The perpetual need of randomized clinical trials: challenges and uncertainties in emulating the REDUCE-AMI trial.

Trial emulations in observational data analyses can complement findings from randomized clinical trials, inform future trial designs, or generate evidence when randomized studies are not feasible due to resource constraints and ethical or practical limitations. Importantly, trial emulation designs facilitate causal inference in observational data analyses by enhancing counterfactual thinking and comparisons of real-world observations (e.g. Mendelian Randomization) to hypothetical interventions. In order to enhance credibility, trial emulations would benefit from prospective registration, publication of statistical analysis plans, and subsequent prospective benchmarking to randomized clinical trials prior to their publication. Confounding by indication, however, is the key challenge to interpreting observed intended effects of an intervention as causal in observational data analyses. We discuss the target trial emulation of the REDUCE-AMI randomized clinical trial (ClinicalTrials.gov ID NCT03278509; beta-blocker use in patients with preserved left ventricular ejection fraction after myocardial infarction) to illustrate the challenges and uncertainties of studying intended effects of interventions without randomization to account for confounding. We furthermore directly compare the findings, statistical power, and clinical interpretation of the results of the REDUCE-AMI target trial emulation to those from the simultaneously published randomized clinical trial. The complexity and subtlety of confounding by indication when studying intended effects of interventions can generally only be addressed by randomization.

Prevalence and clinical correlates of ascending aortic dilatation in patients with noncompaction cardiomyopathy.

Ascending aortic (AoAsc) dilatation can lead to acute aortic syndromes and has been described in various familial cardiac diseases. Its prevalence and clinical significance in patients with noncompaction cardiomyopathy (NCCM) are however unknown. Establishing the prevalence can facilitate recommendations on routine screening in NCCM. In this cross-sectional cohort study based on the Rijnmond Heart Failure/Cardiomyopathy Registry, the patient were enrolment between 2014 and 2021. All NCCM patients (n = 109) were age and sex matched with 109 dilated cardiomyopathy (DCM) patients as controls. The aortic diameters were measured through the parasternal long-axis transthoracic echocardiographic view at the sinuses of valsalva (SoV-Ao), sinotubular junction (STJ) and ascending aorta (AscAo). Dilatation was defined using published criteria adjusted for body surface area (BSA), sex, and age. Median age of age-sex matched NCCM and DCM patients was 45[31-56] vs. 45 [31-55] years with 53% males in both groups. NCCM patients had more familial hereditary patterns and genetic variants (55% vs. 24%, p < 0.001). DCM patients had more heart failure and left ventricular dysfunction (ejection fraction 34 ± 11 vs. 41 ± 12, p = 0.001). Ascending aortic dilatation was present in 8(7%) patients with NCCM and 5(5%) patients with DCM (p = 0.46). All dilatations were classified as mild. In conclusion, in this cross-sectional cohort study the prevalence of ascending aortic dilatation in NCCM patients was 7%, which were only mild dilatations and not significantly different from an age-sex matched cohort of DCM patients. Routine aortic dilatation screening therefore does not seem warranted in patients with NCCM.

Risk of cancer after ST-segment-elevation myocardial infarction.

Analyses from administrative databases have suggested an increased cancer incidence among individuals who experienced a myocardial infarction, especially within the first 6 months. It remains unclear to what extent this represents an underlying biological link, or can be explained by detection of pre-symptomatic cancers and shared risk factors. Cancer incidence among 1809 consecutive patients surviving hospitalization for thrombotic ST-segment-elevation myocardial infarction (STEMI; mean age 62.6 years; 26% women; 115 incident cancers) was compared to the cancer incidence among 10,052 individuals of the general population (Rotterdam Study; mean age 63.1 years; 57% women; 677 incident cancers). Pathology-confirmed cancer diagnoses were obtained through identical linkage of both cohorts with the Netherlands Cancer Registry. Cox models were used to obtain hazards ratios (HRs) adjusted for factors associated with both atherosclerosis and cancer. Over 5-year follow-up, there was no significant difference in the incidence of cancer between STEMI patients and the general population (HR 0.96, 95% CI 0.78-1.19). In the first 3 months after STEMI, cancer incidence was markedly higher among STEMI patients compared to the general population (HR 2.45, 95% CI 1.13-5.30), which gradually dissolved during follow-up (P-for-trend 0.004). Among STEMI patients, higher C-reactive protein, higher platelet counts, and lower hemoglobin were associated with cancer incidence during the first year after STEMI (HRs 2.93 for C-reactive protein > 10 mg/dL, 2.10 for platelet count > 300*109, and 3.92 for hemoglobin < 7.5 mmol/L). Although rare, thrombotic STEMI might be a paraneoplastic manifestation of yet to be diagnosed cancer, and is hallmarked by a pro-inflammatory status and anemia.Trial registration Registered into the Netherlands National Trial Register and WHO International Clinical Trials Registry Platform under shared catalogue number NTR6831.

Plasma Amyloid-ß in Relation to Cardiac Function and Risk of Heart Failure in General Population.

BACKGROUND: Amyloid-ß (Aß) may be related to cardiac function. However, there are limited data on the association of plasma Aß with cardiac function and risk of heart failure (HF) in the general population. OBJECTIVES: This study sought to determine the associations of plasma amyloid-ß40 (Aß40) and amyloid-ß42 (Aß42) with echocardiographic measurements of cardiac dysfunction and with incident HF in the general population. METHODS: The study included 4,156 participants of the population-based Rotterdam Study (mean age: 71.4 years; 57.1% women), who had plasma Aß samples collected between 2002 and 2005 and had no established dementia and HF at baseline. Multivariable linear regression models were used to explore the cross-sectional association of plasma Aß with echocardiographic measures. Participants were followed up until December 2016. Cox proportional hazards models were used to assess the association of Aß levels with incident HF. Models were adjusted for cardiovascular risk factors. RESULTS: A per 1-SD increase in log-transformed plasma Aß40 was associated with a 0.39% (95% CI: -0.68 to -0.10) lower left ventricular ejection fraction and a 0.70 g/m2 (95% CI: 0.06-1.34) larger left ventricular mass indexed by body surface area. Aß42 was not significantly associated with echocardiographic measures cross-sectionally. During follow-up (median: 10.2 years), 472 incident HF cases were identified. A per 1-SD increase in log-transformed Aß40 was associated with a 32% greater risk of HF (HR: 1.32; 95% CI: 1.15-1.51), and the association was significant in men, but not in women. Higher plasma Aß42 levels were associated with an increased risk of HF (HR: 1.12; 95% CI: 1.02-1.24), although the association was attenuated after further adjustment for concomitant Aß40 (HR: 1.03; 95% CI: 0.92-1.16). CONCLUSIONS: Higher levels of Aß40 were associated with worse cardiac function and higher risk of new onset HF in the general population, in particular among men.

Effects of Eligibility Criteria on Patient Selection and Treatment Implications from 10 Multidomain Dementia Prevention Trials: A Population-Based Study.

INTRODUCTION: Dementia prevention trials have so far shown little benefit of multidomain interventions against cognitive decline. Recruitment strategies in these trials often centre around dementia risk or cardiovascular risk profile, but it is uncertain whether this leads to inclusion of individuals who may benefit most from the intervention. We determined the effects of eligibility criteria on the recruitment of potential trial participants in the general population. METHODS: In a systematic search until January 1, 2022, we identified all published and ongoing large (≥500 participants), phase-3 multidomain trials for the prevention of cognitive decline or dementia. We applied trial eligibility criteria to 5,381 participants of the population-based Rotterdam Study (mean age: 72 years, 58% women), to compare participant characteristics, predicted risk of cardiovascular disease, and dementia risk, between trial eligible and ineligible persons. RESULTS: We identified 10 trials, of which 5 had been published (DR's EXTRA, FINGER, preDIVA, MAPT, and HATICE) and 5 are ongoing (US-POINTER, MIND-CHINA, MYB, AgeWell.de, and J-Mint). Among all Rotterdam Study participants, eligibility across published trials ranged from 48% for MAPT to 87% for preDIVA, in line with original trial reports. Variability in eligibility was wider for ongoing trials, from 1% for US-POINTER to over 94% for MYB trial. Over 70% of trial eligible individuals are recommended preventive intervention in routine care based on their cardiovascular risk, similar for lipid-lowering (71%) and blood pressure-lowering treatment (73%). Ten-year risks of dementia were similar for eligible compared to ineligible individuals (12 vs. 11%). CONCLUSION: Multidomain dementia prevention trials fail to preferentially include those at the highest risk of dementia and mostly include individuals who qualify for interventions already on the basis of cardiovascular prevention guidelines. These findings call for better targeted enrolment of individuals for whom trial results can improve clinical decision-making.

Sex-specific added value of cardiac biomarkers for 10-year cardiovascular risk prediction.

AIMS: To evaluate the sex-specific predictive value of N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin T (hs-cTnT) and creatine kinase myocardial band (CK-MB) for 10-year risk prediction of coronary heart disease (CHD), stroke, heart failure (HF) and composite outcomes. METHODS: Five-thousand four-hundred thirty individuals (mean age 68.6 years, 59.9% women) from the Rotterdam Study, with biomarker measurements between 1997 and 2001, were included. Participants were followed until 2015. We fitted 'basic' models using traditional cardiovascular risk factors. Improvements in c-statistics and net reclassification improvement (NRI) for events and non-events were calculated. RESULTS: During a median follow-up of 14 years, 747 (13.8%), 563 (10.4%), and 664 (12.2%) participants were diagnosed with CHD, stroke, and HF, respectively. NT-proBNP improved the discriminative performance of the 'basic' model for all endpoints (c-statistic improvements ranging from 0.007 to 0.050) and provided significant event-NRI for HF (14.3% in women; 10.7% in men) and for stroke in men (9.3%). The addition of hs-cTnT increased c-statistic for CHD in women by 0.029 (95% CI, 0.011-0.047) and for HF in men by 0.034 (95% CI, 0.014-0.053), and provided significant event-NRI for CHD (10.3%) and HF (7.8%) in women, and for stroke (8.4%) in men. The added predictive value of CK-MB was limited. CONCLUSION: NT-proBNP and hs-cTnT provided added predictive value for various cardiovascular outcomes above traditional risk factors. Sex differences were observed in the predictive performance of these biomarkers.

Plasma amyloid-ß40 in relation to subclinical atherosclerosis and cardiovascular disease: A population-based study.

BACKGROUND AND AIMS: We aimed to determine associations of plasma amyloid-ß40 (Aß40) with subclinical atherosclerosis and risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. METHODS: Between 2002 and 2005, plasma Aß40 was measured by single molecule array (SiMoA®) in 3879 participants of the population-based Rotterdam Study (mean age: 71 years, 61% female). Subclinical atherosclerosis was quantified as computed tomography-assessed calcification volumes. We determined the association of Aß40 with calcification volumes and clinical ASCVD event risk, and repeated the analyses for ASCVD in a replication cohort of 1467 individuals. RESULTS: Higher levels of Aß40 were associated with increased volumes of calcification in the coronary arteries and to a lesser extent extracranial carotid arteries, independent of traditional cardiovascular risk factors. Of all 3879 participants, 748 developed ASCVD during a median 9.7 years of follow-up. In age- and sex-adjusted models, higher Aß40 predisposed to a minor increase in ASCVD risk (HR [95%CI]: 1.11[1.02-1.21] per 1-SD increase in Aß40), driven by coronary heart disease (HR: 1.17[1.05-1.29]) rather than stroke (HR: 1.04[0.93-1.16]). However, excess risk of clinical outcomes was largely explained by baseline differences in cardiovascular risk factors and attenuated after further adjustment (for ASCVD- HR: 1.05[0.96-1.15] and for CHD- HR: 1.08[0.96-1.20]). Results were similar in the replication cohort, with highest risk estimates for CHD (HR: 1.24[1.04-1.48]) in age- and sex-adjusted models, attenuated after adjustment for cardiovascular risk factors (HR: 1.15[0.96-1.39]). CONCLUSIONS: In this population-based study, higher plasma amyloid-ß40 is associated with subclinical atherosclerosis, but not risk of first-ever ASCVD after accounting for traditional cardiovascular risk factors.

Changes in the Diagnosis of Stroke and Cardiovascular Conditions in Primary Care During the First 2 COVID-19 Waves in the Netherlands.

BACKGROUND AND OBJECTIVES: Although there is evidence of disruption in acute cerebrovascular and cardiovascular care during the coronavirus disease 2019 (COVID-19) pandemic, its downstream effect in primary care is less clear. We investigated how the pandemic affected utilization of cerebrovascular and cardiovascular care in general practices (GPs) and determined changes in GP-recorded diagnoses of selected cerebrovascular and cardiovascular outcomes. METHODS: From electronic health records of 166,929 primary care patients aged 30 or over within the Rotterdam region, the Netherlands, we extracted the number of consultations related to cerebrovascular and cardiovascular care, and first diagnoses of selected cerebrovascular and cardiovascular risk factors (hypertension, diabetes, lipid disorders), conditions, and events (angina, atrial fibrillation, TIA, myocardial infarction, stroke). We quantified changes in those outcomes during the first COVID-19 wave (March-May 2020) and thereafter (June-December 2020) by comparing them to the same period in 2016-2019. We also estimated the number of potentially missed diagnoses for each outcome. RESULTS: The number of GP consultations related to cerebrovascular and cardiovascular care declined by 38% (0.62, 95% confidence interval 0.56-0.68) during the first wave, as compared to expected counts based on prepandemic levels. Substantial declines in the number of new diagnoses were observed for cerebrovascular events: 37% for TIA (0.63, 0.41-0.96) and 29% for stroke (0.71, 0.59-0.84), while no significant changes were observed for cardiovascular events (myocardial infarction [0.91, 0.74-1.14], angina [0.77, 0.48-1.25]). The counts across individual diagnoses recovered following June 2020, but the number of GP consultations related to cerebrovascular and cardiovascular care remained lower than expected throughout the June to December period (0.93, 0.88-0.98). DISCUSSION: While new diagnoses of acute cardiovascular events remained stable during the COVID-19 pandemic, diagnoses of cerebrovascular events declined substantially compared to prepandemic levels, possibly due to incorrect perception of risk by patients. These findings emphasize the need to improve symptom recognition of cerebrovascular events among the general public and to encourage urgent presentation despite any physical distancing measures.

Arterial calcification at different sites and prediction of atherosclerotic cardiovascular disease among women and men.

BACKGROUND AND AIMS: The sex-specific contributions of arterial calcification to atherosclerotic cardiovascular disease (ASCVD) risk prediction and stratification in the light of recent modifications by cardiovascular prevention guidelines remain unclear. We assessed the sex-specific value of calcification in different arteries, beyond the Pooled Cohort Equations (PCE) risk factors, for 10-year ASCVD risk prediction. METHODS: From 2003 to 2006, participants from the population-based Rotterdam Study (n = 2167) underwent CT to quantify coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial (ECAC) and intracranial carotid artery calcification (ICAC). Follow-up for ASCVD was complete on January 1, 2015. We refitted the PCE (base model), and categorized participants into low (<5%), borderline (5%-7.5%), intermediate (7.5%-20%), and high (≥20%) ASCVD risk. We extended the models with calcifications and calculated c-statistics and net reclassification improvements for events (NRIe) and non-events (NRIne). RESULTS: CAC predicted ASCVD in women [hazard-ratio (95%-CI) per 1-SD: 1.40 (1.14-1.73)] and men [1.62 (1.27-1.93)]. After addition of CAC to the base model, the c-statistic improved from 0.71 to 0.72 in women; from 0.65 to 0.68 in men. Addition of CAC led to NRIe of 14.3% in women, 4.8% in men and NRIne of 1.5% in women, 15.1% in men. Only in women, ICAC predicted ASCVD [hazard-ratio (95%-CI) per 1-SD: 1.62 (1.26-2.08)], and improved the model (c-statistic from 0.71 to 0.73, NRIe: 9.8% and NRIne: 5.9%). CONCLUSIONS: Assessment of CAC improves ASCVD risk prediction and stratification. In women, the added value of ICAC for ASCVD risk prediction is comparable to that of CAC.

Prevalence and determinants of healthcare avoidance during the COVID-19 pandemic: A population-based cross-sectional study.

BACKGROUND: During the Coronavirus Disease 2019 (COVID-19) pandemic, the number of consultations and diagnoses in primary care and referrals to specialist care declined substantially compared to prepandemic levels. Beyond deferral of elective non-COVID-19 care by healthcare providers, it is unclear to what extent healthcare avoidance by community-dwelling individuals contributed to this decline in routine healthcare utilisation. Moreover, it is uncertain which specific symptoms were left unheeded by patients and which determinants predispose to healthcare avoidance in the general population. In this cross-sectional study, we assessed prevalence of healthcare avoidance during the pandemic from a patient perspective, including symptoms that were left unheeded, as well as determinants of healthcare avoidance. METHODS AND FINDINGS: On April 20, 2020, a paper COVID-19 survey addressing healthcare utilisation, socioeconomic factors, mental and physical health, medication use, and COVID-19-specific symptoms was sent out to 8,732 participants from the population-based Rotterdam Study (response rate 73%). All questionnaires were returned before July 10, 2020. By hand, prevalence of healthcare avoidance was subsequently verified through free text analysis of medical records of general practitioners. Odds ratios (ORs) for avoidance were determined using logistic regression models, adjusted for age, sex, and history of chronic diseases. We found that 1,142 of 5,656 included participants (20.2%) reported having avoided healthcare. Of those, 414 participants (36.3%) reported symptoms that potentially warranted urgent evaluation, including limb weakness (13.6%), palpitations (10.8%), and chest pain (10.2%). Determinants related to avoidance were older age (adjusted OR 1.14 [95% confidence interval (CI) 1.08 to 1.21]), female sex (1.58 [1.38 to 1.82]), low educational level (primary education versus higher vocational/university 1.21 [1.01 to 1.46), poor self-appreciated health (per level decrease 2.00 [1.80 to 2.22]), unemployment (versus employed 2.29 [1.54 to 3.39]), smoking (1.34 [1.08 to 1.65]), concern about contracting COVID-19 (per level increase 1.28 [1.19 to 1.38]) and symptoms of depression (per point increase 1.13 [1.11 to 1.14]) and anxiety (per point increase 1.16 [1.14 to 1.18]). Study limitations included uncertainty about (perceived) severity of the reported symptoms and potentially limited generalisability given the ethnically homogeneous study population. CONCLUSIONS: In this population-based cross-sectional study, 1 in 5 individuals avoided healthcare during lockdown in the COVID-19 pandemic, often for potentially urgent symptoms. Healthcare avoidance was strongly associated with female sex, fragile self-appreciated health, and high levels of depression and anxiety. These results emphasise the need for targeted public education urging these vulnerable patients to timely seek medical care for their symptoms to mitigate major health consequences.

Recommendations and Associated Levels of Evidence for Statin Use in Primary Prevention of Cardiovascular Disease: A Comparison at Population Level of the American Heart Association/American College of Cardiology/Multisociety, US Preventive Services Task Force, Department of Veterans Affairs/Department of Defense, Canadian Cardiovascular Society, and European Society of Cardiology/European Atherosclerosis Society Clinical Practice Guidelines.

BACKGROUND: Despite using identical evidence to support practice guidelines for lipid-lowering treatment in primary prevention of cardiovascular disease (CVD), it is unclear to what extent the 2018 American Heart Association/American College of Cardiology/Multisociety, 2016 US Preventive Services Task Force (USPSTF), 2020 Department of Veterans Affairs/Department of Defense, 2021 Canadian Cardiovascular Society, and 2019 European Society of Cardiology/European Atherosclerosis Society guidelines differ in grading and assigning levels of evidence and classes of recommendations (LOE/class) at a population level. METHODS: We included 7262 participants, aged 45 to 75 years, without history of CVD from the prospective population-based Rotterdam Study. Per guideline, proportions of the population recommended statin therapy by LOE/class, sensitivity and specificity for CVD events, and numbers needed to treat at 10 years were calculated. RESULTS: Mean age was 61.1 (SD 6.9) years; 58.2% were women. American Heart Association/American College of Cardiology/Multisociety, USPSTF, Department of Veterans Affairs/Department of Defense, Canadian Cardiovascular Society, and European Society of Cardiology/European Atherosclerosis Society strongly recommended statin initiation in respective 59.4%, 40.2%, 45.2%, 73.7%, and 42.1% of the eligible population based on high-quality evidence. Sensitivity for CVD events for treatment recommendations supported with strong LOE/class was 86.3% for American Heart Association/American College of Cardiology/Multisociety (IA or IB), 69.4% for USPSTF (USPSTF-B), 74.5% for Department of Veterans Affairs/Department of Defense (strong for), 93.3% for Canadian Cardiovascular Society (strong), and 66.6% for European Society of Cardiology/European Atherosclerosis Society (IA). Specificity was highest for the USPSTF at 45.3% and lowest for European Society of Cardiology/European Atherosclerosis Society at 10.0%. Estimated numbers needed to treat at 10 years for those with the strongest LOE/class were ranging from 20 to 26 for moderate-intensity and 12 to 16 for high-intensity statins. CONCLUSIONS: Sensitivity, specificity, and numbers needed to treat at 10 years for assigned LOE/class varied greatly among 5 CVD prevention guidelines. The level of variability seems to be driven by differences in how the evidence is graded and translated into LOE/class underlying the treatment recommendations by different professional societies. Efforts towards harmonizing evidence grading systems for clinical guidelines in primary prevention of CVD may reduce ambiguity and reinforce updated evidence-based recommendations.

The accuracy of mean corpuscular volume guided anaemia classification in primary care.

BACKGROUND: Anemia can be categorized into micro-, normo- or macrocytic anemia based on the mean corpuscular volume (MCV). This categorization might help to define the etiology of anemia. METHODS: The cohort consisted of patients newly diagnosed with anaemia in primary care. Seven aetiologies of anaemia were defined, based on an extensive laboratory protocol. Two assumptions were tested: (i) MCV <80 fl (microcytic) excludes vitamin B12 deficiency, folic acid deficiency, suspected haemolysis and suspected bone marrow disease as anaemia aetiology. (ii) MCV >100 fl (macrocytic) excludes iron deficiency anaemia, anaemia of chronic disease and renal anaemia as anaemia aetiology. RESULTS: Data of 4129 patients were analysed. One anaemia aetiology could be assigned to 2422 (59%) patients, more than one anaemia aetiology to 888 (22%) patients and uncertainty regarding the aetiology remained in 819 (20%) patients. MCV values were within the normal range in 3505 patients (85%). In 59 of 365 microcytic patients (16%), the anaemia aetiology was not in accordance with the first assumption. In 233 of 259 macrocytic patients (90%), the anaemia aetiology was not in accordance with the second assumption. CONCLUSIONS: Anaemia aetiologies might be ruled out incorrectly if MCV guided classification is used as a first step in the diagnostic work-up of anaemia. We recommend using a broader set of laboratory tests, independent of MCV.

Genetic susceptibility, obesity and lifetime risk of type 2 diabetes: The ARIC study and Rotterdam Study.

AIMS: Both lifestyle factors and genetic background contribute to the development of type 2 diabetes. Estimation of the lifetime risk of diabetes based on genetic information has not been presented, and the extent to which a normal body weight can offset a high lifetime genetic risk is unknown. METHODS: We used data from 15,671 diabetes-free participants of European ancestry aged 45 years and older from the prospective population-based ARIC study and Rotterdam Study (RS). We quantified the remaining lifetime risk of diabetes stratified by genetic risk and quantified the effect of normal weight in terms of relative and lifetime risks in low, intermediate and high genetic risk. RESULTS: At age 45 years, the lifetime risk of type 2 diabetes in ARIC in the low, intermediate and high genetic risk category was 33.2%, 41.3% and 47.2%, and in RS 22.8%, 30.6% and 35.5% respectively. The absolute lifetime risk for individuals with normal weight compared to individuals with obesity was 24% lower in ARIC and 8.6% lower in RS in the low genetic risk group, 36.3% lower in ARIC and 31.3% lower in RS in the intermediate genetic risk group, and 25.0% lower in ARIC and 29.4% lower in RS in the high genetic risk group. CONCLUSIONS: Genetic variants for type 2 diabetes have value in estimating the lifetime risk of type 2 diabetes. Normal weight mitigates partly the deleterious effect of high genetic risk.

Lifetime risk to progress from pre-diabetes to type 2 diabetes among women and men: comparison between American Diabetes Association and World Health Organization diagnostic criteria.

INTRODUCTION: Pre-diabetes, a status conferring high risk of overt diabetes, is defined differently by the American Diabetes Association (ADA) and the WHO. We investigated the impact of applying definitions of pre-diabetes on lifetime risk of diabetes in women and men from the general population. RESEARCH DESIGN AND METHODS: We used data from 8844 women without diabetes and men aged ≥45 years from the prospective population-based Rotterdam Study in the Netherlands. In both gender groups, we calculated pre-diabetes prevalence according to ADA and WHO criteria and estimated the 10-year and lifetime risk to progress to overt diabetes with adjustment for competing risk of death. RESULTS: Out of 8844 individuals, pre-diabetes was identified in 3492 individuals (prevalence 40%, 95% CI 38% to 41%) according to ADA and 1382 individuals (prevalence 16%, 95% CI 15% to 16%) according to WHO criteria. In both women and men and each age category, ADA prevalence estimates doubled WHO-defined pre-diabetes. For women and men aged 45 years having ADA-defined pre-diabetes, the 10-year risk of diabetes was 14.2% (95% CI 6.0% to 22.5%) and 9.2% (95% CI 3.4% to 15.0%) compared with 23.2% (95% CI 6.8% to 39.6%) and 24.6% (95% CI 8.4% to 40.8%) in women and men with WHO-defined pre-diabetes. At age 45 years, the remaining lifetime risk to progress to overt diabetes was 57.5% (95% CI 51.8% to 63.2%) vs 80.2% (95% CI 74.1% to 86.3%) in women and 46.1% (95% CI 40.8% to 51.4%) vs 68.4% (95% CI 58.3% to 78.5%) in men with pre-diabetes according to ADA and WHO definitions, respectively. CONCLUSION: Prevalence of pre-diabetes differed considerably in both women and men when applying ADA and WHO pre-diabetes definitions. Women with pre-diabetes had higher lifetime risk to progress to diabetes. The lifetime risk of diabetes was lower in women and men with ADA-defined pre-diabetes as compared with WHO. Improvement of pre-diabetes definition considering appropriate sex-specific and age-specific glycemic thresholds may lead to better identification of individuals at high risk of diabetes.

The association of innate and adaptive immunity, subclinical atherosclerosis, and cardiovascular disease in the Rotterdam Study: A prospective cohort study.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is driven by multifaceted contributions of the immune system. However, the dysregulation of immune cells that leads to ASCVD is poorly understood. We determined the association of components of innate and adaptive immunity longitudinally with ASCVD, and assessed whether arterial calcifications play a role in this association. METHODS AND FINDINGS: Granulocyte (innate immunity) and lymphocyte (adaptive immunity) counts were determined 3 times (2002-2008, mean age 65.2 years; 2009-2013, mean age 69.0 years; and 2014-2015, mean age 78.5 years) in participants of the population-based Rotterdam Study without ASCVD at baseline. Participants were followed-up for ASCVD or death until 1 January 2015. A random sample of 2,366 underwent computed tomography at baseline to quantify arterial calcification volume in 4 vessel beds. We studied the association between immunity components with risk of ASCVD and assessed whether immunity components were related to arterial calcifications at baseline. Of 7,730 participants (59.4% women), 801 developed ASCVD during a median follow-up of 8.1 years. Having an increased granulocyte count increased ASCVD risk (adjusted hazard ratio for doubled granulocyte count [95% CI] = 1.78 [1.34-2.37], P < 0.001). Higher granulocyte counts were related to larger calcification volumes in all vessels, most prominently in the coronary arteries (mean difference in calcium volume [mm3] per SD increase in granulocyte count [95% CI] = 32.3 [9.9-54.7], P < 0.001). Respectively, the association between granulocyte count and incident coronary heart disease and stroke was partly mediated by coronary artery calcification (overall proportion mediated [95% CI] = 19.0% [-10% to 32.3%], P = 0.08) and intracranial artery calcification (14.9% [-10.9% to 19.1%], P = 0.05). A limitation of our study is that studying the etiology of ASCVD remains difficult within an epidemiological setting due to the limited availability of surrogates for innate and especially adaptive immunity. CONCLUSIONS: In this study, we found that an increased granulocyte count was associated with a higher risk of ASCVD in the general population. Moreover, higher levels of granulocytes were associated with larger volumes of arterial calcification. Arterial calcifications may explain a proportion of the link between granulocytes and ASCVD.