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The purpose of this work was to evaluate the relation between serum glucose levels at hospital admission and left ventricular systolic function in nondiabetic patients with an acute coronary syndrome (ACS). Of the 1000 ACS patients who were consecutively enrolled during 2007-2008, 583 (63 ± 13 years, 20% females) nondiabetic patients were studied in this work. Of these, 254 presented left ventricular systolic dysfunction (ejection fraction 155 mg/dl) had lower left ventricular ejection fraction (40% vs 45%, P = 0.003), were older (66 ± 11 vs 61 ± 13, P = 0.004) and less physically active (49% vs 63%, P = 0.02), had higher troponin (14.7 ± 39.7 vs 5.6 ± 13.5, P = 0.03), higher brain natriuretic peptide (510.39 ± 932.33 vs 213.4 ± 301.14, P = 0.008), higher C-RP (42.26 ± 55.26 vs 26.46 ± 38.18, P = 0.04), lower creatinine clearance levels (68 ± 33 vs.81 ± 31, P = 0.009), higher white blood cell count (13 416 ± 16 420 vs 9310 ± 3020, P = 0.001), and lower body mass index (26.8 ± 4 vs 27.2 ± 4.4, P = 0.07), compared to those in the lowest tertile (

Background & aims: Sarcopenia and sarcopenic obesity may be associated with nonalcoholic fatty liver disease (NAFLD). This study examined the association between low skeletal muscle mass, with or without central obesity, with NAFLD, as well as their interaction on predicting 10-year incidence of cardiovascular disease (CVD). Methods: This was a post-hoc analysis of the ATTICA study. At baseline, 3042 participants from the Attica region of Greece were recruited; 2020 completed the 10-year follow-up visit for CVD. NAFLD was assessed through hepatic steatosis index (HSI). Skeletal muscle mass index (SMI) was calculated to assess skeletal muscle mass. SMI was studied in tertiles, stratified by sex; the first tertile corresponds to the lowest SMI, the second to middle, and the third to highest SMI. Abnormal waist circumference was defined as ≥102 cm for men and ≥88 cm for women. The combined 10-year endpoint was the development of a fatal or nonfatal CVD event. Logistic regression analysis was used to assess the association between NAFLD prevalence and SMI as well as Cox regression analysis to assess the interaction of both variables on the incidence of CVD over 10 years. Results: Higher rates of NAFLD were observed in the first (45%) compared to the second [33%; odds ratio (OR): 0.50, 95% confidence interval (95%CI): 0.41–0.61] and the third (22%; OR: 0.24, 95%CI: 0.19–0.29) SMI tertile. This association remained robust after multiple adjustments; significance was marginally lost, when waist circumference was added to the model. When SMI and waist circumference were evaluated jointly, participants with moderate/high SMI and normal waist circumference had the lowest and those with low SMI and abnormal waist circumference the highest NAFLD rate (24.3 and 60.5%, respectively; P < 0.001). Ten-year CVD incidence was gradually lower from the first (22.8%) to second (16.1%) and third SMI tertile (8.2%) (P < 0.001). The hazard ratio (HR) for the third vs. the first SMI tertile for predicting CVD in fully adjusted model was 0.69 (95%CI: 0.46, 1.00). The unadjusted HR for NAFLD predicting CVD was 3.00 (95%CI: 2.28–3.95). Finally, there was a significant interaction among NAFLD, SMI and waist circumference (P = 0.04) in determining the 10-year CVD incidence; the association between NAFLD and 10-year CVD remained significant for the participants with low SMI and normal or abnormal waist circumference, but not those with moderate/high SMI and normal or abnormal waist circumference. Conclusions: Increasing SMI and lower abdominal obesity are independently associated with lower rates of NAFLD, and the two interact as key determinants of NAFLD. Low SMI and central obesity are independent predictors of CVD and were shown to interact with NAFLD in determining 10-year CVD risk. © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism

Background/objectives: We evaluated the role of the presence of non-alcoholic fatty liver disease (NAFLD) at baseline in the transition from metabolically healthy to metabolically unhealthy obesity (MHO to MUO) ten years later. Methods: A prospective cohort study (ATTICA study, Greece) was performed between 2002 and 2012 studying a sample from the greater metropolitan Athens area. In total, 1514 (49·8%) men and 1528 (50.2%) women (aged >18 years old) free-of-CVD were included. Healthy metabolic status was defined as absence of all NCEP ATP III (2005) metabolic syndrome components. NAFLD was defined according to validated liver steatosis indices. Follow-up CVD assessment (2011–2012) was achieved in n = 2020 participants (n = 317 cases). Results: NAFLD prevalence among MHO participants ranged from 29% to 39% according to the specific NAFLD score used. MHO participants who developed metabolically unhealthy status had about two times higher odds to have NAFLD at baseline compared with their metabolically healthy normal weight counterparts whereas stable MHO was not associated significantly with NAFLD. Moreover, MHO status accompanied by NAFLD was associated with increased CVD risk (Hazard Ratio = 2.90 95% Confidence Interval (1.35, 5.40)) in comparison to their non-NAFLD MHO counterparts. Further analysis revealed that in the obese, NAFLD indices and not simply visceral adiposity increased significantly the ability of metabolic status (using standard definition) to predict long-term CVD incidence. Conclusions: Considering NAFLD, even when assessed using validated indices only, in the clinical assessment of apparently healthy obese individuals predicts who is to develop MUO and contributes independently and more accurately to defining future cardiometabolic risk. © 2021 Elsevier Inc.

Background and Objectives: Various bio-psychosocial mechanisms underlying the link between anxiety, depression and cardiovascular disease risk, remain unknown. We investigated the role of irrational beliefs in conjunction with anxiety and depression in the 10-year cardiovascular disease (CVD) incidence, and the effect of biochemical and socio-behavioral factors. Design: 853[453 men (45 ± 13 years) and 400 women (44 ± 18 years)] from the ATTICA study (2002–2012) and without evidence of CVD were assessed. Methods: The Irrational Beliefs Inventory (IBI), the Zung Self-Rating-Depression-Scale (ZDRS) and the State-Trait-Anxiety-Inventory (STAI) were used for the assessments. Incidence of CVD was defined according to the International Coding Diseases (ICD)−10 criteria. Results: Participants with high irrational beliefs and anxiety symptoms had a 138% greater risk of developing CVD during the 10-year follow-up (2.38; 95%CI 1.75, 3.23) as compared to those without anxiety. Among others, C-reactive protein, interleukin-6 and total antioxidant capacity were mediators in the tested association. Interaction of irrational beliefs and depression was not associated with the 10-year CVD in all models. Conclusions: Inflammation and oxidative stress, partially explained the associations between irrational beliefs and anxiety in predicting CVD risk. These findings advance psychological research in the area of primary prevention of mental health and cardiovascular diseases. © 2022 Informa UK Limited, trading as Taylor & Francis Group.

Purpose: We prospectively evaluated the association between quality of plant-based diets and 10-year first fatal/non-fatal cardiovascular disease (CVD) incidence. Methods: ATTICA study was conducted in the greater metropolitan Athens area, Greece, during 2001–2002 studying men and women (aged > 18 years old) free of CVD at baseline. Follow-up CVD assessment (2011–2012) was achieved in n = 2,020 participants (n = 317 cases). Dietary assessment was based on a validated semi-quantitative paper-based food frequency questionnaire. Overall, healthful, and unhealthful plant-based dietary indices (PDI, hPDI and uPDI) were calculated through a standard published procedure. The association between plant-based indices and CVD outcome has been evaluated via Cox regression analysis. Results: The CVD event rate was 15.7% (n = 317) with a median follow-up time of 8.41 years. The highest (3rd PDI tertile) vs. lowest (1st tertile) adherence to plant-based pattern—irrespective to healthfulness of food products consumed—was inversely associated with CVD (hazard ratio (HR) 0.56; 95% confidence interval (95% CI) 0.14, 2.25) yet the CI was wide. Ranking from 1st to 2nd and 3rd hPDI tertile the CVD event rate was 6.4%, 10.5% and 16.2%, respectively (p = 0.003). Multi-variable adjusted analysis revealed that participants assigned in 2nd and 3rd hPDI tertile had 47% (HR 0.53; 95% CI 0.25–1.08) and 68% (HR 0.32; 95% CI 0.16–0.63) lower risk to develop CVD compared with their 1st tertile counterparts. Conversely, a positive association between uPDI and CVD risk was revealed in dose–response analysis (HR(per5unitsincreaseinuPDI) 1.34; 95% CI 0.95–2.37)). Conclusions: Quality of plant-based diets is important and needs to be considered, as not all plant-source foods have beneficial cardiovascular effects. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.

Heterozygous familiar hypercholesterolemia (hFH) is an autosomal dominant inherited dyslipidemia, associated with premature cardiovascular disease (CVD). Aim of the study was to define prognostic factors for cardiovascular events (CVE) in asymptomatic individuals with hFH. All participants with recent diagnosis of hFH were recruited from the outpatient lipid clinic from 1987 to 2016, without any previous clinical evidence of CVD. A detailed clinical evaluation and laboratory investigation was obtained. Exercise tolerance test (ETT) was performed until maximum exercise capacity was achieved, without evidence of ischemia. Primary endpoint of the study was the first CVE. Four hundred fifty one participants were followed up for 10 ± 8 years, with 68 recorded cases of CVD (15%). Cumulative incidence of CVD was 15%, 24% and 32% for the 3 decades, respectively. In univariate analysis, male gender (p = 0.016), progression of age (p < 0.001), menopause (p = 0.030), waist–hip ratio (p = 0.043) and increased levels of Lp(α) (p = 0.014) were significantly associated with increased CVD incidence; whereas, exercise capacity (p = 0.025), low variation of heart rate (HR) during all stages of ETT compared to resting state (p = 0.020), maximum systolic (p = 0.014) and diastolic (p < 0.001) blood pressure were inversely associated with CVD. In multi-adjusted analysis, male gender (p < 0.001), duration of ETT (p = 0.023), estimated HR (p = 0.029), variation of HR during ETT compared to resting state (p < 0.05) and maximum diastolic pressure (p = 0.044) were significantly associated with CVD. Parameters of ETT in asymptomatic individuals with hFH, without any evidence of ischemia, may predict CVD in these high-risk patients after decades of observation. © 2019, Springer Japan KK, part of Springer Nature.

Background: The aim of this work was to evaluate the impact of peritoneal dialysis (PD) on venous congestion, right ventricular function, pulmonary artery systolic pressure (PASP), and clinical functional status in elderly patients with cardiorenal syndrome (CRS) and chronic heart failure (HF). Methods: A case series of 21 (17 males, age 70 ± 11 years) consecutive patients with HF along with diuretic resistance and right ventricular dysfunction (median renal failure duration 60 months, range 13-287 months, mean ejection fraction 36 ± 11%) having been engaged in PD; 76% of the patients were under automated peritoneal dialysis (APD), whereas the rest were under continuous ambulatory PD (CAPD). Patients’ PASP and central venous pressure (CVP) – through compression sonography – and body weight were evaluated before initiating the PD program and at 6 and 12 months. Results: During the follow-up period, the mortality rate was 8 deaths out of 21 patients (38%) A significant reduction by 29.9% in PASP levels (p = 0.013) and by 42% in CVP levels (p < 0.001), and in right ventricular function assessed by tricuspid annulus tissue Doppler velocity (p = 0.04) was observed, whereas patients’ weight increased by 3.7% (p = 0.001). New York Heart Association class improved in 12 patients, whereas in the remaining patients, it remained constant (p = 0.046). In 8 patients, complications were reported (mainly presence of Staphylococcus aureus). In conclusion, PD seems to confer a substantial benefit in clinical status, which is in line with improvement in venous congestion and right ventricular systolic pressure among elderly patients with HF along with CRS. © 2019 Hellenic Society of Cardiology

Background: Nonalcoholic fatty liver disease (NAFLD) is correlated with low-grade inflammation and dietary habits. Until today, there have been limited epidemiologic data assessing the role of diet’s inflammatory potential on NAFLD. The aim was to evaluate the relationship between an anti-inflammatory diet, as reflected by the Dietary Anti-Inflammation Index (D-AII), and NAFLD among cardiovascular disease (CVD)-free adults. Methods: ATTICA is a prospective, population-based study that recruited 3042 adults without pre-existing CVD from the Greek population (Whites; age ⩾18 years; 1514 men and 1528 women). D-AII was calculated using a standard procedure. The baseline study captured various sociodemographic, lifestyle and clinical characteristics as well as hepatic markers. These were used to calculate four NAFLD assessment indices: triglyceride-glucose (TyG) index, fatty liver index (FLI), hepatic steatosis index (HSI), and NAFLD Fatty Liver Score (NAFLD-FLS). Specific cutoffs were applied to capture NAFLD. Results: D-AII showed a significant inverse association with NAFLD, applying the four indices with NAFLD cutoffs [odds ratio (OR) with 95% confidence interval (CI); TyG (0.95, 0.93–0.98); HSI (0.89, 0.86–0.92); FLI (0.88, 0.85–0.91); NAFLD-FLS (0.89, 0.86–0.92)], after adjusting for various confounders. Participants in the highest D-AII tertile had lower odds of having NAFLD, compared with those in the lowest D-AII tertile [(OR, 95% CI); TyG (0.33, 0.24–0.47); HSI (0.13, 0.08–0.23); FLI (0.05, 0.02–0.11); NAFLD-FLS (0.13, 0.07–0.23)]. Anti-inflammatory nutrition was related to lower odds of NAFLD among daily alcohol drinkers and individuals with metabolic syndrome. Conclusions: Anti-inflammatory diet is an important predictor of NAFLD among adults without pre-existing CVD. Adherence to a high anti-inflammatory diet seems to contribute to NAFLD prevention. © The Author(s), 2019.

By 2050, the global population aged 60 years and over is expected to reach nearly 2.1 billion and affective disorders might be also expected to increase. Although nutrition has been related with affective disorders, there is a lack of studies assessing the relation between dietary habits and anxiety among European and Mediterranean older populations. In the present study, we aimed to evaluate the association between dietary habits, energy intake, and anxiety symptoms using data from 1128 Greek older adults (>50 years) without pre-existing cardiovascular disease (CVD) or any other chronic disease who participated in the ATTICA study. Various socio demographic lifestyle, bio-clinical (e.g., blood pressure), and psychological (e.g., depression) characteristics were used, and dietary habits as well as energy intake were calculated using standard procedures. Older people with anxiety were more likely to be sedentary, to be smokers, and to show symptoms of depression. The saturated fat and added sugars (SFAS) dietary pattern was associated with higher anxiety levels (non-standardized b (95% CI): 5.82 (0.03 to 11.61)). No association between energy intake tertiles and anxiety levels pictured in the later regression model. Moreover, female gender, family status, and depression were positively related to anxiety. Therefore, promoting healthy dietary habits could reduce anxiety symptoms of the older adults. © 2019, MDPI AG. All rights reserved.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is correlated with low-grade inflammation and dietary habits. Until today, there have been limited epidemiologic data assessing the role of diet's inflammatory potential on NAFLD. The aim was to evaluate the relationship between an anti-inflammatory diet, as reflected by the Dietary Anti-Inflammation Index (D-AII), and NAFLD among cardiovascular disease (CVD)-free adults. METHODS: ATTICA is a prospective, population-based study that recruited 3042 adults without pre-existing CVD from the Greek population (Whites; age ?18 years; 1514 men and 1528 women). D-AII was calculated using a standard procedure. The baseline study captured various sociodemographic, lifestyle and clinical characteristics as well as hepatic markers. These were used to calculate four NAFLD assessment indices: triglyceride-glucose (TyG) index, fatty liver index (FLI), hepatic steatosis index (HSI), and NAFLD Fatty Liver Score (NAFLD-FLS). Specific cutoffs were applied to capture NAFLD. RESULTS: D-AII showed a significant inverse association with NAFLD, applying the four indices with NAFLD cutoffs [odds ratio (OR) with 95% confidence interval (CI); TyG (0.95, 0.93-0.98); HSI (0.89, 0.86-0.92); FLI (0.88, 0.85-0.91); NAFLD-FLS (0.89, 0.86-0.92)], after adjusting for various confounders. Participants in the highest D-AII tertile had lower odds of having NAFLD, compared with those in the lowest D-AII tertile [(OR, 95% CI); TyG (0.33, 0.24-0.47); HSI (0.13, 0.08-0.23); FLI (0.05, 0.02-0.11); NAFLD-FLS (0.13, 0.07-0.23)]. Anti-inflammatory nutrition was related to lower odds of NAFLD among daily alcohol drinkers and individuals with metabolic syndrome. CONCLUSIONS: Anti-inflammatory diet is an important predictor of NAFLD among adults without pre-existing CVD. Adherence to a high anti-inflammatory diet seems to contribute to NAFLD prevention.

Background: Familial dyslipidemias of either heterozygous (heFH) or combined (FCH) type lead to accelerated atherogenesis and increased cardiovascular risk. Objective: The aim of this study was to investigate in statin-naïve adult patients with familial dyslipidemias whether inflammatory activation and liver, spleen and bone marrow metabolic activity differ compared with normolipidemic subjects and between dyslipidemic groups. Methods: Fourteen patients with FCH, 14 with heFH, and 14 normolipidemic individuals were enrolled. Serum lipids, high-sensitivity C-reactive protein, and fibrinogen levels were measured, followed by 18 F-fluorodeoxyglucose positron-emission tomography/computed tomography imaging. Radiotracer uptake in the aortic wall, spleen, bone marrow, and liver was quantified as tissue-to-background ratio (TBR). Results: Patients with heFH had significantly higher low-density lipoprotein levels compared with those with FCH and controls (P < .001). However, aortic TBRs were higher in FCH compared with heFH patients and controls (P = .02 and P < .001, respectively). FCH patients exhibited higher FDG uptake in the spleen compared with controls (P = .05). In addition, FCH exhibited higher bone marrow FDG uptake compared with heFH patients and controls (P = .03 and P = .02, respectively). FCH had higher liver uptake compared with heFH patients and controls (P < .001 for both). Significant correlations were observed between inflammatory biomarkers and imaging indices as well as between aortic TBR and FDG uptake of hematopoietic organs and liver. Conclusions: Systemic, as well as vascular inflammation and spleen, bone marrow, and hepatic metabolic activity are increased in patients with FCH despite lower levels of low-density lipoprotein. © 2017 National Lipid Association

Background: Aging is characterized by an insidious decline in cognitive function. Several genetic and lifestyle factors have been implicated in the increased risk or early onset of dementia Aim: We sought to assess the role of tumor necrosis factor (TNF) and angiotensin-converting enzyme (ACE) polymorphisms on the development of impaired mental health in respect to indices of arterial aging in nonagenarian individuals. Design: 178 consecutive subjects above 75 years that permanently inhabit in the island of IKARIA, Greece were recruited. Methods: Aortic distensibility (AoD) was calculated and genetic evaluation was performed on the ACE Insertion/Deletion gene polymorphism (intron 16) and the G/A transition (position -308) of the TNF gene. Cognitive function was evaluated using the Mini-mental State Examination (MMSE). Results: The DD genotype for ACE was independently associated (b=-0.44, P = 0.007) with AD while AoD remained an independent determinant of mental status (OR=1.82, P = 0.036). Interestingly though, when a combined genetic index (GI) was calculated for both genes (ACE and TNF), subjects being double homozygous (DD for ACE and GG for TNF) for these loci presented significantly decreased MMSE (adjusted OR=0.259, P = 0.033). This GI independently associated with AD (beta coefficient =-0.785, P = 0.002). When AoD was included, GI lost its predictive role (OR=0.784, P = 0.783) towards MMSE. AoD has marginal indirect mediating effect in the association of the GI with MMSE (P = 0.07). Conclusion: Vascular aging may modulates the genetic substrate of elderly subjects on the risk for developing dementia. © The Author 2017.

Background: Diabetes mellitus type 2 (T2DM) often co-exists with hypertension, and this aggregation of co-morbidities amplifies the risk for future cardiovascular events. Therefore, it appears crucial to understand the essence of choosing oral and non-insulin injectable anti-diabetic drugs (ADs) with a favorable hemodynamic impact that could partially attenuate the increased baseline cardiovascular risk. Objective: We sought to evaluate the effect of ADs on blood pressure (BP) indices and to assess the potential role of certain ADs towards hypertension treatment. Method: We performed a systematic review of the literature searching MEDLINE via Pubmed for all human studies implementing ADs, either individually or in combinations. Results: Metformin was found to reduce BP in small cohorts but failed to confirm its beneficial effect in a metaanalysis of 41 studies. Thiazolidinediones are associated with BP lowering but are contraindicated in patients with heart failure. Sulfonylureas, on the other hand, may increase BP, while a-glucosidase inhibitors, DPP-4 inhibitors, and SGLT2 inhibitors activate favorable pathophysiologic mechanisms serving as potential BP lowering agents. Relevant BP reduction was established for GLP-1 Ras in most clinical trials. Conclusion: The favorable hemodynamic impact of certain classes of ADs might provide synergistic or incremental therapeutic benefits in high-risk patients suffering from both T2DM and hypertension. Additional randomized trials designed under the hypothesis of the emerging beneficial hemodynamic effect of ADs are expected to provide more robust evidence and to guide the optimization of combined treatment strategies in this challenging group of patients. © 2017 Bentham Science Publishers.

Aims Haemodynamic parameters during and after exercise test seem to have a role in predicting cardiovascular events. We sought to evaluate the potential different responses in exercise capacity, heart rate and blood pressure levels in relation to major cardiovascular disease risk factors, among individuals undergoing exercise tolerance testing. Methods and results Consecutive individuals (N = 12,327), aged 55 ± 11.8 years, underwent exercise tolerance testing, using the Bruce protocol. Obese participants showed higher values of peak systolic and diastolic blood pressure (p < 0.01), with no heart rate differences. Diabetic patients presented increased systolic blood pressure across the test (p = 0.02) and decreased tolerance to exercise (p = 0.05), but without differences in diastolic blood pressure or heart rate. Hypertensives showed exaggerated blood pressure, chronotropic response and decreased capacity to exercise (p < 0.001 for all). Smokers had increased baseline systolic blood pressure, peak diastolic blood pressure and recovery heart rate and decreased tolerance to exercise (p < 0.001 for all). For all high-risk subgroups, exercise testing was more often positive. Age-stratified analysis revealed different patterns: all four risk factors significantly decreased peak metabolic equivalent in subjects

Aim: Ikaria Island (North-East Aegean, Greece) has been recognized as one of the places with the highest life expectancy around the world (the Blues Zones). Risk factors in relation to 4-year all-cause mortality and cardiovascular disease (CVD) incidence in elders were studied. Methods: From June to October 2009, 330 men and 343 women, aged 65 to 100 years, were enrolled, and in June to July 2013, they were reevaluated. Results: Age-standardized, gender-specific, all-cause mortality rate was 790 deaths per 10 000 inhabitants, and causes of death were CVD (36%), cancer (21%), infection (10%), respiratory disease (2%), and other (31%). Incidence of CVDwas 520 cases per 10 000 men inhabitants and 320 cases per 10 000 women (P =.03). Age, male gender, heart rate, urea levels, left atrial maximum volume, left ventricular hypertrophy, thyroid-stimulating hormone, and moderate to severe depression were positively associated with mortality, whereas left ventricular ejection fraction as well as coffee and tea drinking, fruit intake, and exclusive olive oil use were inversely associated with CVD. Conclusion: Heart function markers in addition to antioxidant dietary factors were placed in this puzzle of CVD morbidity. © SAGE Publications.

Carotid atherosclerosis (CA) and chronotropic incompetence (CI) during exercise are two independent cardiovascular risk factors. Aim of the current study was to investigate the possible association between them, in apparently healthy individuals, after adjusting for the 10-year cardiovascular disease (CVD) risk score. This cross-sectional study consisted of 139 apparently healthy subjects, 40–65 years old, who underwent treadmill exercise test (Bruce protocol used), which showed no evidence of ischemia. Heart rate reserve (HR reserve) was calculated to assess chronotropic response; a value of ≤0.80 is considered CI. CA was assessed by the presence of carotid plaque(s) in common and internal carotid arteries and carotid bulb bilaterally, using B-mode ultrasound. A calibrated version of SCORE (i.e., HellenicSCORE) was used to estimate the 10-year fatal CVD risk; participants were classified into low-, moderate- or high-risk group. CI was present in 7.9 % and CA in 18.7 % of the participants. After adjusting for 10-year CVD risk and other key confounders, odds of CA were 8.6 times higher in subjects with CI compared to their counterparts with normal chronotropic response to exercise. The results of the study indicate that CI during exercise can lead to high clinical suspicion of CA in apparently healthy individuals. © 2014, Springer Japan.