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Aims: This randomized controlled trial sought to determine the financial impact of an initial diagnostic strategy of coronary computed tomography angiography (CCTA) in patients with heart failure (HF) of unknown aetiology. Invasive coronary angiography (ICA) is used to investigate HF patients. CCTA may be a non-invasive cost-effective alternative to ICA. This randomized controlled trial sought to determine the financial impact of an initial diagnostic strategy of coronary computed tomography angiography (CCTA) in patients with heart failure (HF) of unknown aetiology., Methods and Results: This multicentre, international trial enrolled patients with HF of unknown aetiology. The primary outcome was the cost of CCTA vs. ICA strategies at 12 months. Clinical outcomes were also collected. An 'intention-to-diagnose' analysis was performed and a secondary 'as-tested' analysis was based on the modality received. Two hundred and forty-six patients were randomized (age = 57.8 ± 11.0 years, ejection fraction = 30.1 ± 10.1%). The severity of coronary artery disease was similar in both groups. In the 121 CCTA patients, 93 avoided ICA. Rates of downstream ischaemia and viability testing were similar for both arms. There were no significant differences in the composite clinical outcomes or quality of life measures. The cost of CCTA trended lower than ICA [CDN -$871 (confidence interval, CI -$4116 to $3028)]. Using an 'as-tested' analysis, CCTA was associated with a decrease in healthcare costs (CDN -$2932, 95% CI -$6248 to $746)., Conclusion: In patients with HF of unknown aetiology, costs were not statistically different between the CCTA and ICA strategies., Clinical Trials.gov: NCT01283659., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Coronary microvascular dysfunction (CMD) can cause angina in the absence of obstructive coronary artery disease (CAD). We studied the frequency and angiographic characteristics of CMD in symptomatic patients with suspected stable CAD and identified CMD as diffusely abnormal coronary vasodilator capacity by positron emission tomography (PET) perfusion imaging., Methods and Results: We recruited prospectively 189 patients with intermediate pre-test probability of CAD who underwent coronary computed tomography angiography and quantitative 15O-water PET perfusion imaging followed by invasive coronary angiography, and assessment of fractional flow reserve when feasible. Prevalence of obstructive epicardial CAD was 37%. Absolute myocardial blood flow was diffusely reduced (<2.4 mL/g/min) within the left ventricle during adenosine stress in 32 (17%) patients. In 15 (8%) patients, this was explained by three-vessel obstructive CAD, whereas the remaining 17 (9%) were diagnosed with CMD. Of these, 2 (1% of all patients) had no coronary atherosclerosis, 5 (3% of all patients) had non-obstructive atherosclerosis, and in 10 (5% of all patients) CMD co-existed with obstructive CAD. Atypical angina or non-anginal chest pain (53%) was the most common presentation. Older age and male sex were associated with CMD, but other risk factors of CAD were equally common in patients with or without CMD., Conclusion: Coronary microvascular dysfunction exists in 9% of symptomatic stable patients with suspected CAD. However, the prevalence of microvascular dysfunction without any coronary atherosclerosis is low (1%) in this population., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aims: We investigated associations of pre-clinical coronary heart disease (CHD), adolescence and adulthood CHD risk factors, and epicardial fat volume (EFV), which is thought to influence CHD pathology., Methods and Results: EFV and coronary calcium scores were quantified using computed tomography imaging for 557 subjects from the Cardiovascular Risk in Young Finns Study in 2007. CHD risk marker levels were assessed repeatedly from 1980 to 2007. Carotid intima-media thickness (cIMT), carotid distensibility, and brachial flow-mediated dilatation were measured by vascular ultrasound in 2007. Increased EFV was cross-sectionally associated with male sex, increased waist circumference, body-mass index (BMI), cIMT, metabolic syndrome prevalence, levels of apolipoprotein B, total cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein, blood pressure, insulin, and fasting glucose, as well as ever smoking, alcoholic intake, and lower high-density lipoprotein cholesterol (HDL-C), carotid distensibility and physical activity in adulthood. In BMI-adjusted analyses, only apolipoprotein B, ever smoking, alcohol intake and metabolic syndrome prevalence were independently associated with EFV. In adolescence, skinfold thickness, BMI, and insulin levels were higher and HDL-C lower with increasing EFV. Subjects in the lowest vs. highest quarter of EFV had consistently lower BMI across the early life-course., Conclusion: Associations of CHD risk markers with EFV were attenuated after multivariable adjustment. We found no evidence of increased EFV being independently associated with pre-clinical atherosclerosis. EFV was most strongly associated with BMI and waist circumference. Subjects with higher EFV had consistently higher BMI from age 12 suggesting that life-long exposure to higher BMI influences the development of EFV., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Epidural spinal cord stimulation (SCS) provides symptom relief in refractory angina pectoris, but its mechanism of action remains incompletely understood. We studied effects of short-term SCS therapy on myocardial ischaemia tolerance, myocardial perfusion reserve (MPR), and endothelium-mediated vasodilatation induced by cold pressor test (CPT) in patients with refractory angina pectoris., Methods and Results: We prospectively recruited 18 patients with refractory angina pectoris and studied them after implantation of SCS device at baseline before starting the therapy and after 3 weeks of continuous SCS therapy. Myocardial ischaemia was evaluated by dobutamine stress echocardiography. Global and regional myocardial blood flow (MBF) were measured using positron emission tomography and (15)O-water at rest, during adenosine stress, and in response to CPT. Systemic haemodynamics were comparable before and after 3 weeks of SCS at rest, during adenosine stress and during CPT. Appearance of angina pectoris induced by dobutamine stress was delayed after SCS therapy. Global MPR increased (P = 0.02) from 1.7 ± 0.6 at baseline to 2.0 ± 0.6 after 3-week SCS therapy. This was associated with a significant reduction in global MBF at rest and increase in MBF induced by adenosine in the ischaemic regions. Global MBF response to CPT was improved after SCS (0.27 ± 0.20 vs. 0.40 ± 0.15, P = 0.03)., Conclusion: Short-term SCS therapy improved myocardial ischaemia tolerance, absolute MPR, and endothelium-mediated vasomotor function in refractory angina pectoris, indicating that this therapy can alleviate myocardial perfusion abnormalities in advanced CAD., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Objectives: We compared the accuracy of quantified myocardial flow reserve and absolute stress myocardial blood flow (MBF) alone in the detection of coronary artery disease (CAD)., Background: Myocardial flow reserve, i.e. ratio of stress and rest flow, has been commonly used to detect CAD with many imaging modalities. However, it is not known whether absolute stress flow alone is sufficient for detection of significant CAD., Methods: We enrolled 104 patients with moderate (30-70%) pre-test likelihood of CAD without previous myocardial infarction. MBF was measured by positron emission tomography and O-15-water at rest and during the adenosine stress in the regions of the left anterior descending, left circumflex, and right coronary artery. All the patients underwent invasive coronary angiography including the measurement of fractional flow reserve when appropriate., Results: Quantified myocardial flow reserve (optimal cut-off value 2.5) detected significant coronary stenosis with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 81, 87, 66 and 94%, respectively. When compared with flow reserve, absolute MBF at stress (optimal cut-off value of 2.4 mL/min/g) was more accurate in detecting significant coronary stenosis [area under the curve (AUC) 0.94 vs. 0.90, P = 0.02] with sensitivity, specificity, PPV, and NPV of 95% (P = 0.03 vs. flow reserve), 90, 73, and 98%, respectively. An absolute increase of MBF from rest to stress by <1.5 mL/g/min had also similar accuracy in detecting CAD (AUC: 0.95). The results were comparable in patients who did and did not receive i.v. beta-blockers prior imaging., Conclusions: Absolute stress perfusion alone was superior to perfusion reserve in the detection of haemodynamically significant CAD and allows shorter imaging protocols with smaller radiation dose., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Accelerated flow at the site of flow-limiting stenosis can be detected by transthoracic Doppler echocardiography (TTDE). We studied feasibility and accuracy of sequential coronary computed tomography angiography (CTA) and TTDE in detection of haemodynamically significant coronary artery disease (CAD)., Methods and Results: We prospectively enrolled 107 patients with intermediate (30-70%) pre-test likelihood of CAD. All patients underwent CTA using a 64-slice scanner. Using TTDE, the ratio of maximal diastolic flow velocity to pre-stenotic flow velocity (M/P ratio) was measured in the coronary segments with stenosis in CTA. In all patients, the results were compared with invasive coronary angiography, including measurement of fractional flow reserve when appropriate. All analyses were done blinded. TTDE was feasible in 276 of 285 evaluated coronary segments. Significant coronary stenoses were associated with a higher M/P ratio than non-significant stenoses (3.59 ± 1.82 vs. 1.28 ± 0.60, P < 0.001). The optimal M/P ratio for detection of significant stenosis was 2.2 (area under receiver operating characteristic curve 0.92, P < 0.001). Compared with the strategy of CTA alone, sequential CTA and focused TTDE had a better positive predictive value (PPV; 61 vs. 78%) and diagnostic accuracy (93 vs. 96%, P = 0.006) without impairment of the negative predictive value (97 vs. 97%)., Conclusion: Sequential use of CTA and TTDE is feasible for combined anatomic and functional evaluation of coronary stenoses. Compared with coronary CTA alone, addition of TTDE improved PPV for detection of significant CAD.