)., Conclusions: In a multicenter European population of patients with stable chest pain and low prevalence of CAD, coronary computed tomographic angiography is more accurate than noninvasive functional testing for detecting significant CAD defined invasively., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00979199., (© 2015 American Heart Association, Inc.)

Predictive assessment of the risk of developing cardiovascular diseases is usually provided by computational approaches centred on Cox models. The complex interdependence structure underlying clinical data patterns can limit the performance of Cox analysis and complicate the interpretation of results, thus calling for complementary and integrative methods. Prognostic models are proposed for studying the risk associated with patients with known or suspected coronary artery disease (CAD) undergoing vasodilator stress echocardiography, an established technique for CAD detection and prognostication. In order to complement standard Cox models, network inference is considered a possible solution to quantify the complex relationships between heterogeneous data categories. In particular, a mutual information network is designed to explore the paths linking patient-associated variables to endpoint events, to reveal prognostic factors and to identify the best possible predictors of death. Data from a prospective, multicentre, observational study are available from a previous study, based on 4313 patients (2532 men; 64±11 years) with known (n=1547) or suspected (n=2766) CAD, who underwent high-dose dipyridamole (0.84 mg kg(-1) over 6 min) stress echocardiography with coronary flow reserve (CFR) evaluation of left anterior descending (LAD) artery by Doppler. The overall mortality was the only endpoint analysed by Cox models. The estimated connectivity between clinical variables assigns a complementary value to the proposed network approach in relation to the established Cox model, for instance revealing connectivity paths. Depending on the use of multiple metrics, the constraints of regression analysis in measuring the association strength among clinical variables can be relaxed, and identification of communities and prognostic paths can be provided. On the basis of evidence from various model comparisons, we show in this CAD study that there may be characteristic factors involved in prognostic stratification whose complexity suggests an exploration beyond the analysis provided by the still fundamental Cox approach.

Aim: Genome-wide association studies have identified single-nucleotide polymorphisms at the 10q11 locus as risk factors for myocardial infarction (MI). This locus lies upstream (∼80 kb) of the stromal cell-derived factor-1 (SDF1) gene that codify for a chemokine with protective atherogenetic effects and with a major role in the mobilization, homing, and differentiation of endothelial progenitor cells (EPCs). The purpose of this study was to investigate the possible association of SDF1-3'A polymorphism, that upregulates SDF1 protein expression, with MI and early endothelial dysfunction and atherosclerosis in young healthy subjects., Methods: 200 patients (181 men age 57.3 ± 7.7 years) and 230 healthy controls (96 men, age 52 ± 11.9 years) were recruited to investigate the association between MI and SDF1-3'A polymorphism. The relationship between SDF1-3'A polymorphism and brachial artery flow-mediated dilation and the number of circulating EPCs was examined in 50 healthy young adults., Results: A significant difference in SDF1-3'A genotype distribution was observed between patients and controls (P = 0.006). Patients carrying the A allele had a significantly reduced MI risk compared with subjects with GG genotype (odds ratio = 0.5, 95% CI = 0.3-0.9, P = 0.001). SDF1-3'A polymorphism presented a significant interaction with other cardiovascular risk factors (Pinteraction < 0. 0001). Controls carrying the A allele showed significantly higher flow-mediated dilation (13.9 ± 4.9 vs 10.8 ± 4.3, P = 0.03) and significantly higher values of EPCs (0.029 ± 0.009 vs 0.022 ± 0.008, P = 0.02) compared with GG homozygotes., Conclusion: SDF1-3'A polymorphism is associated with a decreased risk of MI and early endothelial dysfunction, strongly confirming the important atherogenic role of SDF1 gene at clinical level.

Unlabelled: OBJECTIVE To evaluate the predictive value of resting heart rate (RHR) for cardiac and total mortality in a large population of patients referred for coronary angiography with an extended follow-up, stratified in four subpopulations according to gender and age (50th percentile corresponding to 67 years)., Methods: We studied 3559 subjects (2603 males, age: 66 ± 11 years, mean ± SD), obtaining patient data from the Institute electronic databank which saves demographic, clinical, instrumental and follow-up data of patients admitted to our department., Results: During a mean follow-up period of 35 ± 25 months, 296 (8%) patients died; there were 173 (5%) cardiac deaths. In female patients irrespective of age, RHR (≥ 76 bpm, 75th percentile) did not appear predictive for cardiac death. In females, RHR was predictive for overall mortality after multivariate adjustment only in those aged ≥ 67 years (hazard ratio (HR) 1.7, 95% confidence interval (CI) 1-2.8, p ≤ 0.05). In male patients aged < 67 years, RHR remained as an independent predictive factor for overall mortality at the multivariate analysis (HR 2.5, 95% CI 1.5-4.2, p < 0.001), and as an independent predictor for both cardiac mortality (HR 1.8, 95% CI 1.2-2.7, p < 0.01) and total mortality (HR 1.6, 95% CI 1.2-2.3, p < 0.01) in male patients over 67 years., Conclusion: The current study suggests that the prognostic importance of RHR may differ according to the patient's gender and age, suggesting significant differences in cardiovascular physiopathology between female and male patients.

Paediatric patients with non-oncologic chronic illnesses often require ongoing care that may result in repeated imaging and exposure to ionizing radiation from both diagnostic and interventional procedures. In this study the scientific literature on cumulative effective dose (CED) of radiation accrued from medical imaging among specific cohorts of paediatric, non-oncologic chronic patients (inflammatory bowel disease, cystic fibrosis, congenital heart disease, shunt-treated hydrocephalus, hemophilia, spinal dysraphism) was systematically reviewed. We conducted PubMed/Medline, Scopus and EMBASE searches of peer-reviewed papers on CED from diagnostic and therapeutic radiological examinations. No time restriction was introduced in the search. Only studies reporting CEDs accrued for a period >1 year were included. We found that the annual CED was relatively low (<3 mSv/year) in cystic fibrosis, congenital heart disease, patients with cerebrospinal fluid shunts and hemophilia, while being moderate (>3-20 mSv/year) in Crohn's patients. This extra yearly radiation exposure accrues over the lifetime and can reach high values (>100 mSv) in selected cohorts of paediatric chronic patients., (Copyright © 2014 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Several single-nucleotide polymorphisms (SNPs) have been recognized as associated with ischemic heart disease (IHD) although the optimal set of risk genotypes has not be identified. This study aimed to examine whether identified high-risk SNPs are associated with early onset of IHD. In the GENOCOR study, 44 high-risk SNPs were genotyped in 114 patients with early onset of IHD (46.2 ± 5.1 years) and 384 patients with late onset of IHD (60.7 ± 5.9 years). The associations between individual SNPs and early onset IHD were assessed. A multilocus genetic risk score (GRS) for each associated risk genetic markers was constructed by summing the number of risk alleles. The SNPs significantly associated with IHD were: -482C>T of Apolipoprotein C III gene (ApoC3, p=0.02); 1171 5A>6A of Matrix metalloproteinase 3 stromelisine I gene (p=0.01); G98T of Selectin E gene (p=0.05); C/G of 9p21.3 locus (p=0.01). Likelihood ratio test showed a strong interaction for increasing risk of early IHD between the presence of ApoC3 and 9p21.3 locus with hypertriglyceridemia (p=0.0008, 0.0011) as well as between 9p21.3 locus and smoking (p=0.0010) after correction for multiple testing. The OR for premature IHD for GRS unit was 1.3 (95% CI 1.1-1.6, p=0.001). Patients in the top tertile of GRS were estimated to have a 3.2-fold (95% CI 1.5-6.8; p=0.001) increased risk of early IHD compared with those in the bottom tertile. The results show that currently identified high-risk SNPs confer an additive biomarker for cardiovascular events. GRS may provide important incremental information on the genetic component of IHD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Medical imaging is one of the major cause of rising health care costs. Diagnostic imaging has increased more rapidly than any other component of medical care. About 5 billion imaging tests are performed worldwide each year. According to recent estimates, at least one-third of all examinations are partially or totally inappropriate. Two out of 3 imaging tests employ ionizing radiations with radiology or nuclear medicine. The medical use of radiation is the largest man-made source of radiation exposure. Medical X-rays and γ-rays are a proven human carcinogen. The attributable long-term extra-risk of cancer due to diagnostic testing is around 10% in industrialized countries. Cardiologists prescribe and/or directly perform >50% of all imaging examinations, accounting for about two-thirds of the total effective dose given to patients. The dose of common cardiological examinations may be significant: 500 chest X-rays= a stress scintigraphy with sestamibi, 750 chest X-rays= a Multislice Computed Tomography, 1,000 chest X-rays= a coronary angiography and stenting. Unfortunately, few doctors are aware of the level of radiation their patients are exposed to during radiological tests and more intensive use of ionizing testing was not associated with greater awareness. Also as a consequence of unawareness, the rate of inappropriate examinations is unacceptably high in cardiology, even for procedures with high radiation load. Higher exposure doses correspond to higher long-term risks; there are no safe doses, and all doses add up in determining the cumulative risks over a lifetime. Doctors should make every effort so that «each patient should get the right imaging exam, at the right time, with the right radiation dose», as suggested by US Food and Drug Administration in the 2010 initiative to reduce unnecessary radiation exposure from medical imaging. This is best obtained through a systematic implementation of the "3 A's strategy" proposed by the International Atomic Energy Agency in 2010: audit (of true delivered dose); appropriateness (since at least one-third of examinations are inappropriate); awareness (since the knowledge of doses and risks is largely). The regular application of "3 A's strategy" is usually not facilitated by a health system that pays for volumes, not for appropriateness.

Aims: Radiological inappropriateness in medical imaging leads to loss of resources and accumulation of avoidable population cancer risk. Aim of the study was to audit the appropriateness rate of different cardiac radiological examinations., Methods and Principal Findings: With a retrospective, observational study we reviewed clinical records of 818 consecutive patients (67 ± 12 years, 75% males) admitted from January 1-May 31, 2010 to the National Research Council - Tuscany Region Gabriele Monasterio Foundation cardiology division. A total of 940 procedures were audited: 250 chest x-rays (CXR); 240 coronary computed tomographies (CCT); 250 coronary angiographies (CA); 200 percutaneous coronary interventions (PCI). For each test, indications were rated on the basis of guidelines class of recommendation and level of evidence: definitely appropriate (A, including class I, appropriate, and class IIa, probably appropriate), uncertain (U, class IIb, probably inappropriate), or inappropriate (I, class III, definitely inappropriate). Appropriateness was suboptimal for all tests: CXR (A = 48%, U = 10%, I = 42%); CCT (A = 58%, U = 24%, I = 18%); CA (A = 45%, U = 25%, I = 30%); PCI (A = 63%, U = 15%, I = 22%). Top reasons for inappropriateness were: routine on hospital admission (70% of inappropriate CXR); first line application in asymptomatic low-risk patients (42% of CCT) or in patients with unchanged clinical status post-revascularization (20% of CA); PCI in patients either asymptomatic or with miscellaneous symptoms and without inducible ischemia on non-invasive testing (36% of inappropriate PCI)., Conclusion and Significance: Public healthcare system--with universal access paid for with public money--is haemorrhaging significant resources and accumulating avoidable long-term cancer risk with inappropriate cardiovascular imaging prevention.

Background: Several epidemiological reports indicate that the body mass index (BMI) is inversely related with mortality, in spite of the notion that obesity is a recognized cardio-metabolic risk factor. The aim of the study was to evaluate the independent impact of overweight and obesity on long-term mortality in a large cohort of patients with heart disease (HD)., Methods: The study included 10,446 patients hospitalized in the last three decades for ischemic (60%) or non-ischemic HD and followed-up for 10 years. The relationship between BMI and total or cardiovascular mortality was analyzed in the whole cohort, and in age-stratified categories (≤ 65 and >65 years). Considering that survival in HD patients has improved after the introduction of revascularization, beta-blockers, ACE inhibitors, and statins, the relationship was re-examined separately in patients hospitalized before and after 1990., Results: Diabetes, hyperuricemia, hypertension, glycaemia, and triglyceridemia increased across BMI groups. During follow-up (73 ± 59 months) there were 1707 all-cause deaths (47% cardiac). Any relationship between BMI and mortality was lost in the ≤ 65 age category and in patients hospitalized before 1990, but it persisted in old patients hospitalized after 1990. Most significant independent predictors of mortality in all groups were hyperuricemia, diabetes and impaired ejection fraction., Conclusions: No independent relationship was found between BMI and mortality in subjects ≤ 65 years of age. This neutral relationship seems to be partly counteracted by treatment, particularly in old patients. A different effect of obesity onset in old vs. young age cannot be ruled out., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Awareness of radiological risk is low among doctors and patients. An educational/decision tool that considers each patient' s cumulative lifetime radiation exposure would facilitate provider-patient communication., Aim: The purpose of this work was to develop user-friendly software for simple estimation and communication of radiological risk to patients and doctors as a part of the SUIT-Heart (Stop Useless Imaging Testing in Heart disease) Project of the Tuscany Region., Methods: We developed a novel software program (PC-platform, Windows OS fully downloadable at http://suit-heart.ifc.cnr.it) considering reference dose estimates from American Heart Association Radiological Imaging 2009 guidelines and UK Royal College of Radiology 2007 guidelines. Cancer age and gender-weighted risk were derived from Biological Effects of Ionising Radiation VII Committee, 2006., Results: With simple input functions (demographics, age, gender) the user selects from a predetermined menu variables relating to natural (e.g., airplane flights and geo-tracked background exposure), professional (e.g., cath lab workers) and medical (e.g., CT, cardiac scintigraphy, coronary stenting) sources. The program provides a simple numeric (cumulative effective dose in milliSievert, mSv, and equivalent number of chest X-rays) and graphic (cumulative temporal trends of exposure, cancer cases out of 100 exposed persons) display., Conclusions: A simple software program allows straightforward estimation of cumulative dose (in multiples of chest X-rays) and risk (in extra % lifetime cancer risk), with simple numbers quantifying lifetime extra cancer risk. Pictorial display of radiation risk may be valuable for increasing radiological awareness in cardiologists., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Aim: Proteomics is considered a promising tool in the discovery of new biomarkers and/or therapeutic targets. The aim of this study was to identify proteins expressed in the plasma of survivors of myocardial infarction and possible correlations between expression of some proteins and the severity of coronary artery disease (CAD) in this population., Methods: The study included 17 survivors (15 men; age=53±9 years) of myocardial infarction at young age (age<60 years) classified for the severity of CAD graded according to angiography and 10 healthy volunteers (nine men; age=54±9 years). Proteomic analysis was carried out using a high-throughput technology and MALDI TOF/TOF mass spectrometry., Results: Compared with the healthy population, 14 proteins were differentially expressed in patients, and were classified in three principal categories: contraction, inflammation, and coagulation. Results show a correlation between the angiographic severity, the extension of CAD, and the expression of some proteins. In particular decreased levels of vitamin D binding protein (VDBP) in the plasma of patients statistically correlated with the number of affected coronary arteries. Enzyme-linked immunosorbent assay test confirmed modulation of VDBP., Conclusion: Our results suggest that some proteins are differentially expressed in atherosclerotic patients and their disregulation is strongly dependent on the severity of the artery disease. The down regulation of VDBP is confirmed and marked in multivessel disease patients., (© 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.)

Background: Insulin resistance (IR) and endothelial dysfunction are frequently associated in cardiac disease. The T(-786)→C variant in the promoter region of the endothelial nitric oxide synthase (eNOS) gene has been associated with IR in both non-diabetic and diabetic subjects. Aim of the study was to assess the reciprocal relationships between T(-786)→C eNOS polymorphism and IR in ischemic and non-ischemic cardiomyopathy., Method: A group of 132 patients (108 males, median age 65 years) with global left ventricular (LV) dysfunction secondary to ischemic or non-ischemic heart disease was enrolled. Genotyping of T(-786)→C eNOS gene promoter, fasting glucose, insulin, and insulin resistance (defined as HOMA-IR index > 2.5) were determined in all patients., Results: Genotyping analysis yielded 37 patients homozygous for the T allele (TT), 70 heterozygotes (TC) and 25 homozygous for C (CC). Patients with CC genotype had significantly higher systemic arterial pressure, blood glucose, plasma insulin and HOMA index levels than TT. At multivariate logistic analysis, the history of hypertension and the genotype were the only predictors of IR. In particular, CC genotype increased the risk of IR (CI% 1.4-15.0, p < 0.01) 4.5-fold. The only parameter independently associated with the extent of LV dysfunction and the presence of heart failure (HF) was the HOMA index (2.4 CI% 1.1-5.6, p < 0.04)., Conclusions: T(-786)→C eNOS polymorphism was the major independent determinant of IR in a population of patients with ischemic and non-ischemic cardiomyopathy. The results suggest that a condition of primitive eNOS lower expression can predispose to an impairment of glucose homeostasis, which in turn is able to affect the severity of heart disease.

In 2010 the International Atomic Energy Agency launched the "3 A's campaign": Audit, Appropriateness and Awareness for radiological justification, which is an effective tool for cancer prevention. Cardiologists prescribe the majority of radiological testing, but their awareness of doses and risks of ionizing cardiac imaging test is low. To assess radioprotection awareness of prescribing and practicing physicians (mainly cardiologists) before and after a radioprotection course. We held a 1-day 6-h primer of radioprotection for a limited number (20-35) of physicians. The course offered 8 continuing education credits from the Italian Health Ministry and was held 9 times over 3 years. We had 425 attendees, but full data sets (with complete questionnaires) were available for 403 physicians (55% women, age 45 ± 6 years), including 55% cardiologists, 40% general practitioners, 5% others (mainly cardiology fellows). For each attendee, a radiological awareness score was obtained before and after the course, with a survey containing 10 multiple-choice questions (5 answers) on radioprotection basics (doses of common examinations in multiples of chest x-rays; associated cancer risk, etc.). Each answer was scored from 0 ("don't know"), 1 ("strongly disagree") to 4 ("strongly agree"). The radiological awareness score of the 403 attendees improved from 31 ± 3 (before) to 37 ± 2 (after training, P < 0.001 vs. pre-training). As an example, before training, 25% of attendees believed that radiation-induced cancer risk disappears after 6 months (10% of respondents), 12 months (8%) or 5 years (7%), whereas 75% (becoming 98% after training) correctly estimated that radiological damage is cumulative over one's lifetime. Awareness of radiological doses and risks, albeit essential for risk-benefit assessment of radiological testing, is suboptimal among cardiologists, but can dramatically improve with a limited teaching effort through targeted training.