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Objectives To investigate the prevalence of subclinical, myocardial involvement in patients with established idiopathic inflammatory myopathies (IIM) compared to healthy controls using T1 and T2 mapping by cardiac magnetic resonance imaging (CMRI). Method Fifty-five patients with established, stable IIM without overt cardiac involvement were consecutively enrolled in this cross-sectional study. All patients completed questionnaires, underwent clinical examination, blood tests including antibody profiling, electrocardiography, and CMRI with T1 and T2 mapping. Concurrently, CMRI was conducted on 19 healthy controls. Abnormal T1 and T2 values were defined as values exceeding the 95th percentile in the control group. Potential associations between abnormal T1 and T2 values and various cardiac- and IIM-related outcomes were assessed in exploratory analyses. Results Abnormal T1 values were observed in 9% of all IIM patients, displaying significantly higher T1 values compared to healthy controls ( p  = 0.02). T2 values were elevated in 18% of IIM patients, particularly among patients with non-inclusion body myositis (IBM) IIM compared to healthy controls ( p  = 0.03). No significant associations between T1 or T2 values and cardiac or disease-related measures were found in the present cohort of IIM patients. Conclusions Our study demonstrates that subclinical cardiac involvement may be present in established, stable IIM patients, with abnormal T1 and T2 mapping observed in up to 18% of the cohort. These findings underscore the importance of ongoing cardiac monitoring, even during stable phases of the disease. However, prospective studies are needed to determine the prognostic value of T1 and T2 mapping in this disease entity. Key Points • T1 and T2 mapping on cardiac MRI identify subclinical myocardial involvement in patients with IIM . • Subclinical myocardial involvement is present in up to 18% of patients with established, stable IIM . • Cardiac T1 and T2 abnormalities are rare in patients with IBM .

Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (ρ = 0.50; p = 0.0244) and OPG (ρ = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease.

Clinical studies reveal changes in blood eosinophil counts and eosinophil cationic proteins that may serve as risk factors for human coronary heart diseases. Here we report an increase of blood or heart eosinophil counts in humans and mice after myocardial infarction (MI), mostly in the infarct region. Genetic or inducible depletion of eosinophils exacerbates cardiac dysfunction, cell death, and fibrosis post-MI, with concurrent acute increase of heart and chronic increase of splenic neutrophils and monocytes. Mechanistic studies reveal roles of eosinophil IL4 and cationic protein mEar1 in blocking H 2 O 2 - and hypoxia-induced mouse and human cardiomyocyte death, TGF-β-induced cardiac fibroblast Smad2/3 activation, and TNF-α-induced neutrophil adhesion on the heart endothelial cell monolayer. In vitro-cultured eosinophils from WT mice or recombinant mEar1 protein, but not eosinophils from IL4-deficient mice, effectively correct exacerbated cardiac dysfunctions in eosinophil-deficient ∆dblGATA mice. This study establishes a cardioprotective role of eosinophils in post-MI hearts. Blood eosinophil (EOS) counts may serve as risk factors for human coronary heart diseases. Here the authors show that increased circulating and myocardial EOS after myocardial infarction play a cardioprotective role by reducing cardiomyocyte death, cardiac fibroblast activation and fibrosis, and endothelium activation-mediated inflammatory cell accumulation.

Objectives Coronary computed tomography angiography (CCTA) has higher diagnostic accuracy than coronary artery calcium (CAC) score for detecting obstructive coronary artery disease (CAD) in patients with stable chest pain, while the added diagnostic value of combining CCTA with CAC is unknown. We investigated whether combining coronary CCTA with CAC score can improve the diagnosis of obstructive CAD compared with CCTA alone. Methods A total of 2315 patients (858 women, 37%) aged 61.1 ± 10.2 from 29 original studies were included to build two CAD prediction models based on either CCTA alone or CCTA combined with the CAC score. CAD was defined as at least 50% coronary diameter stenosis on invasive coronary angiography. Models were built by using generalized linear mixed-effects models with a random intercept set for the original study. The two CAD prediction models were compared by the likelihood ratio test, while their diagnostic performance was compared using the area under the receiver-operating-characteristic curve (AUC). Net benefit (benefit of true positive versus harm of false positive) was assessed by decision curve analysis. Results CAD prevalence was 43.5% (1007/2315). Combining CCTA with CAC improved CAD diagnosis compared with CCTA alone (AUC: 87% [95% CI: 86 to 89%] vs. 80% [95% CI: 78 to 82%]; p  < 0.001), likelihood ratio test 236.3, df: 1, p  < 0.001, showing a higher net benefit across almost all threshold probabilities. Conclusion Adding the CAC score to CCTA findings in patients with stable chest pain improves the diagnostic performance in detecting CAD and the net benefit compared with CCTA alone. Clinical relevance statement CAC scoring CT performed before coronary CTA and included in the diagnostic model can improve obstructive CAD diagnosis, especially when CCTA is non-diagnostic. Key Points • The combination of coronary artery calcium with coronary computed tomography angiography showed significantly higher AUC (87%, 95% confidence interval [CI]: 86 to 89%) for diagnosis of coronary artery disease compared to coronary computed tomography angiography alone (80%, 95% CI: 78 to 82%, p < 0.001). • Diagnostic improvement was mostly seen in patients with non-diagnostic C. • The improvement in diagnostic performance and the net benefit was consistent across age groups, chest pain types, and genders.

Objectives There is conflicting evidence about the comparative diagnostic accuracy of the Agatston score versus computed tomography angiography (CTA) in patients with suspected obstructive coronary artery disease (CAD). Purpose To determine whether CTA is superior to the Agatston score in the diagnosis of CAD. Methods In total 2452 patients with stable chest pain and a clinical indication for invasive coronary angiography (ICA) for suspected CAD were included by the Collaborative Meta-analysis of Cardiac CT (COME-CCT) Consortium. An Agatston score of > 400 was considered positive, and obstructive CAD defined as at least 50% coronary diameter stenosis on ICA was used as the reference standard. Results Obstructive CAD was diagnosed in 44.9% of patients (1100/2452). The median Agatston score was 74. Diagnostic accuracy of CTA for the detection of obstructive CAD (81.1%, 95% confidence interval [CI]: 77.5 to 84.1%) was significantly higher than that of the Agatston score (68.8%, 95% CI: 64.2 to 73.1%, p < 0.001). Among patients with an Agatston score of zero, 17% (101/600) had obstructive CAD. Diagnostic accuracy of CTA was not significantly different in patients with low to intermediate (1 to < 100, 100–400) versus moderate to high Agatston scores (401–1000, > 1000). Conclusions Results in our international cohort show CTA to have significantly higher diagnostic accuracy than the Agatston score in patients with stable chest pain, suspected CAD, and a clinical indication for ICA. Diagnostic performance of CTA is not affected by a higher Agatston score while an Agatston score of zero does not reliably exclude obstructive CAD. Key Points • CTA showed significantly higher diagnostic accuracy (81.1%, 95% confidence interval [CI]: 77.5 to 84.1%) for diagnosis of coronary artery disease when compared to the Agatston score (68.8%, 95% CI: 64.2 to 73.1%, p < 0.001). • Diagnostic performance of CTA was not affected by increased amount of calcium and was not significantly different in patients with low to intermediate (1 to <100, 100–400) versus moderate to high Agatston scores (401–1000, > 1000). • Seventeen percent of patients with an Agatston score of zero showed obstructive coronary artery disease by invasive angiography showing absence of coronary artery calcium cannot reliably exclude coronary artery disease.

ObjectivesTo describe carotid plaque composition by computed tomography angiography (CTA) in asymptomatic subjects and to compare this to carotid plaque assessment by ultrasound, coronary plaques by coronary CTA, and inflammatory biomarkers in plasma.MethodsMiddle-aged asymptomatic men, n = 43, without known cardiovascular disease and diabetes were included. Plaques in coronary and carotid arteries were evaluated using CTA. Total plaque volumes and plaque composition were assessed by a validated plaque analysis software. The 60% centile cut point was used to divide the population into low or high carotid total plaque volumes. The occurrence of carotid plaques and intima-media thickness (IMT) was estimated by ultrasound.ResultsCarotid plaque by ultrasound was undiagnosed in 13 of 28 participants (46%) compared to CTA. Participants having carotid plaques by ultrasound had significantly higher absolute volumes of all CTA-defined carotid plaque subtypes and a higher fraction of calcified plaque. A high carotid total plaque volume was independently associated with age (adjusted odds ratio (OR) 1.41 [95% confidence interval (CI) 1.14–1.74], p = 0.001), IMT (adjusted OR 2.26 [95% CI 1.10–4.65], p = 0.03), and D-dimer (adjusted OR 8.86 [95% CI 1.26–62.37], p = 0.03). All coronary plaque features were significantly higher in participants with a high carotid total plaque volume.ConclusionThe occurrence of carotid plaques in asymptomatic individuals is underestimated by ultrasound compared to plaque assessment by CTA. Carotid plaque composition by CTA is different in individuals with and without carotid plaques by ultrasound.Key Points• The occurrence of carotid plaques by ultrasound was underestimated in 46% of participants who had plaques by carotid CTA.• Participants with carotid plaques by ultrasound had higher volumes of all plaque subtypes and a higher calcified plaque component as determined by carotid CTA compared to participants without carotid plaques by ultrasound.• A high carotid total plaque volume was independently associated with age, intima-media thickness, and D-dimer.

Background and Aim: Coronary calcification has been described as a manifestation of subclinical atherosclerosis. However, its predictors are not well established. The aim of this study was to evaluate the relationship between coronary artery calcium score (CACs) evaluated by multi-detector computed tomography (MDCT) and atherosclerotic cardiovascular disease (CVD) risk factors in symptomatic patients in three European countries. Method: We retrospectively analyzed 550 patients (age 62.7 ± 12 year, 47.5% females) who presented with atypical chest pain in Germany, Denmark, and Sweden. The demographic indices, CVD risk factors, and CACs were analyzed. The CV risk factors were classified as low (no risk factors), intermediate (1–2 risk factors), and high (≥3 risk factors). Patients were geographically classified into: Gr. I–German (n = 344), Gr. II–Danish (n = 84), and Gr. III–Swedish (n = 122) patients. Results: In the cohort as a whole, the mean CACs was 270.3 ± 72, and the intermediate risk was more prevalent than low and high-risk (p < 0.05 for all). Among the CVD risk profile, arterial hypertension (AH) was the most prevalent, followed by hypercholesterolemia, obesity, smoking, and diabetes (53, 38.2, 23.7, 17.6, and 10.5%; p < 0.05 for all). The German population was younger and had less CVD risk factors compared to the Danish and Swedish populations (p < 0.05, for all). CACSs adjusted to age and sex was lowest in Swedish patients, followed by German patients, and highest in Danish patients (p < 0.05). The CACs modestly correlated with age (rpb = 0.52, p < 0.001), sex (rpb = 0.48, p < 0.001), and extent of risk (rpb = 0.35, p = 0.001). On multivariate regression analysis, hypercholesterolemia β = 185.1 (63.11 to 307.1), the extent of risk adjusted for age and sex β 3.741 (2.566 to 4.916; p < 0.001), and AH, β = 142.6 (11.25 to 274.1; p = 0.03) independently correlated with CACs. Furthermore, hypercholesterolemia was the only risk factor, consistently associated with CACs across all three countries. Conclusions: In symptomatic European patients, hypercholesterolemia is the main player in coronary calcium formation.

AimsPlatelets are pivotal in arterial thrombosis, and platelet hyperresponsiveness may contribute to the increased incidence of cardiovascular events in diabetes mellitus. Consequently, we hypothesized that increased in vitro platelet aggregation responses exist in men with diabetes mellitus.MethodsThe Danish Cardiovascular Screening Trial (DANCAVAS) is a community-based cardiovascular screening trial including men aged 65–74 years. Platelet aggregation was tested using 96-well light transmission aggregometry with thrombin receptor-activating peptide (TRAP), adenosine diphosphate, collagen type 1, arachidonic acid and protease-activated receptor-4 in three concentrations. Further, cardiovascular risk factors and coronary artery calcification (CAC), estimated by CT scans and ankle–brachial index, were obtained.ResultsIncluded were 720 men aged 65–74 years, 110 with diabetes mellitus. Overall, there was no difference in platelet aggregation among men with versus without diabetes mellitus when adjusting for or excluding platelet inhibitor treatment and men with established cardiovascular disease (CVD). This was true for all agonists, e.g., 10 µM TRAP-induced platelet aggregation of median 69% (IQR 53–75) versus 70% (IQR 60–76) in men with versus without diabetes mellitus. Platelet aggregation did not correlate with HbA1c or CAC. Men with diabetes mellitus displayed higher CAC, median 257 Agatston units (IQR 74–1141) versus median 111 Agatston units (IQR 6–420) in the remaining individuals, p < 0.0001.ConclusionsAmong outpatients with diabetes mellitus, but no CVD and no platelet inhibitor treatment, neither are platelets hyperresponsive in diabetes mellitus, nor is platelet aggregation associated with glycemic status or with the degree of coronary atherosclerosis.Trial RegistrationISRCTN12157806.

IntroductionCardiovascular disease (CVD) risk remains high but unevenly distributed in patients with type 2 diabetes mellitus (T2DM). Current risk stratification strategies are far from optimal, leading to both undertreatment and overtreatment of patients. The STENO INTEN-CT trial aims to evaluate a strategy of improved CVD risk management by using cardiac CT (coronary artery calcification (CAC)) for stratification and tailoring of multifactorial cardiovascular treatment based on CAC score. We hypothesise that (1) intensified medical treatment will lower CVD event rates in high-risk patients (CAC≥100), and (2) less intensive multifactorial treatment is safe in very low-risk patients (CAC=0).Methods and analysisThe Steno INTEN-CT trial is an investigator-initiated, pragmatic, open-label, event-driven randomised controlled trial including patients with T2DM without known CVD. All participants (expected n=7300) will be invited for a non-contrast coronary CT scan. After the scan, participants will be randomised to either standard treatment (blinded for CAC results) or CAC-based treatment. Participants in CAC-based treatment and their general practitioner (GP) will receive information on CAC and a recommendation of multifactorial treatment. High-risk participants in the interventional arm will be invited for one or more initial study visits to intensify treatment with a combination of sodium glucose co-transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, high-dose lipid-lowering, antihypertensive and antithrombotic treatment. Very low-risk patients in the interventional arm will be recommended less intensive treatment targets. After initial study-related activities, all participants will continue to be taken care of by their GP guided by specific treatment recommendations. The primary outcome in the primary hierarchical analysis (the rate of the combined CVD endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for heart failure) will be monitored through national health registries. The trial is event-driven, but a median follow-up of 5 years is expected. Key secondary outcomes include patient-reported outcomes, quality-adjusted life years and healthcare costs.Ethics and disseminationThe protocol V.1.9 is approved by the Research Ethics Committee and the Danish Medicines Agency and the Danish Data Protection Agency. The results of the study—positive, negative or neutral—will be published in peer-reviewed journals and through www.clinicaltrials.org.Trial registration numberNCT05700877.

Background Fibulin-1 is one of a few extracellular matrix proteins present in blood in high concentrations. We aimed to define the relationship between plasma fibulin-1 levels and risk markers of cardiovascular disease. Methods Plasma fibulin-1 was determined in subjects with chronic kidney disease (n = 32; median age 62.5, inter-quartile range 51 – 73 years) and 60 age-matched control subjects. Among kidney disease patients serological biomarkers related to cardiovascular disease (fibrinogen, interleukin 6, C-reactive protein) were measured. Arterial applanation tonometry was used to determine central hemodynamic and arterial stiffness indices. Results We observed a positive correlation of fibulin-1 levels with age (r = 0.38; p = 0.033), glycated hemoglobin (r = 0.80; p = 0.003), creatinine (r = 0.35; p = 0.045), and fibrinogen (r = 0.39; p = 0.027). Glomerular filtration rate and fibulin-1 were inversely correlated (r = −0.57; p = 0.022). There was a positive correlation between fibulin-1 and central pulse pressure (r = 0.44; p = 0.011) and central augmentation pressure (r = 0.55; p = 0.001). In a multivariable regression model, diabetes, creatinine, fibrinogen and central augmentation pressure were independent predictors of plasma fibulin-1. Conclusion Increased plasma fibulin-1 levels were associated with diabetes and impaired kidney function. Furthermore, fibulin-1 levels were associated with hemodynamic cardiovascular risk markers. Fibulin-1 is a candidate in the pathogenesis of cardiovascular disease observed in chronic kidney disease and diabetes.