Bone Mineral Density Derived from Cardiac CT Scans: Using Contrast Enhanced Scans for Opportunistic Screening.

PURPOSE: Osteoporosis is under-diagnosed and often co-exists with other diseases. Very low bone mineral density (BMD) indicates risk of osteoporosis and opportunistic screening for low BMD in CT-scans has been suggested. In a non-contrast enhanced thoracic CT scan, the scan-field-of-view includes vertebrae enabling BMD estimation. However, many CT scans are obtained by administration of contrast material. If the impact of contrast enhancement on BMD measurements could be quantified, considerably more patients are eligible for screening. METHODS: This study investigated the impact of intravenous contrast on thoracic BMD measurements in cardiac CT scans pre- and post-contrast, including different contrast trigger levels of 130 and 180 Hounsfield units (HU). BMD was measured using quantitative CT with asynchronous calibration. RESULTS: In 195 participants undergoing cardiac CT (mean age 57±9 years, 37 % females) contrast increased mean thoracic BMD from 116±33 mg/cm3 (non-enhanced CT) to 130±38 mg/cm3 (contrast-enhanced CT) (p<0.001). Using clinical cut-off values for very low (<80 mg/cm3) and low BMD (<120 mg/cm3) showed that 24 % (47/195 participants) were misclassified when BMD was measured on contrast-enhanced CT-scans. Of the misclassified patients, 6 % (12/195 participants) were categorized as having low BMD despite having very low BMD on the non-enhanced images. Contrast-CT using a higher contrast trigger level showed a significant increase in BMD compared to the lower trigger level (119±32 vs. 135±40 mg/cm3, p<0.01). CONCLUSION: For patients undergoing cardiac CT, using contrast-enhanced images to assess BMD entails substantial overestimation. Contrast protocol trigger levels also affect BMD measurements. Adjusting for these factors is needed before contrast-enhanced images can be used clinically. MINI ABSTRACT: Osteoporosis is under-diagnosed. Contrast-enhanced CT made to examine other diseases might be utilized simultaneously for bone mineral density (BMD) screening. These scans, however, likely entails overestimation of BMD due to the effect of contrast. Adjusting for this effect is needed before contrast-enhanced images can be implemented clinically for BMD screening.

Childhood socioeconomic position and cardiometabolic risk in young adulthood- the impact of mental health.

BACKGROUND: Low socioeconomic position in childhood is associated with greater cardiometabolic disease risk later in life. The aim of the current study is to examine the mediating impact of mental health on the association between childhood socioeconomic position and cardiometabolic disease risk in young adulthood. METHODS: We used a combination of national registers, longitudinal questionnaire-data and clinical measurements from a sub-sample (N = 259) of a Danish youth cohort. Childhood socioeconomic position was indicated by the educational level of the mother and the father at age 14. Mental health was measured by four different symptom scales at four age-points (age 15, 18, 21 and 28), and combined into one global score. Cardiometabolic disease risk was measured by nine biomarkers at age 28-30 and combined into one global score by sample-specific z-scores. We conducted analyses within the causal inference framework and evaluated the associations using nested counterfactuals. RESULTS: We found an inverse association between childhood socioeconomic position and cardiometabolic disease risk in young adulthood. The proportion of the association which was mediated by mental health was 10 (95% CI: -4; 24) % and 12 (95% CI: -4; 28) % using educational level of the mother and the father as indicator, respectively. CONCLUSIONS: Accumulated poorer mental health in childhood, youth and early adulthood partially explained the association between low childhood socioeconomic position and increased cardiometabolic disease risk in young adulthood. The results of the causal inference analyses rely on the underlying assumptions and correct depiction of the DAG. Since these are not all testable, we cannot exclude violations that potentially could bias the estimates. If the findings can be replicated, this would support a causal relationship and direct potentials for intervention. However, the findings point to a potential for intervention in young age in order to impede the translation of childhood social stratification into later cardiometabolic disease risk disparities.

Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease.

Sortilin, an intracellular sorting receptor, has been identified as a cardiovascular risk factor in the general population. Patients with chronic kidney disease (CKD) are highly susceptible to develop cardiovascular complications such as calcification. However, specific CKD-induced posttranslational protein modifications of sortilin and their link to cardiovascular calcification remain unknown. To investigate this, we examined two independent CKD cohorts for carbamylation of circulating sortilin and detected increased carbamylated sortilin lysine residues in the extracellular domain of sortilin with kidney function decline using targeted mass spectrometry. Structure analysis predicted altered ligand binding by carbamylated sortilin, which was verified by binding studies using surface plasmon resonance measurement, showing an increased affinity of interleukin 6 to in vitro carbamylated sortilin. Further, carbamylated sortilin increased vascular calcification in vitro and ex vivo that was accelerated by interleukin 6. Imaging by mass spectrometry of human calcified arteries revealed in situ carbamylated sortilin. In patients with CKD, sortilin carbamylation was associated with coronary artery calcification, independent of age and kidney function. Moreover, patients with carbamylated sortilin displayed significantly faster progression of coronary artery calcification than patients without sortilin carbamylation. Thus, carbamylated sortilin may be a risk factor for cardiovascular calcification and may contribute to elevated cardiovascular complications in patients with CKD.

The West Jutland Tele-Electrocardiogram Registry (WEJU-tECG): content, data quality, and research potential.

AIM: To present the content, data quality, and research potential of the West Jutland Tele-Electrocardiogram Registry (WEJU-tECG). METHODS: Danish patients reporting symptoms indicating heart disease in the prehospital setting are subjected to a 12-lead tele-electrocardiogram (ECG) in the ambulance, which is digitally sent to a local tele-centre. WEJU-tECG is a newly established Danish registry containing information from the individual tele-ECGs received at the Regional Hospital West Jutland tele-centre. RESULTS: WEJU-tECG holds extracted information from all tele-ECGs with a valid Civil Personal Register number between 2011 and 2020. WEJU-tECG contains information on patient characteristics, tele-ECG data (including a computerised tele-ECG interpretation), vital signs, and time information. A unique Civil Personal Register number allows individual-level linkage between WEJU-tECG and other Danish registries and enables complete follow-up. WEJU-tECG contains 43,696 tele-ECGs from 29,489 different patient contacts among 20,280 different patients. WEJU-tECG contains 5566 patients with ST-segment deviations. The median age is 67 years and 45% are women. Completeness is highest for time information (100% for all variables), tele-ECG data (99% for heart rate, the specific intervals and axes, and QRS duration, and 86% for J-point deviation), and patient characteristics (100% for all variables). Completeness is lowest for vital signs (13% for systolic, diastolic, and mean arterial blood pressure, and 12% for blood oxygen saturation). The computerised tele-ECG interpretation had a negative predictive value of 80% for ST-segment elevation myocardial infarction and 94% for non-ST-segment elevation myocardial infarction and a positive predictive value of 45% for ST-segment elevation myocardial infarction and 32% for non-ST-segment elevation myocardial infarction. CONCLUSIONS: WEJU-tECG is a novel population-based tele-ECG registry with high research potential.

Evaluating the association between socioeconomic position and cardiometabolic risk markers in young adulthood by different life course models.

BACKGROUND: Cardiometabolic health in adulthood is associated with socioeconomic position (SEP) in childhood. Although this has been studied by previous research several questions need to be addressed. E.g. knowledge about the association with timing, extent of the exposure as well as lifestyle and adult SEP, is essential to address the increasing social gradient in cardiometabolic diseases. METHODS: This study included a sub-sample (N = 264, 50% women, age 28-30) from an ongoing cohort study. We used a combination of national registers, longitudinal questionnaire data and clinical data. We examined the association between childhood SEP and cardiometabolic risk, measured by a score of multiple risk markers in young adulthood. SEP-indicators included mother's educational level and household income. The association was evaluated by four different life course models; the latent effects model, the pathway model, the cumulative model and the social mobility model. RESULTS: We found an inverse association between mother's educational level and cardiometabolic risk. The association was statistically significant evaluated by the pathway and cumulative life course models, however statistically insignificant evaluated by the latent effects model. No specific association with social mobility was observed. However, high adult educational level seems to have a protecting impact on the association. No association was found between household income and cardiometabolic risk in any of the applied life course models. CONCLUSION: Low childhood SEP, represented by mother's educational level but not household income, is associated with increased cardiometabolic risk in young adulthood. The accumulation of exposure, lifestyle and adult educational attainment are important for the association. In contrast, intergenerational social mobility does not seem to have a specific impact on the association and we find no evidence for a particular timing in childhood.

Validation of the European Society of Cardiology pre-test probability model for obstructive coronary artery disease.

AIMS: Estimation of pre-test probability (PTP) of disease in patients with suspected coronary artery disease (CAD) is a common challenge. Due to decreasing prevalence of obstructive CAD in patients referred for diagnostic testing, the European Society of Cardiology suggested a new PTP (2019-ESC-PTP) model. The aim of this study was to validate that model. METHODS AND RESULTS: Symptomatic patients referred for coronary computed tomography angiography (CTA) due to suspected CAD in a geographical uptake area of 3.3 million inhabitants were included. The reference standard was a combined endpoint of CTA and invasive coronary angiography (ICA) with obstructive CAD defined at ICA as a ≥50% diameter stenosis or fractional flow reserve ≤0.80 when performed. The 2019-ESC-PTP, 2013-ESC-PTP, and CAD Consortium basic PTP scores were calculated based on age, sex, and symptoms. Of the 42 328 identified patients, coronary stenosis was detected in 8.8% using the combined endpoint. The 2019-ESC-PTP and CAD Consortium basic scores classified substantially more patients into the low PTP groups (PTP < 15%) than did the 2013-ESC-PTP (64% and 65% vs. 16%, P < 0.001). Using the combined endpoint as reference, calibration of the 2019-ESC-PTP model was superior to the 2013-ESC-PTP and CAD Consortium basic score. CONCLUSION: The new 2019-ESC-PTP model is well calibrated and superior to the previously recommended models in predicting obstructive stenosis detected by a combined endpoint of CTA and ICA.

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Resting distal to aortic pressure ratio and fractional flow reserve discordance affects the diagnostic performance of quantitative flow ratio: Results from an individual patient data meta-analysis.

OBJECTIVE: To evaluate the diagnostic performance of quantitative flow ratio (QFR) related to fractional flow reserve (FFR) and resting distal-to-aortic pressure ratio (resting Pd/Pa) concordance. BACKGROUND: QFR is a method for computation of FFR based on standard coronary angiography. It is unclear how QFR is performed in patients with discordance between FFR and resting pressure ratios (distal-to-aortic pressure ratio [Pd/Pa]). MATERIALS AND METHODS: The main comparison was the diagnostic performance of QFR with FFR as reference stratified by correspondence between FFR and resting Pd/Pa. Secondary outcome measures included distribution of clinical or procedural characteristics stratified by FFR and resting Pd/Pa correspondence. RESULTS: Four prospective studies matched the inclusion criteria. Analysis was performed on patient level data reaching a total of 759 patients and 887 vessels with paired FFR, QFR, and resting Pd/Pa. Median FFR was 0.85 (IQR: 0.77-0.90). Diagnostic accuracy of QFR with FFR as reference was higher if FFR corresponded to resting Pd/Pa: accuracy 90% (95% CI: 88-92) versus 72% (95% CI: 64-80), p < .001, and sAUC 0.95 (95% CI: 0.92-0.96) versus 0.73 (95% CI: 0.69-0.77), p < .001. Resting Pd/Pa and FFR discordance were related to age, sex, hypertension, and lesion severity. CONCLUSION: Diagnostic performance of QFR with FFR as reference is reduced for lesions with discordant FFR (≤0.80) and resting Pd/Pa (≤0.92) measurements.

Prospective validation of an acoustic-based system for the detection of obstructive coronary artery disease in a high-prevalence population.

Recent guidelines recommend a risk-adjusted, non-invasive work-up in patients presenting with chest discomfort to exclude coronary artery disease (CAD). However, a risk-adjusted diagnostic approach remains challenging in clinical practice. An acoustic detection device for analyzing micro-bruits induced by stenosis-generated turbulence in the coronary circulation has shown potential for ruling out CAD in patients with low-to-intermediate likelihood. We examined the diagnostic value of this acoustic detection system in a high-prevalence cohort. In total, 226 patients scheduled for clinically indicated invasive coronary angiography (ICA) were prospectively enrolled at two centers and examined using a portable, acoustic detection system. The acoustic analysis was performed in double-blinded fashion prior to quantitative ICA and following percutaneous coronary intervention (PCI). An acoustic detection result (CAD score) was obtained in 94% of all patients. The mean baseline CAD score was 41.2 ± 11.9 in patients with obstructive CAD and 33.8 ± 13.4 in patients without obstructive CAD (p < 0.001). ROC analysis revealed an AUC of 0.661 (95% CI 0.584-0.737). Sensitivity was 97.6% (95% confidence interval (CI) 91.5-99.7%), specificity was 14.5% (CI 9.0-21.7%), negative predictive value was 90.5% (CI 69.6-98.8%), and positive predictive value was 41.7% (CI 34.6-49.0%). Following PCI, the mean CAD score decreased from 40.5 ± 11.2 to 38.3 ± 13.7 (p = 0.039). Using an acoustic detection device identified individuals with CAD in a high-prevalence cohort with high sensitivity but relatively low specificity. The negative predictive value was within the predicted range and may be of value for a fast rule-out of obstructive CAD even in a high-prevalence population.

Sex Differences in the Association Between Bone Mineral Density and Coronary Artery Disease in Patients Referred for Cardiac Computed Tomography.

Atherosclerosis and osteoporosis are both common and preventable diseases. Evidence supports a link between coronary artery disease (CAD) and low bone mineral density (BMD). This study aimed to assess the association between thoracic spine BMD and CAD in men and women with symptoms suggestive of CAD. This cross-sectional study included 1487 (mean age 57 years (range 40-80), 47% men) patients referred for cardiac computed tomography (CT). Agatston coronary artery calcium score (CACS), CAD severity (no, mild, moderate, and severe), vessel involvement (no, 1-, 2-, and 3/left main disease), and invasive measurements were evaluated. BMD of three thoracic vertebrae was measured using quantitative CT. We used the American college of radiology cut-off values for lumbar spine BMD to categorize patients into very low (<80 mg/cm3), low (80-120 mg/cm3), or normal BMD (>120 mg/cm3). BMD as a continuous variable was included in the linear regression analyses to assess associations between CACS (CACS=0, CACS 1- 399, and CACS ≥ 400) and BMD, and CAD severity and BMD. Significant lower BMD was present with increasing CACS and stenosis degree unadjusted. Multivariate linear regression analyses in women revealed a significant correlation between BMD and CACS groups (ß = -4.06, p<0.05), but no correlation between BMD and CAD severity (ß = -1.59, p = 0.14). No association was found between BMD and CACS (ß = -1.50, p = 0.36) and CAD severity (ß = 0.07, p = 0.94) in men. BMD is significantly correlated to CACS after adjusting for confounders in women, but not in men, suggesting a possible sex difference in pathophysiology.

Familial analysis reveals rare risk variants for migraine in regulatory regions.

The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.

Association between circulating proprotein convertase subtilisin/kexin type 9 levels and prognosis in patients with severe chronic kidney disease.

BACKGROUND: Chronic kidney disease is a risk factor for premature development of coronary atherosclerosis and mortality. A high level of proprotein convertase subtilisin/kexin type 9 (PCSK9) is a recently recognized cardiovascular risk factor and has become the target of effective inhibitory treatment. In 167 kidney transplantation candidates, we aimed to: (i) compare levels of PCSK9 with those of healthy controls, (ii) examine the association between levels of PCSK9 and low-density lipoprotein cholesterol (LDL-c) and the degree of coronary artery disease (CAD) and (iii) evaluate if levels of PCSK9 predict major adverse cardiac events (MACE) and mortality. METHODS: Kidney transplant candidates (n = 167) underwent coronary computed tomography angiography (CCTA) and invasive coronary angiography (ICA) before transplantation. MACE and mortality data were extracted from the Western Denmark Heart Registry, a review of patient records and patient interviews. A group of 79 healthy subjects were used as controls. RESULTS: Mean PCSK9 levels did not differ between healthy controls and kidney transplant candidates. In patients not receiving lipid-lowering therapy, PCSK9 correlated positively with LDL-c (rho = 0.24, P < 0.05). Mean PCSK9 was similar in patients with and without obstructive CAD at both CCTA and ICA. In a multiple regression analysis, PCSK9 was associated with neither LDL-c (ß=-6.45, P = 0.44) nor coronary artery calcium score (ß=2.17, P = 0.84). During a follow-up of 3.7 years, PCSK9 levels were not associated with either MACE or mortality. CONCLUSIONS: The ability of PCSK9 levels to predict cardiovascular disease and prognosis does not seem to apply to a cohort of kidney transplant candidates.

Feasibility of Opportunistic Screening for Low Thoracic Bone Mineral Density in Patients Referred for Routine Cardiac CT.

Despite being a frequent and treatable disease, osteoporosis remains under-diagnosed worldwide. Our study aim was to characterize the bone mineral density (BMD) status in a group of patients with symptoms suggestive of coronary artery disease (CAD) with low/intermediate risk profile undergoing routine cardiac computed tomography (CT) to rule out CAD. This cross-sectional study used prospectively acquired data from a large consecutively included cohort. Participants were referred for cardiac CT based on symptoms of CAD. Quantitative CT (QCT) dedicated software was used to obtain BMD measurements in 3 vertebrae starting from the level of the left main coronary artery. We used the American College of Radiology cut-off values for lumbar spine QCT to categorize patients into very low (<80 mg/cm3), low (80-120 mg/cm3), or normal BMD (>120 mg/cm3). Analyses included 1487 patients. Mean age was 57 years (range 40-80), and 52% were women. The number of patients with very low BMD was 105 women (14%, 105/773) and 74 men (10%, 74/714). The majority of patients with very low BMD was not previously diagnosed with osteoporosis (87%) and received no anti-osteoporotic treatment (90%). Opportunistic screening in patients referred for cardiac CT revealed a substantial number of patients with very low BMD. The majority of these patients was not previously diagnosed with osteoporosis and received no anti-osteoporotic treatment. Identification of these patients could facilitate initiation of anti-osteoporotic treatment and reduce the occurrence of osteoporosis-related complications.

Danish study of Non-Invasive testing in Coronary Artery Disease 2 (Dan-NICAD 2): Study design for a controlled study of diagnostic accuracy.

BACKGROUND: Coronary computed tomography angiography (CTA) is the preferred primary diagnostic modality when examining patients with low to intermediate pre-test probability of coronary artery disease (CAD). Only 20-30% of these have potentially obstructive CAD. Because of the relatively poor positive predictive value of coronary CTA, unnecessary invasive coronary angiographies (ICAs) are conducted with the costs and risks associated with the procedure. Hence, an optimized diagnostic CAD algorithm may reduce the numbers of ICAs not followed by revascularization. The Dan-NICAD 2 study has 3 equivalent main aims: (1) To examine the diagnostic precision of a sound-based diagnostic algorithm, The CADScor®System (Acarix A/S, Denmark), in patients with a low to intermediate pre-test risk of CAD referred to a primary examination by coronary CTA. We hypothesize that the CADScor®System provides better stratification prior to coronary CTA than clinical risk stratification scores alone. (2) To compare the diagnostic accuracy of 3T cardiac magnetic resonance imaging (3T CMRI), 82rubidium positron emission tomography (82Rb-PET), and CT-derived fractional flow reserve (FFRCT) in patients where obstructive CAD cannot be ruled out by coronary CTA using ICA fractional flow reserve (FFR) as reference standard. (3) To compare the diagnostic performance of quantitative flow ratio (QFR) and ICA-FFR in patients with low to intermediate pre-test probability of CAD using 82Rb-PET as reference standard. METHODS: Dan-NICAD 2 is a prospective, multicenter, cross-sectional study including approximately 2,000 patients with low to intermediate pre-test probability of CAD and without previous history of CAD. Patients are referred to coronary CTA because of symptoms suggestive of CAD, as evaluated by a cardiologist. Patient interviews, sound recordings, and blood samples are obtained in connection with the coronary CTA. If coronary CTA does not rule out obstructive CAD, patients will be examined by 3T CMRI 82Rb-PET, FFRCT, ICA, and FFR. Reference standard is ICA-FFR. Obstructive CAD is defined as an FFR ≤0.80 or as high-grade stenosis (>90% diameter stenosis) by visual assessment. Diagnostic performance will be evaluated as sensitivity, specificity, predictive values, likelihood ratios, calibration, and discrimination. Enrolment started January 2018 and is expected to be completed by June 2020. Patients are followed for 10 years after inclusion. DISCUSSION: The results of the Dan-NICAD 2 study are expected to contribute to the improvement of diagnostic strategies for patients suspected of CAD in 3 different steps: risk stratification prior to coronary CTA, diagnostic strategy after coronary CTA, and invasive wireless QFR analysis as an alternative to ICA-FFR.

Aortic Calcification Affects Noninvasive Estimates of Central Blood Pressure in Patients with Severe Chronic Kidney Disease.

BACKGROUND: Central blood pressure (BP) assessed noninvasively considerably underestimates true invasively measured aortic BP in chronic kidney disease (CKD) patients. The difference between the estimated and the true aortic BP increases with decreasing estimated glomerular filtration rates (eGFR). The present study investigated whether aortic calcification affects noninvasive estimates of central BP. METHODS: Twenty-four patients with CKD stage 4-5 undergoing coronary angiography and an aortic computed tomography scan were included (63% males, age [mean ± SD ] 53 ± 11 years, and eGFR 9 ± 5 mL/min/1.73 m2). Invasive aortic BP was measured through the angiography catheter, while non-invasive central BP was obtained using radial artery tonometry with a SphygmoCor® device. The Agatston calcium score (CS) in the aorta was quantified on CT scans using the CS on CT scans. RESULTS: The invasive aortic systolic BP (SBP) was 152 ± 23 mm Hg, while the estimated central SBP was 133 ± 20 mm Hg. Ten patients had a CS of 0 in the aorta, while 14 patients had a CS >0 in the aorta. The estimated central SBP was lower than the invasive aortic SBP in patients with aortic calcification compared to patients without (mean difference 8 mm Hg, 95% CI 0.3-16; p = 0.04). The brachial SBP was lower than the aortic SBP in patients with aortic calcification compared to patients without (mean difference 10 mm Hg, 95% CI 2-19; p = 0.02). CONCLUSION: In patients with advanced CKD the presence of aortic calcification is associated with a higher difference between invasively measured central aortic BP and non-invasive estimates of central BP as compared to patients without calcifications.

Sclerostin is not associated with cardiovascular event or fracture in kidney transplantation candidates
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BACKGROUND: Sclerostin, a bone-derived protein, has been linked to cardiovascular calcifications in chronic kidney disease (CKD). The aim of this study was to investigate the associations between sclerostin and mineral and bone disorder in CKD, specifically whether sclerostin levels could predict cardiovascular event, fracture, or all-cause mortality. MATERIALS AND METHODS: Kidney transplantation candidates (n = 157) underwent computed tomography scans of the chest, abdomen, and pelvis. Calcification scores were calculated for coronary arteries, thoracic aorta, and the aortic and mitral valves. Volumetric bone mineral density (BMD) was measured at the spine and hip. Sclerostin and markers of bone turnover were determined from fasting blood samples. RESULTS: Compared to patients with a calcification score of 0, sclerostin levels were higher in patients with calcifications at the coronary arteries (+23%, p < 0.001) and the thoracic aorta (+27%, p = 0.001), but not in patients with calcifications at the aortic (+1%, p = 0.85) or mitral (+8%, p = 0.20) valves. During a median follow-up of 3.7 years, 28 patients had a major cardiovascular event, 19 patients sustained a fragility fracture, and 32 patients died. Sclerostin levels above the median did not predict major cardiovascular event (p = 0.15), fracture (p = 0.58), or mortality (p = 0.65). CONCLUSION: Sclerostin was positively associated with the presence of vascular calcifications, but was not predictive of events associated with mineral and bone disorder in a cohort of kidney transplantation candidates.
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Vertebral Bone Mineral Density Measured by Quantitative Computed Tomography With and Without a Calibration Phantom: A Comparison Between 2 Different Software Solutions.

Quantitative computed tomography (CT) can be used to quantify bone mineral density (BMD) in the spine from clinical CT scans. We aimed to determine agreement and precision of BMD measurements by 2 different methods: phantom-less internal tissue calibration and asynchronous phantom-based calibration in a cohort of patients with chronic kidney disease (CKD). Patients with CKD were recruited for CT angiography of the chest, abdomen, and pelvis. BMD was analyzed by 2 different software solutions using different calibration techniques; phantom-based by QCT Pro (Mindways Inc.) and phantom-less by Extended Brilliance Workspace (Philips Healthcare). Intraoperator reanalysis was performed on 53 patients (36%) for both methods. An interoperator reanalysis on 30 patients (20%) using the phantom-based method and 29 patients (19%) using the phantom-less method was made. XY- and Bland-Altman plots were used to evaluate method agreement. Phantom-based measured BMD was systematically higher than phantom-less measured BMD. Despite a small absolute difference of 3.3 mg/cm3 (CI: -0.2-6.9 mg/cm3) and a relative difference of 5.1% (CI: 2.2%-8.1%), interindividual differences were large, as seen by a wide prediction interval (PI: -47-40 mg/cm3). The Bland-Altman plot showed no systematic bias, apart from 5 outliers. Intraoperator variability was high for the phantom-less method (5.8%) compared to the phantom-based (0.8%) and the interoperator variability was also high for the phantom-less method (5.8%) compared to the phantom-based (1.8%). Despite high correlation between methods, the between-method difference on an individual level showed great variability. Our results suggest agreement between these 2 methods is insufficient to allow them to be used interchangeably in patients with CKD.

Prognostic assessment of stable coronary artery disease as determined by coronary computed tomography angiography: a Danish multicentre cohort study.

Aims: To examine the 3.5 year prognosis of stable coronary artery disease (CAD) as assessed by coronary computed tomography angiography (CCTA) in real-world clinical practice, overall and within subgroups of patients according to age, sex, and comorbidity. Methods and results: This cohort study included 16,949 patients (median age 57 years; 57% women) with new-onset symptoms suggestive of CAD, who underwent CCTA between January 2008 and December 2012. The endpoint was a composite of late coronary revascularization procedure >90 days after CCTA, myocardial infarction, and all-cause death. The Kaplan-Meier estimator was used to compute 91 day to 3.5 year risk according to the CAD severity. Comparisons between patients with and without CAD were based on Cox-regression adjusted for age, sex, comorbidity, cardiovascular risk factors, concomitant cardiac medications, and post-CCTA treatment within 90 days. The composite endpoint occurred in 486 patients. Risk of the composite endpoint was 1.5% for patients without CAD, 6.8% for obstructive CAD, and 15% for three-vessel/left main disease. Compared with patients without CAD, higher relative risk of the composite endpoint was observed for non-obstructive CAD [hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.01-1.63], obstructive one-vessel CAD (HR: 1.83; 95% CI: 1.37-2.44), two-vessel CAD (HR: 2.97; 95% CI: 2.09-4.22), and three-vessel/left main CAD (HR: 4.41; 95% CI :2.90-6.69). The results were consistent in strata of age, sex, and comorbidity. Conclusion: Coronary artery disease determined by CCTA in real-world practice predicts the 3.5 year composite risk of late revascularization, myocardial infarction, and all-cause death across different groups of age, sex, or comorbidity burden.

Bone turnover markers are associated with bone density, but not with fracture in end stage kidney disease: a cross-sectional study.

BACKGROUND: Fracture risk is increased in chronic kidney disease (CKD), but assessment of bone fragility remains controversial in these patients. This study investigated the associations between bone turnover markers, bone mineral density (BMD), and prevalent fragility fracture in a cohort of kidney transplantation candidates. METHODS: Volumetric BMD of spine and hip was measured by quantitative computed tomography. Parathyroid hormone (PTH), bone-specific alkaline phosphatase, procollagen type-1 N-terminal propeptide, tartrate resistant alkaline phosphatase, and C- and N-terminal telopeptides of type 1 collagen were analyzed from fasting morning blood samples. Fragility fractures included prevalent vertebral fractures and previous low-trauma clinical fractures. RESULTS: The fracture prevalence was 18% in 157 adult kidney transplant candidates. Fractured patients had reduced BMD and Z-score at both spine and hip. Levels of bone turnover markers were significantly higher in patients on maintenance dialysis than in pre-dialysis patients; but did not differ between patients with and without fracture. There were strong, positive correlations between PTH and all bone turnover markers. PTH was negatively associated with Z-score at lumbar spine and total hip; in contrast, bone turnover markers were only negatively associated with total hip Z-score. CONCLUSIONS: Bone turnover markers were negatively associated with bone density, but not associated with prevalent fracture in kidney transplantation candidates. The role of bone turnover markers in assessing bone fragility in CKD will require further investigation. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov with identifier NCT01344434 .