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For patients presenting with non–ST-segment elevation acute coronary syndrome (NSTEACS), large-scale studies have been unable to show effect of an early invasive strategy in an all-comers populations, and the search for subgroups in whom an early invasive strategy could be advantageous remains an important challenge.1,2 Previous studies have shown benefit of an early invasive strategy in patients at high risk according to the GRACE (Global Registry of Acute Coronary Events) risk score >140.1,2 In addition, early coronary computed tomographic angiography (CTA) may be used not only to rule out coronary artery disease, but also to stratify patients with NSTEACS into high risk categories due to the extent of obstructive coronary artery disease who may benefit from early revascularization.3,4 As a prespecified observational component of the VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial, coronary CTA blinded for the treating physicians was conducted before invasive coronary angiography. We tested the hypotheses that in patients with NSTEACS: 1) the extent of coronary pathology according to coronary CTA identifies patients at risk of adverse outcome independently from GRACE score; and 2) coronary CTA may identify patients in whom a very early invasive strategy is associated with improved clinical outcome.

Aims: The role of atherosclerosis in the pathogenesis of aortic enlargement is uncertain. We aimed to evaluate the relationship between the diameters of the ascending, descending and abdominal aorta, and coronary artery calcification. Methods and results: Individuals in the Copenhagen General Population Study underwent thoracic and abdominal computed tomography. Maximal aortic diameters were measured in each aortic segment and coronary artery calcium scores (CACS) were calculated. Participants were stratified into five predefined groups according to CACSs and compared to aortic dimensions. The relation between aortic diameter and CACS was adjusted for risk factors for aortic dilatation in a multivariable model. A total of 2678 eligible individuals were included. In all segments of the aorta, aortic diameter was associated to CACSs, with mean increases in aortic diameters ranging from 0.7 to 3.5 mm in individuals with calcified coronary arteries compared to non-calcified subjects (P-value < 0.001). After correction for risk factors, individuals with CACS above 400 had larger ascending, descending and abdominal aortic diameter than the non-calcified reference group (P-value < 0.01). Conclusion: Enlarged thoracic and abdominal aortic vascular segments are associated with co-existing coronary artery calcification in the general population.

BACKGROUND: Patients diagnosed with ischemic heart disease (IHD) are becoming increasingly multi-morbid, and studies designed to analyze the full spectrum are few.METHODS: Disease trajectories, defined as time-ordered series of diagnoses, were used to study the temporality of multi-morbidity. The main data source was The Danish National Patient Register (NPR) comprising 7,179,538 individuals in the period 1994-2018. Patients with a diagnosis code for IHD were included. Relative risks were used to quantify the strength of the association between diagnostic co-occurrences comprised of two diagnoses that were overrepresented in the same patients. Multiple linear regression models were then fitted to test for temporal associations among the diagnostic co-occurrences, termed length two disease trajectories. Length two disease trajectories were then used as basis for constructing disease trajectories of three diagnoses.RESULTS: In a cohort of 570,157 IHD disease patients, we identified 1447 length two disease trajectories and 4729 significant length three disease trajectories. These included 459 distinct diagnoses. Disease trajectories were dominated by chronic diseases and not by common, acute diseases such as pneumonia. The temporal association of atrial fibrillation (AF) and IHD differed in different IHD subpopulations. We found an association between osteoarthritis (OA) and heart failure (HF) among patients diagnosed with OA, IHD, and then HF only.CONCLUSIONS: The sequence of diagnoses is important in characterization of multi-morbidity in IHD patients as the disease trajectories. The study provides evidence that the timing of AF in IHD marks distinct IHD subpopulations; and secondly that the association between osteoarthritis and heart failure is dependent on IHD.

Bleeding is known to influence the prognosis in patients with acute coronary syndromes. In this predefined secondary outcome analysis of the Very EaRly vs Deferred Invasive evaluation using Computerized Tomography (VERDICT) trial, we investigated whether a very early invasive coronary angiography (ICA), compared with one performed within 48 to 72 hours (standard care), was associated with fewer serious bleedings. Furthermore, we tested the association between demographic data including GRACE score and serious bleedings as well as bleedings and mortality. In the 2,147 patients included in the main study, bleedings within 30 days of admission were assessed based on Thrombolysis In Myocardial Infarction and Bleeding Academic Research Consortium criteria. Differences were calculated by cumulative incidence methods and Grays test. Variables associated with bleeding and mortality were estimated by Cox proportional hazard models. Serious (Bleeding Academic Research Consortium 3abc) bleeding rates were low (15 [1.4%, standard] vs 12 [1.2%, early], p = 0.56). There were no fatal bleedings or serious bleedings before ICA in either group. By multivariate analysis, there was no difference in bleedings between the 2 groups. Female gender (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.2 to 6.4; p = 0.02), anemia (HR 7.0, 95% CI 2.8 to 17.0; p <0.001), and increasing blood pressure (HR 1.3, 95% CI 1.1 to 1.5; p = 0.01) were individually associated with serious bleeding, whereas GRACE score >140 was not (HR 1.03, 95% CI 0.4 to 2.9; p = 0.96). In conclusion, serious bleedings were few, and there were none before ICA in either group. A very early invasive strategy did not reduce serious bleedings within 30 days, which was associated with female gender, increasing blood pressure, and anemia.

Background: Targeted temperature management (TTM) following out-of-hospital cardiac arrest (OHCA) prolongs the QT-interval but our knowledge of different temperatures and risk of arrhythmia is incomplete. Objective: To assess whether the QTc, QT-peak (QTp) and T-peak to T-end interval (TpTe) may be useful markers of ventricular arrhythmia in contemporary post cardiac arrest treatment. Methods: An ECG-substudy of the TTM-trial (TTM at 33 °C vs. 36 °C) with serial ECGs from 680 (94%) patients. Bazett's (B) and Fridericia's (F) formula were used for heart rate correction of the QT, QTp and TpTe. Ventricular arrhythmia (VT/VF) were registered during the first three days of post cardiac arrest care. Results: The QT, QTc and QTp intervals were prolonged more at 33 °C compared to 36 °C and restored to similar and lower levels after rewarming. The TpTe-interval remained between 92–100 ms throughout TTM in both groups. The QTc intervals were associated with ventricular arrhythmia, but not after adjustment for cardiac arrest characteristics. The QTp-interval was not associated with risk of ventricular arrhythmia. Heart rate corrected TpTe-intervals were associated with higher risk of arrhythmia (Odds ratio (OR): TpTe(B): 1.12 (1.02–1.23, p = 0.01 TpTe(F): 1.12 (1.02–1.23, p = 0.02) per 20 ms). Further a prolonged TpTe-interval ≥ 90 ms was consistently associated with higher risk (ORadjusted: TpTe(B): 2.05 (1.25–3.37), p < 0.01, TpTe(F): 2.14 (1.32–3.49), p < 0.01). Conclusions: TTM prolongs the QT-interval by prolongation of the QTp-interval without association to increased risk. The TpTe-interval is not significantly affected by core temperature, but heart rate corrected TpTe intervals are robustly associated with risk of ventricular arrhythmia. Trial registration: The TTM-trial is registered and accessible at ClinicalTrials.gov (Identifier: NCT01020916).

OBJECTIVES: In patients with arterial hypertension (AH), hypertension-mediated organ damage may be manifested by cardiac chamber enlargement and/or remodeling. Cardiac computed tomography imaging has emerged as an important method for morphological assessment of cardiac chambers. We tested the hypothesis that prevalence of cardiac chamber abnormalities is specifically related to clinical categories of AH in the general population. METHODS: We studied 4747 individuals, mean age was 60 years (range: 40-93), 46% were men, undergoing 320-detector computed tomography in the Copenhagen General Population Study. Clinical categories of AH were: normotensive (n = 2484), untreated hypertensive (n = 1301), treated controlled hypertensive (n = 412) and treated uncontrolled hypertensive (n = 550). Chamber abnormalities in the form of left ventricular (LV) concentric remodeling, LV eccentric hypertrophy, LV concentric hypertrophy or left atrial enlargement were assessed, in addition to LV or right ventricular enlargement. RESULTS: Chamber abnormalities were present in 23% of all individuals. Combined LV and left atrial abnormalities were rare (<2%). LV concentric remodeling (10%) was the most prevalent abnormality, and most commonly found in individuals with treated hypertension. LV and right ventricular enlargements were unrelated to hypertension. The highest frequencies of chamber abnormalities were found in individuals of elevated blood pressure (BP) with (40%) or without (32%) treatment, as opposed to individuals of normal BP with (27%) or without (14%) treatment, P less than 0.0001. CONCLUSION: In a general population cohort, untreated or inadequately treated AH was associated with the highest prevalence of cardiac chamber enlargement and remodeling. These observations suggest a strong link between elevated BPs and development of hypertension-mediated organ damage.

Aims: Chronic hyperglycaemia, assessed by elevated glycated haemoglobin (A1C), is a known risk factor for heart failure (HF) and cardiovascular (CV) death among subjects with diabetes. Whether this risk varies with left ventricular ejection fraction (LVEF) is unknown. This study evaluated whether A1C influences a composite outcome of either HF hospitalization or CV death differently along the spectrum of LVEF. Methods and results: We assessed the relationships of baseline A1C and LVEF with a composite outcome of either CV death or HF hospitalization in the 4091 patients with type 2 diabetes and a recent acute coronary syndrome enrolled in the ELIXA trial who had available LVEF. We assessed for interaction between A1C and LVEF as continuous variables with respect to this outcome. During a median follow-up of 25.7 months, 343 patients (8.4%) had HF hospitalization or died of CV causes. In a multivariable model, A1C and LVEF were each associated with an increased risk of HF hospitalization or CV death [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01–1.21 per 1% higher A1C, and adjusted HR 1.39, 95% CI 1.27–1.51 per 10% lower in LVEF]. Both A1C and LVEF were independently and incrementally associated with risk without evidence of interaction (P for interaction = 0.31). Patients with A1C ≥ 8% and LVEF <40% were at threefold higher risk than those with A1C < 7% and LVEF ≥50% (adjusted HR 3.18, 95% CI 2.03–4.98, P < 0.001). Conclusion: In a contemporary cohort of patients with type 2 diabetes and acute coronary syndrome, baseline chronic hyperglycaemia was associated with an increased risk of HF hospitalization or CV death independently of LVEF.

Aims: To investigate the relationship between heart rate and outcomes in heart failure and reduced ejection fraction (HFrEF) patients in sinus rhythm (SR) and atrial fibrillation (AF) adjusting for natriuretic peptide concentration, a powerful prognosticator. Methods and results: Of 13 562 patients from two large HFrEF trials, 10 113 (74.6%) were in SR and 3449 (25.4%) in AF. The primary endpoint was the composite of cardiovascular death or heart failure hospitalization. Heart rate was analysed as a categorical (tertiles, T1–3) and continuous variable (per 10 bpm), separately in patients in SR and AF. Outcomes were adjusted for prognostic variables, including N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and also examined using change from baseline heart rate to 1 year (≤ −10 bpm, ≥ +10 bpm, < ±10 bpm). SR patients with a higher heart rate had worse symptoms and quality of life, more often had diabetes and higher NT-proBNP concentrations. They had higher risk of the primary endpoint [T3 vs. T1 adjusted hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.35–1.66; P < 0.001; per 10 bpm: 1.12, 95% CI 1.09–1.16; P < 0.001]. In SR, heart rate was associated with a relatively higher risk of pump failure than sudden death (adjusted HR per 10 bpm 1.17, 95% CI 1.09–1.26; P < 0.001 vs. 1.07, 95% CI 1.02–1.13; P = 0.011). Heart rate was not predictive of any outcome in AF. Conclusions: In HFrEF, an elevated heart rate was an independent predictor of adverse cardiovascular outcomes in patients in SR, even after adjustment for NT-proBNP. There was no relationship between heart rate and outcomes in AF. Clinical Trial Registration: ClinicalTrials.gov Identifiers NCT01035255 and NCT00853658.

BACKGROUND: In patients with non-ST-segment elevation acute coronary syndrome (NSTEACS), coronary pathology may range from structurally normal vessels to severe coronary artery disease.OBJECTIVES: The purpose of this study was to test if coronary computed tomography angiography (CTA) may be used to exclude coronary artery stenosis ≥50% in patients with NSTEACS.METHODS: The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial (NCT02061891) evaluated the outcome of patients with confirmed NSTEACS randomized 1:1 to very early (within 12 h) or standard (48 to 72 h) invasive coronary angiography (ICA). As an observational component of the trial, a clinically blinded coronary CTA was conducted prior to ICA in both groups. The primary endpoint was the ability of coronary CTA to rule out coronary artery stenosis (≥50% stenosis) in the entire population, expressed as the negative predictive value (NPV), using ICA as the reference standard.RESULTS: Coronary CTA was conducted in 1,023 patients-very early, 2.5 h (interquartile range [IQR]: 1.8 to 4.2 h), n = 583; and standard, 59.9 h (IQR: 38.9 to 86.7 h); n = 440 after the diagnosis of NSTEACS was made. A coronary stenosis ≥50% was found by coronary CTA in 68.9% and by ICA in 67.4% of the patients. Per-patient NPV of coronary CTA was 90.9% (95% confidence interval [CI]: 86.8% to 94.1%) and the positive predictive value, sensitivity, and specificity were 87.9% (95% CI: 85.3% to 90.1%), 96.5% (95% CI: 94.9% to 97.8%) and 72.4% (95% CI: 67.2% to 77.1%), respectively. NPV was not influenced by patient characteristics or clinical risk profile and was similar in the very early and the standard strategy group.CONCLUSIONS: Coronary CTA has a high diagnostic accuracy to rule out clinically significant coronary artery disease in patients with NSTEACS.

AIMS: Accurate assessment of aortic dimensions can be achieved using contrast-enhanced computed tomography. The aim of this study was to define normal values and determinants of aortic dimensions throughout multiple key anatomical landmarks of the aorta in healthy individuals from the Copenhagen General Population Study.METHODS AND RESULTS: The study group consisted of 902 healthy subjects selected from 3000 adults undergoing cardiovascular thoracic and abdominal computed tomography-angiography (CTA), where systematic measurements of aortic dimensions were performed retrospectively. Individuals included were without any of the following predefined cardiovascular risk factors: (i) self-reported angina pectoris; (ii) hypertension; (iii) hypercholesterolaemia; (iv) taking cardiovascular prescribed medication including diuretics, statins, or aspirin; (v) overweight (defined as body mass index ≥30 kg/m2); (vi) diabetes mellitus (self-reported or blood glucose >8 mmol/L); and (vii) chronic obstructive pulmonary disease. Maximal aortic diameters were measured at seven aortic regions: sinuses of Valsalva, sinotubular junction, ascending aorta, mid-descending aorta, abdominal aorta at the diaphragm, abdominal aorta at the coeliac trunk, and infrarenal abdominal aorta. Median age was 52 years, and 396 (40%) were men. Men had significantly larger aortic diameters at all levels compared with women (P < 0.001). Multivariable analysis revealed that sex, age, and body surface area were associated with increasing aortic dimensions.CONCLUSION: Normal values of maximal aortic dimensions at key aortic anatomical locations by contrast-enhanced CTA have been defined. Age, sex, and body surface area were significantly associated with these measures at all levels of aorta. Aortic dimensions follow an almost identical pattern throughout the vessel regardless of sex.

BACKGROUND: The association between low bone mineral density (BMD) and the presence of coronary artery calcium (CAC) as a marker of atherosclerosis is unclear. The aim of this study was to assess the potential relationship between volumetric thoracic bone mineral density and coronary calcification in a large population of men and women.METHODS: Participants from the Copenhagen General Population Study underwent multidetector computed tomography. Volumetric thoracic BMD and CAC were assessed in the same scan. CAC was measured using calibrated mass score (cMS). cMS was dichotomized as cMS = 0 or cMS > 0. The association between BMD and cMS was analyzed using multiple logistic regression in men, premenopausal and postmenopausal women. The model was adjusted for age, BMI, hypertension, hypercholesterolemia, diabetes, known cardiovascular disease and smoking.RESULTS: Of 2548 eligible participants, 1163 men and 1385 women, mean age 61 ± 10 were included in the study. Mean BMD was 138 ± 46 mg/cm3 for men and 151 ± 49 mg/cm3 women. In 696 men (67%) and 537 women (41%) cMS was found to be above zero. For men, a decrease in BMD of 100 mg/cm3 was associated to an odds ratio of 1.49 for cMS > 0 (95% confidence interval: 1.04-2.13, P = 0.03). In postmenopausal women, a decrease in BMD of 100 mg/cm3 was associated to an odds ratio of 1.47 for MS > 0 (95% confidence interval: 1.04-2.08, P = 0.03). For premenopausal women, no significant association was found between BMD and cMS (odds ratio = 0.74, 95% confidence interval: 0.36-1.52, P = 0.4).CONCLUSION: Bone mineral density and coronary calcification are inversely related in both men and postmenopausal women, supporting the hypothesis that a direct relation between bone loss and development of atherosclerosis exists irrespective of gender.

Introduction. We investigated the association of diabetic retinopathy and neuropathy with increased risk of recurrent cardiovascular (CV) events in 6068 patients with type 2 diabetes mellitus (T2DM) and recent acute coronary syndrome (ACS) enrolled in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA). Methods. History of retinopathy and neuropathy as well as duration of T2DM were self-reported at screening. Proportional hazards regression models were used to assess relationships between retinopathy, neuropathy, and recurrent CV events. Results. At screening, retinopathy and neuropathy were reported in 10.7% and 17.5% of patients, respectively, while 5.7% reported both. When adjusted for randomized treatment only, both retinopathy and neuropathy were associated with a primary composite outcome (CV death, nonfatal MI, stroke, or hospitalization for unstable angina) (retinopathy: HR 1.44, 95% CI 1.19–1.75; neuropathy: HR 1.33, 95% CI 1.12–1.57), CV composite (CV death, nonfatal MI, stroke, hospitalization for heart failure (HF)) (retinopathy: HR 1.57, 95% CI 1.31–1.88; neuropathy: HR 1.38, 95% CI 1.19–1.62), myocardial infarction (retinopathy: HR 1.38, 95% CI 1.08–1.76; neuropathy: HR 1.26, 95% CI 1.02–1.54), HF hospitalization (retinopathy: HR 2.03, 95% CI 1.48–2.78; neuropathy: HR 1.71, 95% CI 1.30–2.27), and all-cause mortality (retinopathy: HR 1.65, 95% CI 1.28–2.12; neuropathy: HR 1.43, 95% CI 1.14–1.78). When included in the same model, and adjusted for T2DM duration, there were no independent associations of either with CV outcomes, while T2DM duration remained strongly associated with all outcomes. Addition of demographic characteristics and CV risk factors did not further alter these relationships. Conclusions. In patients with T2DM and recent ACS, a history of retinopathy and/or neuropathy and longer T2DM duration could be considered clinical markers for high risk of recurrent CV events. This trial is registered with the ELIXA (Evaluation o