Considerations for the use of biochemical laboratory registry data in clinical and public health research.

OBJECTIVES: To inform researchers of central considerations and limitations when applying biochemical laboratory-generated registry data in clinical and public health research. STUDY DESIGN AND SETTING: After review of literature on registry-based studies and the utilization of clinical laboratory registry data, relevant paragraphs and their applicability toward the creation of considerations for the use of biochemical registry data in research were evaluated. This led to the creation of an initial ten considerations. These were elaborated, edited, and merged after several read-throughs by all authors and discussed thoroughly under influence by the authors' personal experiences with laboratory databases and research registries in Denmark, leading to the formulation of five central considerations with corresponding items and illustrative examples. RESULTS: We recommend that the following considerations should be addressed in studies relying on biochemical laboratory-generated registry data: why are biochemical laboratory data relevant to examine the hypothesis, and how were the variable(s) utilized in the study? What were the primary indications for specimen collection in the study population of interest? Were there any pre-analytical circumstances that could influence the test results? Are data comparable between producing laboratories and within the single laboratory over time? Is the database representative in terms of completeness of study populations and key variables? CONCLUSION: It is crucial to address key errors in laboratory registry data and acknowledge potential limitations.

Exploring Drug Re-Purposing for Treatment of Abdominal Aortic Aneurysms: a Systematic Review and Meta-analysis.

OBJECTIVE: Large abdominal aortic aneurysms (AAAs) present a significant mortality risk. While numerous medical interventions have been proposed, no drugs have convincingly reduced AAA progression, rupture rates, or repair risk. This systematic review and meta-analysis aimed to assess the impact of re-purposed drugs or dietary supplements on slowing expansion rates, reducing the risk of rupture, or minimising the risk of repair for individuals with AAA. METHODS: A systematic search was conducted in five databases. Both observational studies and randomised controlled trials were included. Unpublished data from two screening trials were incorporated. Risk of bias was assessed using the Newcastle-Ottawa scale and revised Cochrane risk of bias tool. Meta-analyses were performed for each identified drug subclass and were stratified by overall risk of bias. Results were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Of 7 484 screened studies, 39 met the inclusion criteria. No studies on dietary supplements were included. A total of 84 cohorts were derived from the included studies, and twelve distinct drug groups underwent meta-analyses. Two drug groups, metformin and statins, were statistically significant in slowing AAA growth. No low risk of bias studies were included for these two drug groups, and the results had very high heterogeneity (I2 > 80%). Both groups had a GRADE certainty of very low. Metformin, excluding high risk of bias studies, presented an estimated mean growth difference of AAA diameter between users and non-users of -0.73 mm/year, whilst statins had an overall estimated mean difference of -0.84 mm/year. CONCLUSION: This systematic review and meta-analysis suggests that metformin and statins may provide some effect in slowing AAA progression. However, no definitive evidence was found for any of the investigated drugs included in this study. Further research is needed to identify effective medical treatments for AAA progression with more robust methodology.

Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor ß signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis.

AIMS: Blood eosinophil count and eosinophil cationic protein (ECP) concentration are risk factors of cardiovascular diseases. This study tested whether and how eosinophils and ECP contribute to vascular calcification and atherogenesis. METHODS AND RESULTS: Immunostaining revealed eosinophil accumulation in human and mouse atherosclerotic lesions. Eosinophil deficiency in ΔdblGATA mice slowed atherogenesis with increased lesion smooth muscle cell (SMC) content and reduced calcification. This protection in ΔdblGATA mice was muted when mice received donor eosinophils from wild-type (WT), Il4-/-, and Il13-/- mice or mouse eosinophil-associated-ribonuclease-1 (mEar1), a murine homologue of ECP. Eosinophils or mEar1 but not interleukin (IL) 4 or IL13 increased the calcification of SMC from WT mice but not those from Runt-related transcription factor-2 (Runx2) knockout mice. Immunoblot analyses showed that eosinophils and mEar1 activated Smad-1/5/8 but did not affect Smad-2/3 activation or expression of bone morphogenetic protein receptors (BMPR-1A/1B/2) or transforming growth factor (TGF)-ß receptors (TGFBR1/2) in SMC from WT and Runx2 knockout mice. Immunoprecipitation showed that mEar1 formed immune complexes with BMPR-1A/1B but not TGFBR1/2. Immunofluorescence double-staining, ligand binding, and Scatchard plot analysis demonstrated that mEar1 bound to BMPR-1A and BMPR-1B with similar affinity. Likewise, human ECP and eosinophil-derived neurotoxin (EDN) also bound to BMPR-1A/1B on human vascular SMC and promoted SMC osteogenic differentiation. In a cohort of 5864 men from the Danish Cardiovascular Screening trial and its subpopulation of 394 participants, blood eosinophil counts and ECP levels correlated with the calcification scores of different arterial segments from coronary arteries to iliac arteries. CONCLUSION: Eosinophils release cationic proteins that can promote SMC calcification and atherogenesis using the BMPR-1A/1B-Smad-1/5/8-Runx2 signalling pathway.

Gender-specific Predicted Normal Aortic Size and Its Consequences of the Population-Based Prevalence of Abdominal Aortic Aneurysms.

BACKGROUND: To investigate if a relative-size-index of the abdominal aortic diameter influences the prevalence estimates of abdominal aortic dilatations compared to absolute diameters. METHODS: Cross-sectional study. Participants from the Viborg Vascular Screening Trial, Viborg Women Cohort, and the Viborg Screening Program. Through multivariate linear regression analyses, 2 gender-specific prediction-equations were developed based upon body-surface area and age. The definitions of absolute and relative size of aortic ectasies were 25-29 mm and 1.25-1.49× individual-predicted size (IPS), abdominal aortic aneurysm (AAA) 30 mm and 1.5× IPS, and large repair-recommendable AAA ≥55 mm or ≥ 2.75× IPS, respectively. RESULTS: Nineteen thousand two hundred and sixty nine males (69.6 years) and 2,426 females (67.1 years) attended the population- and ultrasound-based screening studies for AAA. The mean peak systolic abdominal anterior-posterior inner to inner diameter was 19.1 mm (±5.3 mm) and 16.6 mm (±2.8 mm) (P < 0.001) in males and females, respectively. Body surface area showed the strongest correlation with aortic diameters in both males (r = 0.19, P < 0.001) and females (r = 0.17, P < 0.001). Age correlated significantly with size, but only in males (r = 0.03, P < 0.001). The prevalence in men of absolute size-defined and relative size index-defined screening-detected aortic ectasies, AAAs and repair-recommendable AAAs were: 5.9% and 9.5% (P < 0.001), 3.3% and 4.2% (P < 0.001) and 9.9% and 15.2% (P = 0.004), respectively. Prevalence in females of absolute-size-defined and relative-size-index-defined screening-detected aortic ectasies, AAAs and repair-recommendable AAAs were 1.2% and 5.8% (P < 0.001), 0.5% and 1.3% (P = 0.003) and 0.0% and 23.1% (P = 0.553), respectively. CONCLUSIONS: Despite statistical differences, ultrasound-based absolute diameters to detect AAA seem acceptable in men. In females, poor agreements were noticed concerning all 3 categories of aneurysms, indicating that the current absolute diagnostic cut-points do not reflect female anatomy.

Clinical Characteristics, Incidences, and Mortality Rates for Type A and B Aortic Dissections: A Nationwide Danish Population-Based Cohort Study From 1996 to 2016.

BACKGROUND: Population-based epidemiologic studies of aortic dissections (ADs) are needed. This study aimed to report clinical characteristics, incidences, and mortality rates for adult patients admitted to Danish hospitals with type A AD (TAAD) or type B AD (TBAD) from 1996 through 2016. METHODS: We conducted a nationwide, population-based register study. All cases of AD registered with International Classification of Diseases, Tenth Revision codes in the Danish National Patient Registry at time of admission to a hospital with available medical records underwent validation. Data were merged between nationwide health registries including the cause of death registry. Patients with validated AD were matched 1:10 on sex and age with patients with hypertension from the general Danish population. RESULTS: Of 5018 registered cases of AD, 4183 cases underwent review and 3023 (60.2%) were validated as AD. After exclusions, the distribution of validated TAAD and TBAD was 1620 (60.5%) and 1059 (39.5%; P<0.001), 67.5% and 67.0% of patients were men, and mean ages at dissection were 63.5±12.9 and 67.5±12.2 years (P<0.001), respectively. The most prevalent comorbidities for TAAD were hypertension (55.2%), thoracic aortic aneurysms (14.6%), and chronic obstructive pulmonary disease (13.1%); for TBAD, the most prevalent comorbidities were hypertension (64.1%), aortic aneurysms at any location (7.5% to 12.0%), and chronic obstructive pulmonary disease (15.7%). The overall mean annual incidence rate was 4.2/100 000 patient-years. Incidence was significantly higher for TAAD (2.2/100 000) compared with TBAD (1.5/100 000; P<0.001). The 30-day mortality rates for validated TAAD and TBAD were 22.0% and 13.9% (P<0.001), respectively, with no significant changes over time or between sexes. Adjusted 5-year overall mortality rates for TAAD and TBAD were hazard ratio 3.2 (2.9 to 3.5; P<0.001; aortic-related cause of death, 57.0%) and hazard ratio 2.1 (1.9 to 2.4; P<0.001; aortic-related cause of death, 42.8%), respectively, compared with the general hypertensive population. Among patients who survived 30 days from dissection, the adjusted 5-year overall mortality rates were hazard ratio 1.1 (1.0 to 1.3; P=0.12; aortic-related cause of death, 23.2%) and hazard ratio 1.4 (1.2 to 1.6; P<0.001; aortic-related cause of death, 25.6%) for TAAD and TBAD, respectively. CONCLUSIONS: Hypertension, aortic aneurysms, and chronic obstructive pulmonary disease were the most prevalent comorbidities. The 30-day mortality frequencies were consistent over time with no significant differences between sexes. The 5-year mortality rate was higher for TAAD than TBAD. If the patient survived 30 days from dissection, the mortality rate for patients with TAAD was comparable with that of the general hypertensive population, but the mortality rate was significantly higher in patients with TBAD.

Aortic valve calcification among elderly males from the general population, associated echocardiographic findings, and clinical implications.

AIMS: Aortic valve calcification (AVC) detected by non-contrast computed tomography (NCCT) associates with morbidity and mortality in patients with aortic valve stenosis. However, the importance of AVC in the general population is sparsely evaluated. We intend to describe the associations between AVC score on NCCT and echocardiographic findings as left atrial (LA) dilatation, left ventricular (LV) hypertrophy, aortic valve area (AVA), peak velocity, mean gradient, and aortic valve replacement (AVR) in a population with AVC scores ≥300 AU. METHODS AND RESULTS: Of 10 471 males aged 65-74 years from the Danish Cardiovascular Screening trial (DANCAVAS), participants with AVC score ≥300 AU were invited for transthoracic echocardiography and 828 (77%) of 1075 accepted the invitation. AVC scores were categorized (300-599, 600-799, 800-1199, and ≥1200 AU). AVR was obtained from registries. AVC was significantly associated with a steady increase in LA dilation (10.5%, 16.3%, 15.8%, 19.6%, P = 0.031), LV hypertrophy (3.9%, 6.6%, 8.9%, 10.1%, P = 0.021), peak velocity (1.7, 1.9, 2.1, 2.8 m/s, P = 0001), mean gradient (6, 8, 11, 19 mmHg, P = 0.0001), and a decrease in AVA (2.0, 1.9, 1.7, 1.3 cm2, P = 0.0001). The area under the curve was 0.79, 0.93, and 0.92 for AVA ≤1.5 cm2, peak velocity ≥3.0 m/s, and mean gradient ≥20 mmHg, respectively, and the associated optimal AVC score thresholds were 734, 1081, and 1019 AU. AVC > 1200 AU was associated with AVR (P < 0.0001). CONCLUSION: Among males from the background population, increasing AVC scores were associated with LA dilatation, LV hypertrophy, AVA, peak aortic velocity, mean aortic gradient, and AVR.

Population-Based Risk Factors for Ascending, Arch, Descending, and Abdominal Aortic Dilations for 60-74-Year-Old Individuals.

BACKGROUND: Aortic dilations (ectasias and aneurysms) may occur on any segment of the aorta. Pathogenesis varies between locations, suggesting that etiology and risk factors may differ. Despite this discrepancy, guidelines recommend screening of the whole aorta if 1 segmental dilation is discovered. OBJECTIVES: The purpose of this study was to determine the most dominant predictors for dilations at the ascending, arch, descending, and abdominal part of the aorta, and to establish comprehensive risk factor profiles for each aortic segment. METHODS: Individuals aged 60-74 years were randomly selected to participate in DANCAVAS I+II (Danish Cardiovascular Multicenter Screening Trials). Participants underwent cardiovascular risk assessments, including blood samples, blood pressure readings, medical records, and noncontrast computed tomography scans. Adjusted odds ratios for potential risk factors of dilations were estimated by multivariate logistic analyses. RESULTS: The study population consisted of 14,989 participants (14,235 men, 754 women) with an average age of 68 ± 4 years. The highest adjusted odd ratios for having any aortic dilation were observed when coexisting aortic dilations were present. Other noteworthy predictors included coexisting iliac dilations, hypertension, increasing body surface area, male sex, familial disposition, and atrial fibrillation, which were present in various combinations for the different aortic parts. Smoking and acute myocardial infarction were inversely associated with ascending and abdominal dilations. Diabetes was a shared protective factor. CONCLUSIONS: Risk factors differ for aortic dilations between locations. The most dominant predictor for having a dilation at any aortic segment is the presence of an aortic dilation elsewhere. This supports current guidelines when recommending a full screening of the aorta if a focal aortic dilation is discovered.

Individual, expected diameters of the ascending aorta and prevalence of dilations in a study-population aged 60-74 years: a DANCAVAS substudy.

To determine individual, expected normal diameters of the ascending aorta (AAo) and prevalence of dilations based upon an absolute cut-off point (≥ 40 mm) and individual cut-off point (≥ 25% than expected normal). Non-contrast computed tomography (CT) scans were obtained in 14,993 individuals (95.0% male, mean age 67.8 ± 3.8). A sub-group (n = 291) had AAo diameter measured by transthoracic echocardiography. A prediction formula for AAo diameters was created from multivariate linear regression analysis based upon gender, age, and body surface area. An index was made by dividing observed diameters with predicted diameters. A size-index ≥ 1.25 was defined as dilated. Prevalence of AAo dilations among males and females using 40 mm as cut-off point were 10.6% and 2.1% (p < 0.001), respectively, while 3.3% and 2.6% (p = 0.305) using the size-index ≥ 1.25, respectively. Proportion of agreement between cases of AAo dilations from the size-index and 40 mm was 93.0%. Using the size-index as 'golden standard' for dilation, the sensitivity and specificity using 40 mm as cut-off point for males were 100.0% and 92.4%, respectively, while 75.0% and 99.9%, respectively, for females. For males and females, the positive predicted values were 31.3% and 93.8%, respectively; the negative predicted values were 100.0% and 99.3%, respectively. An absolute echocardiographic size-criterion of 40 mm entails a significant number of females with missed AAo dilation, and a large number of males are mistaken to have dilated AAo. Thus, AAo diameters should be evaluated in relation to gender, age and BSA. This study provides a formula for potential clinical implementation.