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Background Treatment for breast cancer (BC) frequently involves radiotherapy. Guidelines recommend screening for cardiac adverse events starting 10 years after radiotherapy. The rationale for this interval is unclear. Methods and Results We aimed to study cardiovascular event rates in the first decade following curative radiotherapy for BC. We compared mortality and cardiovascular event rates with an age‐ and risk factor‐matched control population. We included 1095 patients with BC (mean age 56±12 years). Two hundred and eighteen (19.9%) women died. Cancer and cardiovascular mortality caused 107 (49.1%) and 22 (10.1%) deaths, respectively. A total of 904 cases were matched to female FLEMENGHO (Flemish Study on Environment, Genes and Health Outcomes) participants. Coronary artery disease incidence was similar (risk ratio [RR], 0.75 [95% CI, 0.48–1.18]), yet heart failure (RR, 1.97 [95% CI, 1.19–3.25]) and atrial fibrillation/flutter (RR, 1.82 [95% CI, 1.07–3.08]) occurred more often in patients with BC. Age (hazard ratio [HR], 1.033 [95% CI, 1.006–1.061], P=0.016), tumor grade (HR, 1.739 [95% CI, 1.166–2.591], P=0.007), and neoadjuvant treatment setting (HR, 2.782 [95% CI, 1.304–5.936], P=0.008) were risk factors for mortality. Risk factors for major adverse cardiac events were age (HR, 1.053 [95% CI, 1.013–1.093]; P=0.008), mean heart dose (HR, 1.093 [95% CI, 1.025–1.167]; P=0.007), history of cardiovascular disease (HR, 2.386 [95% CI, 1.096–6.197]; P=0.029) and Mayo Clinic Cardiotoxicity Risk Score (HR, 2.664 [95% CI, 1.625–4.367]; P

Abstract Aims Cardiac allograft vasculopathy (CAV) is the major long‐term complication after heart transplantation, leading to mortality and re‐transplantation. As available non‐invasive biomarkers are scarce for CAV screening, we aimed to identify a proteomic signature for CAV. Methods and results We measured urinary proteome by capillary electrophoresis coupled with mass spectrometry in 217 heart transplantation recipients (mean age: 55.0 ± 14.4 years; women: 23.5%), including 76 (35.0%) patients with CAV diagnosed by coronary angiography. We randomly and evenly grouped participants into the derivation cohort (n = 108, mean age: 56.4 ± 13.8 years; women: 22.2%; CAV: n = 38) and the validation cohort (n = 109, mean age: 56.4 ± 13.8 years; women: 24.8%, CAV: n = 38), stratified by CAV. Using the decision tree‐based machine learning methods (extreme gradient boost), we constructed a proteomic signature for CAV discrimination in the derivation cohort and verified its performance in the validation cohort. The proteomic signature that consisted of 27 peptides yielded areas under the curve of 0.83 [95% confidence interval (CI): 0.75–0.91, P

Abstract Aims Recent trials evaluating the effect of aspirin in the primary prevention of cardiovascular disease showed little or no benefit. However, the role of aspirin on the risk of incident heart failure (HF) remains elusive. This study aimed to evaluate the role of aspirin use on HF incidence in primary and secondary prevention and whether aspirin use increases the risk of incident HF in patients at risk. Methods and results Data from 30 827 patients at risk for HF enrolled in six observational studies were analysed [women 33.9%, mean age (±standard deviation) 66.8 ± 9.2 years]. Cardiovascular risk factors and aspirin use were recorded at baseline, and patients were followed up for the first incident of fatal or non‐fatal HF. The association of incident HF with aspirin use was assessed using multivariable‐adjusted proportional hazard regression, which accounted for study and cardiovascular risk factors. Over 5.3 years (median; 5th–95th percentile interval, 2.1–11.7 years), 1330 patients experienced HF. The fully adjusted hazard ratio (HR) associated with aspirin use was 1.26 [95% confidence interval (CI) 1.12–1.41; P ≤ 0.001]. Further, in a propensity‐score‐matched analysis, the HR was 1.26 (95% CI 1.10–1.44; P ≤ 0.001). In 22 690 patients (73.6%) without history of cardiovascular disease, the HR was 1.27 (95% CI 1.10–1.46; P = 0.001). Conclusions In patients, at risk, aspirin use was associated with incident HF, independent of other risk factors. In the absence of conclusive trial evidence, our observations suggest that aspirins should be prescribed with caution in patients at risk of HF or having HF.

Abstract Background Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. Methods Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan’s multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. Results Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. Conclusions Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

Background Hypertension and diabetes cause chronic kidney disease (CKD) and diastolic left ventricular dysfunction (DVD) as forerunners of disability and death. Home blood pressure telemonitoring (HTM) and urinary peptidomic profiling (UPP) are technologies enabling prevention. Methods UPRIGHT-HTM (Urinary Proteomics Combined with Home Blood Pressure Telemonitoring for Health Care Reform [NCT04299529]) is an investigator-initiated 5-year clinical trial with patient-centred design, which will randomise 1148 patients to be recruited in Europe, sub-Saharan Africa and South America. During the whole study, HTM data will be collected and freely accessible for patients and caregivers. The UPP, measured at enrolment only, will be communicated early during follow-up to 50% of patients and their caregivers (intervention), but only at trial closure in 50% (control). The hypothesis is that early knowledge of the UPP risk profile will lead to more rigorous risk factor management and result in benefit. Eligible patients, aged 55–75 years old, are asymptomatic, but have ≥5 CKD- or DVD-related risk factors, preferably including hypertension, type-2 diabetes, or both. The primary endpoint is a composite of new-onset intermediate and hard cardiovascular and renal outcomes. Demonstrating that combining UPP with HTM is feasible in a multicultural context and defining the molecular signatures of early CKD and DVD are secondary endpoints. Expected outcomes The expected outcome is that application of UPP on top of HTM will be superior to HTM alone in the prevention of CKD and DVD and associated complications and that UPP allows shifting emphasis from treating to preventing disease, thereby empowering patients.

Abstract From 1990 until 2017, global air-pollution related mortality increased by 40%. Few studies addressed the renal responses to ultrafine particulate [≤ 2.5 µm (PM2.5)], including black carbon (BC), which penetrate into the blood stream. In a Flemish population study, glomerular filtration estimated from serum creatinine (eGFR) and the urinary albumin-to-creatinine ratio were measured in 2005–2009 in 820 participants (women, 50.7%; age, 51.1 years) with follow-up of 523 after 4.7 years (median). Serum creatinine, eGFR, chronic kidney disease (eGFR 3.5/> 2.5 mg per mmol creatinine in women/men) were correlated in individual participants via their residential address with PM2.5 [median 13.1 (range 0.3–2.9) μg/m3] and BC [1.1 (0.3–18) μg/m3], using mixed models accounting for address clusters. Cross-sectional and longitudinally, no renal outcome was associated with PM2.5 or BC in models adjusted for sex and baseline or time varying covariables, including age, blood pressure, heart rate, body mass index, plasma glucose, the total-to-HDL serum cholesterol ratio, alcohol intake, smoking, physical activity, socioeconomic class, and antihypertensive treatment. The subject-level geocorrelations of eGFR change with to BC and PM2.5 were 0.13 and 0.02, respectively (P ≥ 0.68). In conclusion, in a population with moderate exposure, renal function was unrelated to ultrafine particulate.

BackgroundTwenty-four-hour and nighttime blood pressure (BP) levels are more strongly associated with cardiovascular risk than office or daytime BP measurements. However, it remains undocumented which of the office and ambulatory BP measurements have the strongest association and predictive information in relation to the presence of type I, or arteriolosclerosis type, cerebral small vessel diseases (CSVD).MethodsA subset of 429 participants from the Maracaibo Aging Study [aged ≥40 years (women, 73.7%; mean age, 59.3 years)] underwent baseline brain magnetic resonance imaging (MRI) to visualize CSVD, which included log-transformed white matter hyperintensities (log-WMH) volume and the presence (yes/no) of lacunes, cerebral microbleeds (CMB), or enlarged perivascular spaces (EPVS). Linear and logistic regression models were applied to examine the association between CSVD and each +10-mmHg increment in the office and ambulatory systolic BP measurements. Improvement in the fit of nested logistic models was assessed by the log-likelihood ratio and the generalized R2 statistic.ResultsOffice and ambulatory systolic BP measurements were related to log-WMH (β-correlation coefficients ≥0.08; P < 0.001). Lacunes and CMB were only associated with ambulatory systolic BP measurements (odds ratios [OR] ranged from 1.31 [95% confidence interval, 1.10-1.55] to 1.46 [1.17–1.84], P ≤ 0.003). Accounted for daytime systolic BP, both the 24-h (β-correlation, 0.170) and nighttime (β-correlation, 0.038) systolic BP measurements remained related to log-WMH. When accounted for 24-h or daytime systolic BP levels, the nighttime systolic BP retained the significant association with lacunes (ORs, 1.05–1.06; 95% CIs, ≥1.01 to ≤ 1.13), whereas the 24-h and daytime systolic BP levels were not associated with lacunes after adjustments for nighttime systolic BP (ORs, ≤ 0.88; 95% CI, ≥0.77 to ≤ 1.14). On top of covariables and office systolic BP, ambulatory systolic BP measurements significantly improved model performance (1.05% ≥ R2 ≤ 3.82%). Compared to 24-h and daytime systolic BP, nighttime systolic BP had the strongest improvement in the model performance; for WMH (1.46 vs. 1.05%) and lacunes (3.06 vs. ≤ 2.05%).ConclusionsTwenty-four-hour and nighttime systolic BP were the more robust BP measurements associated with CSVD, but the nighttime systolic BP level had the strongest association. Controlling ambulatory BP levels might provide additional improvement in the prevention of CSVD.

OBJECTIVES: Lead exposure causes neurocognitive dysfunction in children, but its association with neurocognition in adults at current occupational exposure levels is uncertain mainly due to the lack of longitudinal studies. In the Study for Promotion of Health in Recycling Lead (NCT02243904), we assessed the two-year responses of neurocognitive function among workers without previous known occupational exposure newly hired at lead recycling plants. METHODS: Workers completed the digit-symbol test (DST) and Stroop test (ST) at baseline and annual follow-up visits. Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 µg/dL). Statistical methods included multivariable-adjusted mixed models with participants modelled as random effect. RESULTS: DST was administered to 260 participants (11.9% women; 46.9%/45.0% whites/Hispanics; mean age 29.4 years) and ST to 168 participants. Geometric means were 3.97 and 4.13 µg/dL for baseline BL, and 3.30 and 3.44 for the last-follow-up-to-baseline BL ratio in DST and ST cohorts, respectively. In partially adjusted models, a doubling of the BL ratio was associated with a 0.66% [95% confidence interval (CI) 0.03–1.30; P=0.040] increase in latency time (DST) and a 0.35% (95% CI ‑1.63–1.63; P=0.59) decrease in the inference effect (ST). In fully adjusted models, none of the associations of the changes in the DST and ST test results with the blood lead changes reached statistical significance (P≥0.12). CONCLUSIONS: An over 3-fold increase in blood lead over two years of occupational exposure was not associated with a relevant decline in cognitive performance.

Background The underlying mechanisms of arterial stiffness remain not fully understood. This study aimed to identify a urinary proteomic profile to illuminate its pathogenesis and to determine the prognostic value of the profile for adverse outcomes. Methods and Results We measured aortic stiffness using pulse wave velocity (PWV) and analyzed urinary proteome using capillary electrophoresis coupled with mass spectrometry in 669 randomly recruited Flemish patients (mean age, 50.2 years; 51.1% women). We developed a PWV‐derived urinary proteomic score (PWV‐UP) by modeling PWV with proteomics data at baseline through orthogonal projections to latent structures. PWV‐UP that consisted of 2336 peptides explained the 65% variance of PWV, higher than 36% explained by clinical risk factors. PWV‐UP was significantly associated with PWV (adjusted β=0.73 [95% CI, 0.67–0.79]; P

Purpose: Arterial stiffness predicts cardiovascular complications. The association between arterial stiffness and blood lead (BL) remains poorly documented. We aimed to assess the association of central hemodynamic measurements, including pulse wave velocity (aPWV), with blood lead in a Flemish population. Materials and Methods: In this Flemish population study (mean age, 37.0 years; 48.3% women), 267 participants had their whole BL and 24-h urinary cadmium (UCd) measured by electrothermal atomic absorption spectrometry in 1985–2005. After 9.4 years (median), they underwent applanation tonometry to estimate central pulse pressure (cPP), the augmentation index (AI), pressure amplification (PA), and aPWV. The amplitudes of the forward (Pf) and backward (Pb) pulse waves and reflection index (RI) were derived by a pressure-based wave separation algorithm. Results: BL averaged 2.93 μg/dL (interquartile range, 1.80–4.70) and UCd 4.79 µg (2.91–7.85). Mean values were 45.0 ± 15.2 mm Hg for cPP, 24.4 ± 12.4% for AI, 1.34 ± 0.21 for PA, 7.65 ± 1.74 m/s for aPWV, 32.7 ± 9.9 mm Hg for Pf, 21.8 ± 8.4 mm Hg for Pb, and 66.9 ± 18.4% for RI. The multivariable-adjusted association sizes for a 2-fold higher BL were: +3.03% (95% confidence interval, 1.56, 4.50) for AI; −0.06 (−0.08, −0.04) for PA; 1.02 mm Hg (0.02, 2.02) for Pb; and 3.98% (1.71, 6.24) for RI (p ≤ .045). In 206 participants never on antihypertensive drug treatment, association sizes were +2.59 mm Hg (0.39, 4.79) for cPP and +0.26 m/s (0.03, 0.50) for aPWV. Analyses adjusted for co-exposure to cadmium were consistent. Conclusion: In conclusion, low-level environmental lead exposure possibly contributes to arterial stiffening and wave reflection from peripheral sites.

Purpose: Previous studies that addressed whether left ventricular hypertrophy is more closely associated with central than peripheral blood pressure (BP) have been inconsistent. Radial artery wave generated by applanation tonometry and calibrated with brachial BP in 162 adult Nigerians were analysed by using generalized transfer function to derive central BP. Materials and methods: We compared the associations of ECG voltages and left ventricular hypertrophy (ECG-LVH) as continuous and binary variables respectively with central and brachial BP indices. Results: In a multivariable adjusted analysis, 1 standard deviation (SD) increase in brachial systolic, diastolic, pulse and mean arterial pressures increased the Sokolow–Lyon QRS voltage by 0.34 (CI, 0.21–0.48; p 0.05) corresponding Sokolow–Lyon QRS increase of 0.26 (0.12–0.40, p 0.05) corresponding OR of 2.41 (1.33–4.36, p

Abstract Rationale The urinary proteome reflects molecular drivers of disease. Objectives To construct a urinary proteomic biomarker predicting 1-year post-ICU mortality. Methods In 1243 patients, the urinary proteome was measured on ICU admission, using capillary electrophoresis coupled with mass spectrometry along with clinical variables, circulating biomarkers (BNP, hsTnT, active ADM, and NGAL), and urinary albumin. Methods included support vector modeling to construct the classifier, Cox regression, the integrated discrimination (IDI), and net reclassification (NRI) improvement, and area under the curve (AUC) to assess predictive accuracy, and Proteasix and protein-proteome interactome analyses. Measurements and main results In the discovery (deaths/survivors, 70/299) and test (175/699) datasets, the new classifier ACM128, mainly consisting of collagen fragments, yielding AUCs of 0.755 (95% CI, 0.708–0.798) and 0.688 (0.656–0.719), respectively. While accounting for study site and clinical risk factors, hazard ratios in 1243 patients were 2.41 (2.00–2.91) for ACM128 (+ 1 SD), 1.24 (1.16–1.32) for the Charlson Comorbidity Index (+ 1 point), and ≥ 1.19 (P ≤ 0.022) for other biomarkers (+ 1 SD). ACM128 improved (P ≤ 0.0001) IDI (≥ + 0.50), NRI (≥ + 53.7), and AUC (≥ + 0.037) over and beyond clinical risk indicators and other biomarkers. Interactome mapping, using parental proteins derived from sequenced peptides included in ACM128 and in silico predicted proteases, including/excluding urinary collagen fragments (63/35 peptides), revealed as top molecular pathways protein digestion and absorption, lysosomal activity, and apoptosis. Conclusions The urinary proteomic classifier ACM128 predicts the 1-year post-ICU mortality over and beyond clinical risk factors and other biomarkers and revealed molecular pathways potentially contributing to a fatal outcome.

Introduction and ObjectivesGenome-wide association studies have identified a high number of genetic loci associated with hypertension suggesting the presence of an underlying polygenic architecture. In this study, we aimed to dissect the polygenic component of primary hypertension searching also for pathway-specific components.MethodsThe polygenic risk score (PRS) models, based on the UK biobank genetic signals for hypertension status, were obtained on a target Italian case/control cohort including 561 cases and 731 hyper-normal controls from HYPERGENES, and were then applied to an independent validation cohort composed by multi-countries European-based samples including 1,284 cases and 960 hyper-normal controls.ResultsThe resulting genome-wide PRS was capable of stratifying the individuals for hypertension risk by comparing between individuals in the last PRS decile and the median decile: we observed an odds ratio (OR) of 3.62, CI = [2.01, 6.32] (P = 9.01E-07) and 3.22, 95% CI = [2.06, 5.10] (P = 6.47E-08) in the target and validation cohorts, respectively. The relatively high case/control ORs across PRS quantiles corroborates the presence of strong polygenic components which could be driven by an enrichment of risk alleles within the cases but also by potential enrichment of protective alleles in the old normotensive controls. Moreover, novel pathway-specific PRS revealed an enrichment of the polygenic signal attributable to specific biological pathways. Among those the most significantly associated with hypertension status was the calcium signaling pathway together with other mainly related such as the phosphatidylinositol/inositol phosphate pathways.ConclusionsThe development of pathway-specific PRS could prioritize biological mechanisms, according to their contribution to the genetic susceptibility, whose regulations might be a potential pharmacological preventive target.

Platelet Endothelial Aggregation Receptor 1 (PEAR1) modulates angiogenesis and platelet contact-induced activation, which play a role in the pathogenesis of colorectal cancer. We therefore tested the association of incident colorectal cancer and genetic and epigenetic variability in PEAR1 among 2532 randomly recruited participants enrolled in the family-based Flemish Study on Environment, Genes and Health Outcomes (51.2% women; mean age 44.8 years). All underwent genotyping of rs12566888 located in intron 1 of the PEAR1 gene; in 926 participants, methylation at 16 CpG sites in the PEAR1 promoter was also assessed. Over 18.1 years (median), 49 colorectal cancers occurred, all in different pedigrees. While accounting for clustering of risk factors within families and adjusting for sex, age, body mass index, the total-to-HDL cholesterol ratio, serum creatinine, plasma glucose, smoking and drinking, use of antiplatelet and nonsteroidal anti-inflammatory drug, the hazard ratio of colorectal cancer contrasting minor-allele (T) carriers vs. major-allele (GG) homozygotes was 2.17 (95% confidence interval, 1.18-3.99; P = 0.013). Bootstrapped analyses, from which we randomly excluded from two to nine cancer cases, provided confirmatory results. In participants with methylation data, we applied partial least square discriminant analysis (PLS-DA) and identified two methylation sites associated with higher colorectal cancer risk and two with lower risk. In-silico analysis suggested that methylation of the PEAR1 promoter at these four sites might affect binding of transcription factors p53, PAX5, and E2F-1, thereby modulating gene expression. In conclusion, our findings suggest that genetic and epigenetic variation in PEAR1 modulates the risk of colorectal cancer in white Flemish. To what extent, environmental factors as exemplified by our methylation data, interact with genetic predisposition and modulate penetrance of colorectal cancer risk is unknown.

Background: Aortic pulse wave velocity (aPWV) predicts cardiovascular complications, but the association of central arterial properties with blood lead level (BL) is poorly documented. We therefore assessed their association with BL in 150 young men prior to occupational lead exposure, using baseline data of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods: Study nurses administered validated questionnaires and performed clinical measurements. Venous blood samples were obtained after 8–12 h of fasting. The radial, carotid and femoral pulse waves were tonometrically recorded. We accounted for ethnicity, age, anthropometric characteristics, mean arterial pressure, heart rate, smoking and drinking, and total and high-density lipoprotein serum cholesterol, as appropriate. Results: Mean values were 4.14 μg/dL for BL, 27 years for age, 108/79/28 mm Hg for central systolic/diastolic/pulse pressure, 100/10% for the augmentation ratio/index, 1.63 for pressure amplification, 5.94 m/s for aPWV, 27/11 mm Hg for the forward/backward pulse pressure height, and 43% for the reflection index. Per 10-fold BL increase, central diastolic pressure and the augmentation ratio were respectively 5.37 mm Hg (95% confidence interval [CI], 1.00–9.75) and 1.57 (CI, 0.20–2.94) greater, whereas central pulse pressure and the forward pulse pressure height were 3.74 mm Hg (CI, 0.60–6.88) and 3.37 mm Hg (CI, 0.22–6.53) smaller (p ≤ .036 for all). The other hemodynamic measurements were unrelated to BL. The reflected pulse peak time was inversely correlated with diastolic pressure (r = −0.20; p ≤ .017). Conclusion: At the exposure levels observed in our current study, aPWV, the gold standard to assess arterial stiffness, was not associated with BL. Increased peripheral arterial resistance, as reflected by higher diastolic pressure, might bring reflection points closer to the heart, thereby moving the backward wave into systole and increasing the augmentation ratio in relation to BL.

Abstract Background Previous studies highlighted the usefulness of integrating left ventricular (LV) deformation (strain) and hemodynamic parameters to quantify LV performance. In a population sample, we investigated the anthropometric and clinical determinants of a novel non-invasive index of LV systolic performance derived from simultaneous registration of LV strain and brachial pressure waveforms. Methods Three hundred fifty-six randomly recruited subjects (44.7% women; mean age, 53.9 years; 47.5% hypertensive) underwent echocardiographic and arterial data acquisition. We constructed pressure-strain loops from simultaneously recorded two-dimensional LV strain curves and brachial pressure waveforms obtained by finger applanation tonometry. We defined the area of this pressure-strain loop during ejection as LV ejection work density (EWD). We reported effect sizes as EWD changes associated with a 1-SD increase in covariables. Results In multivariable-adjusted analyses, higher EWD was associated with age, female sex and presence of hypertension (P ≤ 0.0084). In both men and women, EWD increased independently with augmentation pressure (effect size: + 59.1 Pa), central pulse pressure (+ 65.7 Pa) and pulse wave velocity (+ 44.8 Pa; P ≤ 0.0006). In men, EWD decreased with relative wall thickness (− 29.9 Pa) and increased with LV ejection fraction (+ 23.9 Pa; P ≤ 0.040). In women, EWD increased with left atrial (+ 76.2 Pa) and LV end-diastolic (+ 43.8 Pa) volume indexes and with E/e’ ratio (+ 51.1 Pa; P ≤ 0.026). Conclusion Older age, female sex and hypertension were associated with higher EWD. Integration of the LV pressure-strain loop during ejection might be a useful tool to non-invasively evaluate sex-specific and interdependent effects of preload and afterload on LV myocardial performance.

OBJECTIVES: Higher than contemporary exposure levels and advanced age of study participants have limited the interpretation of previous studies relating neurocognitive function to lead exposure. We reassessed this association in young American men prior to chronic occupational exposure at lead recycling plants, using baseline measurements of the Study for Promotion of Health in Recycling Lead (NCT02243904). METHODS: We administered the Stroop test (ST) and the digit-symbol test (DST) to 339 men (mean age, 28.6 years; participation rate 82.7%). Whole blood lead (BL) was determined by inductively coupled plasma mass spectrometry and related ST and DST test results using multivariable-adjusted regression. RESULTS: Average values were 4.26 μg/dL for BL, 1624 ms and 1474 ms for mean reaction time in incongruent and congruent ST trials, and 109 sec for mean total latency in DST. The number of participants with fully correct answers amounted to 281 (82.9%) and 334 (98.5%) in incongruent and congruent ST trials, respectively, and to 198 (58.4%) in the DST. In multivariable-adjusted analyses, there was no association between cognitive performance and BL except for a weak but opposite association in DST; for a 10-fold BL increment, mean total latency was 5.4% (95% confidence interval, -0.4‒11.5%; P=0.066) higher, whereas the error score was 42% (-10‒69%; P=0.096) lower. To exclude an effect of the cumulative lead dose, sensitivity analyses restricted to workers

BackgroundThis study aimed to determine the within-person and between-persons associations of low-grade inflammation (LGI) and endothelial dysfunction (ED) with echocardiographic measures related to diastolic dysfunction (DD) in two general populations and whether these associations differed by sex.MethodsBiomarkers and echocardiographic measures were measured at both baseline and follow-up in the Hoorn Study (n = 383) and FLEMENGHO (n = 491). Individual biomarker levels were combined into either a Z-score of LGI (CRP, SAA, IL-6, IL-8, TNF-α and sICAM-1) or ED (sICAM-1, sVCAM-1, sE-selectin and sTM). Mixed models were used to determine within-person and between-persons associations of biomarker Z-scores with left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) and left atrial volume index (LAVI). These associations were adjusted for a-priori selected confounders.ResultsOverall Z-scores for LGI or ED were not associated with echocardiographic measures. Effect modification by sex was apparent for ED with LVEF in both cohorts (P-for interaction = 0.08 and 0.06), but stratified results were not consistent. Effect modification by sex was apparent for TNF-α in the Hoorn Study and E-selectin in FLEMENGHO with LVEF (P-for interaction≤0.05). In the Hoorn Study, women whose TNF-α levels increased with 1-SD over time had a decrease in LVEF of 2.2 (-4.5;0.01) %. In FLEMENGHO, men whose E-selectin levels increased with 1-SD over time had a decrease in LVEF of 1.6 (-2.7;-0.5) %.ConclusionOur study did not show consistent associations of LGI and ED with echocardiographic measures. Some evidence of effect modification by sex was present for ED and specific biomarkers.

Background Data on the association of systolic and diastolic blood pressure with the structure and function of failing hearts with preserved ejection fraction (EF) are sparse. Methods and Results This analysis included 935 patients with heart failure (49.4% women; mean age, 69.9 years) with preserved EF (≥45%) enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) Trial before initiation of randomized therapy. Left ventricular (LV) structure (dimensions, wall thickness, and mass index), diastolic function (left atrial volume index, transmitral blood flow, and mitral annular velocities), and systolic function (EF and longitudinal strain) were assessed echocardiographically. In multivariable‐adjusted analyses, association sizes expressed per 1‐SD (14.8–mm Hg) increment in systolic blood pressure were 0.020 cm (P=0.003) and 0.018 cm (P=0.004) for LV septal and posterior wall thickness, respectively, and 2.42 mg/m2 (P=0.018) for LV mass index. The corresponding associations with diastolic blood pressure were nonsignificant (P≥0.067). In similarly adjusted analyses, the association sizes expressed per 1‐SD (10.7–mm Hg) increment in diastolic blood pressure were −0.15 for E/A (P

Background Prematurity disrupts the perinatal maturation of the microvasculature and macrovasculature and confers high risk of vascular dysfunction later in life. No previous studies have investigated the crosstalk between the microvasculature and macrovasculature in childhood. Methods and Results In a case‐control study, we enrolled 55 children aged 11 years weighing

Background: Guidelines on the required number of ambulatory blood pressure (ABP) readings focus on individual patients. Clinical researchers often face the dilemma of applying recommendations and discarding potentially valuable information or accepting fewer readings. Methods: Starting from ABP recordings with ≥30/≥10 awake/asleep readings in 4277 participants enrolled in eight population studies in the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes (IDACO), we randomly selected a certain number of readings (from 30 to 1 awake and 10 to 1 asleep readings) at a time over 1000 bootstraps at each step. We evaluated: (i) concordance of the ABP level; (ii) consistency of the cross-classification based on office blood pressure and ABP; and (iii) accuracy in predicting cardiovascular complications. For each criterion, we fitted a regression line joining data points relating outcome to the number of readings covering the ranges of 30-20/10-7 for awake/asleep readings. Results: Reducing readings widened the SD of the systolic/diastolic differences between full (reference) and selected recordings from 1.7/1.2 (30 readings) to 14.3/10.3 mm Hg (single reading) during wakefulness, and from 1.9/1.4 to 10.3/7.7 mm Hg during sleep; lowered the κ statistic from 0.94 to 0.63, and decreased the hazard ratio associated with 10/5 mm Hg increments in systolic/diastolic ABP from 1.21/1.14 to 1.06/1.04 during wakefulness and from 1.26/1.17 to 1.14/1.08 during sleep. The first data points falling off these regression lines during wakefulness/sleep corresponded to 8/3 and 8/4 readings for criteria (i) and (iii) and to 5 awake readings for criterion (ii). Conclusions: 24-h ambulatory recordings with ≥8/≥4 awake/asleep readings yielded ABP levels similar to recordings including the guideline-recommended ≥20/≥7 readings. These criteria save valuable data in a research setting, but are not applicable to clinical practice.

Abstract Retinal arteriolar narrowing increases with age and predict adverse cardiovascular outcomes. Telomere length keeps track of the division of somatic cells and is a biomarker of biological age. We investigated to what extent retinal arteriolar diameters are associated with biological age, as captured by leukocyte telomere length (LTL). In 168 randomly selected Flemish participants from the family-based population study FLEMENGHO (mean age, 46.2 years) at baseline, of whom 85 underwent a follow-up examination (median, 4.1 years), we post-processed nonmydriatic retinal photographs and measured LTL. In men only, central retinal arteriolar equivalents (CRAE) and arteriole-to-venule ratio (AVR) were associated with LTL with stronger associations at higher age and body mass index. In men aged 57.6 years (75th percentile) a 20% shorter LTL was associated with a decrease in CRAE of 4.57 µm. A 20% shorter LTL was associated with a decrease of 5.88 µm in CRAE at a BMI of 29.9 kg/m2 (75th percentile). Similar associations were observed between AVR and LTL. In women, no retinal microvascular traits were associated with LTL. Retinal arteriolar narrowing in men but not in women is associated with biological age. Our findings support the idea that avoiding overweight contributes to maintaining a healthier microcirculation.

Purpose: Although self-measurement of home blood pressure (HBP) is common in Japan and HBP telemonitoring via the Internet is possible, whether telemonitoring improves HBP control better than conventional practice remains unclear. Furthermore, hypertension care with online communication using telemonitored HBP is feasible, whereas the efficacy and safety of such telemedicine have not been established. We aim to compare traditional care, care with office visits using HBP telemonitoring, and antihypertensive telemedicine based on HBP telemonitoring. Methods and design: In total, 444 patients with uncontrolled hypertension will be recruited and randomly assigned to three groups: (1) control: usual care with office visits and HBP self-report, (2) telemonitoring: weekly assessment of transmitted HBP by physicians and treatment adjustment upon office visits, or (3) telemedicine: online communication instead of office visits to adjust medication using telemonitored HBP. Primary outcome is the time to control of HBP, and secondary outcomes include achieved HBP levels, adherence, treatment intensity, adverse events, patient satisfaction and cost-effectiveness. Discussion: Hypertension care with telemonitoring and telemedicine are expected to require shorter time to achieve HBP control compared to usual care. Combining HBP telemonitoring with telemedicine may lower the hurdles for starting and persisting to hypertension treatment and eventually reduce cardiovascular events.

Objective: Previous trials of catheter-based renal-artery denervation (RDN) as treatment modality in resistant hypertension (rHT) generated unconvincing results. In the Investigator-Steered Project on Intravascular Denervation for Management of Treatment-Resistant Hypertension (INSPiRED; NCT01505010), we optimized selection and management of rHT patients. Methods: With ethical clearance to randomize 18 patients, three Belgian hypertension centers screened 29 rHT patients on treatment with ≥3 drugs, of whom 17 after optimization of treatment (age

CKD273 is a urinary biomarker, which in advanced chronic kidney disease predicts further deterioration. We investigated whether CKD273 can also predict a decline of estimated glomerular filtration rate (eGFR) to

Sequencing peptides included in the urinary proteome identifies the parent proteins and may reveal mechanisms underlying the pathophysiology of chronic kidney disease. Methods: In 805 randomly recruited Flemish individuals (50.8% women; mean age, 51.1 years), we determined the estimated glomerular filtration rate (eGFR) from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. We categorized eGFR according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guideline. We analyzed 74 sequenced urinary peptides with a detectable signal in more than 95% of participants. Follow-up measurements of eGFR were available in 597 participants. Results: In multivariable analyses, baseline eGFR decreased (P ≤ 0.022) with urinary fragments of mucin-1 (standardized association size expressed in ml/min/1.73 m2, −4.48), collagen III (−2.84), and fibrinogen (−1.70) and was bi-directionally associated (P ≤ 0.0006) with 2 urinary collagen I fragments (+2.28 and −3.20). The eGFR changes over 5 years (follow-up minus baseline) resulted in consistent estimates (P ≤ 0.025) for mucin-1 (−1.85), collagen (−1.37 to 1.43) and fibrinogen (−1.45) fragments. Relative risk of having or progressing to eGFR

Abstract Background Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. Methods In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. Results Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056). Conclusions In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.

Background Stiffening and calcification of the large arteries are forerunners of cardiovascular complications. MGP (Matrix Gla protein), which requires vitamin K–dependent activation, is a potent locally acting inhibitor of arterial calcification. We hypothesized that the central hemodynamic properties might be associated with inactive desphospho‐uncarboxylated MGP (dp‐ucMGP). Methods and Results In 835 randomly recruited Flemish individuals (mean age, 49.7 years; 45.6% women), we measured plasma dp‐ucMGP, using an ELISA‐based assay. We derived central pulse pressure and carotid‐femoral pulse wave velocity (PWV) from applanation tonometry and calculated forward and backward pulse waves using an automated, pressure‐based wave separation analysis algorithm. Aortic PWV (n=657), central pulse pressure, forward pulse wave, and backward pulse wave mean±SD values were 7.34±1.64 m/s, 45.2±15.3 mm Hg, 33.2±10.2 mm Hg, and 21.8±8.6 mm Hg, respectively. The geometric mean plasma concentration of dp‐ucMGP was 4.09 μg/L. All hemodynamic indexes increased across tertiles of dp‐ucMGP distribution. In multivariable‐adjusted analyses, a doubling of dp‐ucMGP was associated with higher PWV (0.15 m/s; 95% CI, 0.01–0.28 m/s), central pulse pressure (1.70 mm Hg; 95% CI, 0.49–2.91 mm Hg), forward pulse wave (0.93 mm Hg; 95% CI, 0.01–1.84 mm Hg), and backward pulse wave (0.71 mm Hg; 95% CI, 0.11–1.30 mm Hg). Categorization of aortic PWV by tertiles of its distribution highlighted a decreasing trend of PWV at low dp‐ucMGP (

Background Serial imaging studies in the general population remain important to evaluate the usefulness of pathophysiologically relevant biomarkers in predicting progression of left ventricular (LV) remodeling and dysfunction. Here, we assessed in a general population whether these circulating biomarkers at baseline predict longitudinal changes in LV structure and function. Methods and Results In 592 participants (mean age, 50.8 years; 51.4% women; 40.5% hypertensive), we derived echocardiographic indexes reflecting LV structure and function at baseline and after 4.7 years. At baseline, we measured alkaline phosphatase, markers of collagen turnover (procollagen type I, C‐terminal telopeptide, matrix metalloproteinase‐1) and high‐sensitivity cardiac troponin T. We regressed longitudinal changes in LV indexes on baseline biomarker levels and reported standardized effect sizes as a fraction of the standard deviation of LV change. After full adjustment, a decline in LV longitudinal strain (−14.2%) and increase in E/e′ ratio over time (+18.9%; P≤0.019) was associated with higher alkaline phosphatase activity at baseline. Furthermore, longitudinal strain decreased with higher levels of collagen I production and degradation at baseline (procollagen type I, −14.2%; C‐terminal telopeptide, −16.4%; P≤0.029). An increase in E/e′ ratio over time was borderline associated with lower matrix metalloproteinase‐1 (+9.8%) and lower matrix metalloproteinase‐1/tissue inhibitor of metalloproteinase‐1 ratio (+11.9%; P≤0.041). Higher high‐sensitivity cardiac troponin T levels at baseline correlated significantly with an increase in relative wall thickness (+23.1%) and LV mass index (+18.3%) during follow‐up (P≤0.035). Conclusions We identified a set of biomarkers predicting adverse changes in LV structure and function over time. Circulating biomarkers reflecting LV stiffness, injury, and collagen composition might improve the identification of subjects at risk for subclinical cardiac maladaptation.

Background: Following activation by vitamin K (VK), matrix Gla protein (MGP) inhibits arterial calcification, but its role in preserving renal function remains unknown. Methods: In 1166 white Flemish (mean age, 38.2 years) and 714 South Africans (49.2% black; 40.6 years), we correlated estimated glomerular filtration (eGFR [CKD-EPI formula]) and stage of chronic kidney disease (CKD [KDOQI stages 2–3]) with inactive desphospho-uncarboxylated MGP (dp-ucMGP), using multivariable linear and logistic regression. Results: Among Flemish and white and black Africans, between-group differences in eGFR (90, 100 and 122 mL/min/1.73 m2), dp-ucMGP (3.7, 6.5 and 3.2 μg/L), and CKD prevalence (53.5, 28.7 and 10.5%) were significant, but associations of eGFR with dp-ucMGP did not differ among ethnicities (P ≥ 0.075). For a doubling of dp-ucMGP, eGFR decreased by 1.5 (P = 0.023), 1.0 (P = 0.56), 2.8 (P = 0.0012) and 2.1 (P

Background. This proof-of-concept study investigated the feasibility of using biomarkers to monitor right heart pressures (RHP) in heart transplanted (HTx) patients. Methods. In 298 patients, we measured 7.6 years post-HTx mean pressures in the right atrium (mRAP) and pulmonary artery (mPAP) and capillaries (mPCWP) along with plasma high-sensitivity troponin T (hsTnT), a marker of cardiomyocyte injury, and the multidimensional urinary classifiers HF1 and HF2, mainly consisting of dysregulated collagen fragments. Results. In multivariable models, mRAP and mPAP increased with hsTnT (per 1-SD, +0.91 and +1.26 mm Hg; P < 0.0001) and with HF2 (+0.42 and +0.62 mm Hg; P ≤ 0.035), but not with HF1. mPCWP increased with hsTnT (+1.16 mm Hg; P < 0.0001), but not with HF1 or HF2. The adjusted odds ratios for having elevated RHP (mRAP, mPAP or mPCWP ≥10, ≥24, ≥17 mm Hg, respectively) were 1.99 for hsTnT and 1.56 for HF2 (P ≤ 0.005). In detecting elevated RHPs, areas under the curve were similar for hsTnT and HF2 (0.63 vs 0.65; P = 0.66). Adding hsTnT continuous or per threshold or HF2 continuous to a basic model including all covariables did not increase diagnostic accuracy (P ≥ 0.11), whereas adding HF2 per optimized threshold increased both the integrated discrimination (+1.92%; P = 0.023) and net reclassification (+30.3%; P = 0.010) improvement. Conclusions. Correlating RHPs with noninvasive biomarkers in HTx patients is feasible. However, further refinement and validation of such biomarkers is required before their clinical application can be considered.

BackgroundPopulation data on the longitudinal changes of left ventricular (LV) structure and function in relation to insulin resistance are sparse. Therefore, we assessed in a general population whether hyperinsulinemia predicts longitudinal changes in LV and arterial characteristics. Methods and ResultsIn 627 participants (mean age 50.7 years, 51.4% women), we assessed echocardiographic indexes of LV structure and function and carotid‐femoral pulse wave velocity by applanation tonometry at baseline and after 4.7 years. We regressed longitudinal changes in these indexes on baseline insulin and its change during follow‐up, and reported standardized effect sizes as a percentage of the SD of LV changes associated with a doubling of insulin. After adjustment, higher baseline insulin predicted a greater temporal increase in LV mass index (effect size: +15.1%) and E/e′ ratio (+22.1%), and a greater decrease in e′ peak and longitudinal strain (−11.2% to −17.1%). A greater increase in insulin during follow‐up related to a greater increase in LV mass index (+10.7%) and decline in ejection fraction and longitudinal strain (−11.4% to −15.7%). Participants who became or remained insulin resistant during follow‐up experienced worse changes in longitudinal strain, E/e′, and LV mass index as compared with participants who did not develop or had improved insulin resistance over time (P≤0.033). Moreover, multivariable‐adjusted increase in pulse wave velocity was higher in participants with diabetes mellitus than in participants without diabetes mellitus (+1.46 m/s versus +0.71 m/s; P=0.039). ConclusionsHyperinsulinemia at baseline and during follow‐up predicted worsening of LV function and remodeling over time. Our findings underline the importance of management of insulin resistance.

BackgroundNo longitudinal study compared associations of echocardiographic indexes of diastolic left ventricular function studies with conventional (CBP) and daytime ambulatory (ABP) blood pressure in the general population. Methods and ResultsIn 780 Flemish (mean age, 50.2 years; 51.7% women), we measured left atrial volume index (LAVI), peak velocities of the transmitral blood flow (E) and mitral annular movement (e′) in early diastole and E/e′ 9.6 years (median) after CBP and ABP. In adjusted models including CBP and ABP, we expressed associations per 10/5‐mm Hg systolic/diastolic blood pressure increments. LAVI and E/e′ were 0.65/0.40 mL/m2 and 0.17/0.09 greater with higher systolic/diastolic ABP (P≤0.028), but not with higher baseline CBP (P≥0.086). e′ was lower (P≤0.032) with higher diastolic CBP (−0.09 cm/s) and ABP (−0.19 cm/s). When we substituted baseline CBP by CBP recorded concurrently with echocardiography, LAVI and E/e′ remained 0.45/0.38 mL/m2 and 0.15/0.08 greater with baseline ABP (P≤0.036), while LAVI (+0.53 mL/m2) and E/e′ (+0.19) were also greater (P

Background: Recent studies proposed that deceleration in pulse wave velocity (PWV) following reactive hyperaemia might reflect arterial distensibility and endothelial function. We therefore investigated methodological aspects and clinical determinants of new indexes of flow-mediated slowing (FMS) of PWV in a community-based sample. Methods: In 71 subjects (mean age, 60.3 years; 50.7% women), we continuously assessed brachial-radial PWV using Vicorder® at baseline and after 3-min or 5-min suprasystolic upper-arm cuff occlusion. We calculated the relative change (Δ) in PWV per each 30 s intervals during 4 min of post-occlusion. We performed stepwise regression analyses to assess determinants of the PWV response. Results: The peak FMS was detected at the first PWV recording obtained after occlusion. Overall, the decline in PWV during hyperaemia was significantly greater after 5-min of occlusion as compared to 3-min (effect sizes for 0–240 s intervals: −1.83% to −9.63%; P ≤ 0.037). PWV declined significantly less with higher age during the 0–60 s post-occlusion intervals (P ≤ 0.0053). On the other hand, after 120 s of post-occlusion, ΔPWV remained significantly lower in subjects with high diastolic blood pressure and oxidized LDL, and in smokers (P ≤ 0.028). Consequently, as compared to healthy reference group, participants with cardiovascular risk factors exhibited a delay in age-adjusted recovery of PWV after 5-min of occlusion (P ≤ 0.039). Conclusions: Our findings confirm the use of a 5-min occlusion time for the assessment of vasomotor function by FMS. Whereas the early FMS response might deteriorate with ageing, cardiovascular risk factors such as smoking, oxidative stress and hypertension might affect recovery of PWV after reactive hyperaemia.

OBJECTIVES:Heart transplant (HTx) recipients have a high heart rate (HR), because of graft denervation and are frequently started on β-blockade (BB). We assessed whether BB and HR post HTx are associated with a specific urinary proteomic signature. METHODS:In 336 HTx patients (mean age, 56.8 years; 22.3% women), we analyzed cross-sectional data obtained 7.3 years (median) after HTx. We recorded medication use, measured HR during right heart catheterization, and applied capillary electrophoresis coupled with mass spectrometry to determine the multidimensional urinary classifiers HF1 and HF2 (known to be associated with left ventricular dysfunction), ACSP75 (acute coronary syndrome) and CKD273 (renal dysfunction) and 48 sequenced urinary peptides revealing the parental proteins. RESULTS:In adjusted analyses, HF1, HF2 and CKD273 (p ≤ 0.024) were higher in BB users than non-users with a similar trend for ACSP75 (p = 0.06). Patients started on BB within 1 year after HTx and non-users had similar HF1 and HF2 levels (p ≥ 0.098), whereas starting BB later was associated with higher HF1 and HF2 compared with non-users (p ≤ 0.014). There were no differences in the urinary biomarkers (p ≥ 0.27) according to HR. BB use was associated with higher urinary levels of collagen II and III fragments and non-use with higher levels of collagen I fragments. CONCLUSIONS:BB use, but not HR, is associated with a urinary proteomic signature that is usually associated with worse outcome, because unhealthier conditions probably lead to initiation of BB. Starting BB early after HTx surgery might be beneficial.

A novel paradigm of diastolic left ventricular (LV) dysfunction proposes involvement of the cardiac microvasculature. Vitamin K dependent matrix Gla protein (MGP) plays a role in preserving microcirculatory integrity. We hypothesized that LV filling pressure-a measure of diastolic LV dysfunction-increases with higher plasma level of inactive desphospho-uncarboxylated MGP (dp-ucMGP). We also studied the distribution of active and inactive MGP in human myocardium.We measured echocardiographic diastolic LV function and plasma dp-ucMGP (ELISA) in 668 Flemish and for replication in 386 Swiss.Among Flemish and Swiss, E/e' (6.78 vs. 6.73) and dp-ucMGP (3.94 μg/L vs. 4.20 μg/L) were similarly distributed. In multivariable-adjusted models, for each doubling of dp-ucMGP, E/e' increased by 0.26, 0.33 and 0.31 in Flemish, Swiss and both cohorts combined (P≤0.026); the odds ratios for having E/e' ≥ 8.5 were 1.99, 3.29 and 2.36, respectively (P≤0.017). Cardiac biopsies from patients with ischemic or dilated cardiomyopathy and healthy hearts (n = 4 for each) were stained with conformation-specific MGP antibodies. In diseased compared with normal hearts, uncarboxylated inactive MGP was more prevalent (P≤0.004) in the perivascular matrix and interstitium (204.4 vs. 8.6 μm2 per field) and phosphorylated active MGP in and around capillaries and interstitial cells (31.3 vs. 6.6 number of positive capillaries and cells per field).Our study supports a role of activated MGP in maintaining myocardial integrity and diastolic LV performance and can potentially be translated into new strategies for managing diastolic LV dysfunction and preventing its progression to heart failure.

Background: Recent studies proposed that deceleration in pulse wave velocity (PWV) following hyperemia might reflect arterial distensibility and endothelial function. We therefore investigated methodological aspects and clinical determinants of newly proposed indexes of such flow-mediated slowing (FMS) in a community-based sample. Methods: In 71 subjects (60.3±13.7 years; 50.7% women), we continuously assessed brachial- radial pulse wave velocity (PWV) using Vicorder® equipment at rest and after 3 or 5 minutes suprasystolic occlusion to induce reactive hyperemia. We calculated the relative change (Δ) in PWV per 30s post-occlusion intervals. We performed stepwise regression analyses to assess determinants of the PWV response. Results: The decline in PWV during hyperemia was significantly stronger after 5 minutes of occlusion as compared to 3 minutes (effect sizes for 0–180s intervals: −3.58% to −0.1%; P≤0.0019). PWV declined significantly less with higher age during the 0–90s post-occlusion intervals (+1.61 to +3.99%; P≤0.023). On the other hand, we observed that, after 120s of hyperemic response, ΔPWV remained significantly lower in smokers (−4.28% to −5.37%) and subjects with high mean arterial pressure (−2.14% to −2.23%) and low pulse pressure (+2.06% to +2.07%; P≤0.046 for all). Hence, compared to non-smoking normotensives, subjects with cardiovascular risk factors exhibited a delayed age-adjusted recovery of PWV after 5 minutes of occlusion (P≤0.039). Conclusions: Our findings confirm an occlusion time of 5 minutes for assessment of endothelial function by FMS. Whereas early FMS response might deteriorate with ageing, cardiovascular risk factors such as smoking and hypertension might impair the late recovery of PWV following reactive hyperemia.

Background: The interaction between the heart and arteries (i.e. ventricular-arterial coupling, VAC) is a key determinant of cardiovascular performance. As such, VAC indexes might reflect the interplay between arterial stiffness and left ventricular (LV) dysfunction. In a community-based sample, we assessed the determinants of a new, non-invasive VAC index reflecting myocardial performance. Methods: In 364 subjects (45.1% women; mean age, 53.8 years; 46.7% hypertensive), we derived echocardiographic indexes of LV structure and function and tonometric measures of central haemodynamics and aortic stiffness. From two-dimensional LV strain curves and simultaneously recorded pressure waveforms, we constructed the pressure-strain loop and calculated ejection work density (EWD), a myocardial performance index, as the area of the pressure-strain loop during LV ejection. Results: In multivariable-adjusted analysis, EWD increased linearly with age (P < 0.0001). While adjusting for age, anthropometric measures and heart rate, EWD was significantly higher in women and patients with hypertension as compared to men and normotensives, respectively (P < 0.0001 for all). After full adjustment, EWD increased with higher augmentation pressure, central pulse pressure and carotid- femoral pulse wave velocity in both men and women (P≤0.031). Furthermore, EWD correlated independently and directly with left atrial and LV end-diastolic volumes (P≤0.015) as well as peak early diastolic velocities of transmitral flow and mitral annulus movement (P≤0.025). Conclusion: Higher age, female sex and hypertension were independent determinants of higher EWD. Being associated with indexes reflecting central haemodynamics, arterial stiffness and LV diastolic function, this myocardial performance index might reflect the interaction between LV performance and arterial properties.

Background: Recent studies showing an inverse association between estimated glomerular filtration rate (eGFR), a microvascular trait, and inactive desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) support the hypothesis that after vitamin K dependent activation MGP is renoprotective, but were limited by their cross-sectional design. Methods: In 1009 randomly recruited Flemish (50.6% women), we assessed the association between eGFR and plasma dp-ucMGP, using multivariable-adjusted analyses. Results: From baseline to follow-up 8.9 years later (median), dp-ucMGP increased by 3.7%, whereas eGFR decreased by 4.05 ml/min/1.73 m2 (P < 0.001). In 938 participants with baseline eGFR ≥ 60 ml/min/1.73 m2, incidence of eGFR < 60 ml/min/1.73 m2 at follow-up was 8.0% vs. 4.1% in the top vs. the bottom halve of baseline dp-ucMGP. For each doubling of baseline dp-ucMGP, eGFR at follow-up decreased by 1.36 ml/min/1.73 m2 [95% confidence interval (CI) 0.55–2.17 ml/min/1.73 m2; P = 0.001]. The hazard ratio expressing the risk of progression to eGFR < 60 ml/min/1.73 m2 was 1.67 (95% CI 1.16–2.41; P = 0.006). The hazard ratio relating the presence of microalbuminuria at follow-up to baseline dp-ucMGP was 1.96 (95% CI 1.22–3.12; P = 0.005). Conclusions: In conclusion, circulating inactive dp-ucMGP, a biomarker of poor vitamin K status, predicts renal dysfunction. Possible underlying mechanisms include protection by activated MGP against calcification and inhibition of bone morphogenetic protein signaling pathway.

Background: Central blood pressure (BP) is a predictor of target organ damage. No previous study addressed the question to what extent central compared with peripheral is related to left ventricular (LV) structure and function in a general population. Methods: In 577 Flemish recruited from the general population (47.8% women; mean age 50.5 years), we assessed the multivariable-adjusted associations of echocardiographic LV structure and systolic and diastolic LV function (Vivid7 Pro device; EchoPac software, version 4.0.4; GE Vingmed, Horten, Norway) with peripheral and central pressure, as recorded by radial applanation tonometry (SphygmoCor software, version 9.0). Association sizes were expressed per 15/10 mmHg increment in peripheral or central systolic/diastolic BP. Results: Peripheral compared with central systolic BP was 10.2 mm Hg higher (P < 0.0001), whereas diastolic BP was similar peripherally and centrally (P = 0.50). Associations were closer (P≤0.020) with central than peripheral systolic BP for LV mass (+0.59 g/m2) and left atrial volume (+0.29 ml/m2) indexed to body surface area, peak A transmitral flow (+0.12 cm/s), peak e′ mitral annular movement (−0.18 cm/s) and the E/A ratio (−0.017). Associations were closer (P≤0.038) with central than peripheral diastolic BP for left atrial volume index (+0.289 ml/m2), e′ (−0.123 cm/s) and E/e′ (+0.094). Ejection fraction and global longitudinal strain were similarly associated with central and peripheral systolic (P≥0.62) and diastolic (P≥0.18) BP. Conclusions: In asymptomatic people recruited from the general population, LV mass and atrial volume indexes and selected haemodynamic measurements reflecting diastolic LV function are slightly but significantly closer associated with central than peripheral BP.

Background: Molecular pathways leading to stiffening of the central arteries are poorly understood. We searched for differentially expressed proteins by urinary peptidomic analysis in patients with arterial stiffness and healthy controls in a case–control study. Methods: To identify urinary peptides associated with aortic stiffening, we applied capillary electrophoresis coupled to mass spectrometry. We compared 18 cardiovarscular disease-free patients with carotid-femoral pulse wave velocity (PWV > 10 m/s standardised to a heart rate of 75/minute as measured by the SphygmoCor method) with 18 controls matched for sex, age and mean arterial pressure. Results: 69 urinary peptides had a different signal amplitude between cases and controls (P ≤ 0.049). Among 33 peptides with known sequence, 26 were members of the extracellular matrix family, including collagen type I α-1 and α-2, collagen type III α-1, collagen type IV α-5, collagens IX, XXI and XXVII. Collagen type I was down-regulated, whereas collagen type III was up-regulated. Epidermal growth factor receptor (EGFR), a key regulator of myoblast differentiation, and interactions of laminin with other proteins were down-regulated. Atherosclerosis signalling pathways and intrinsic prothrombin activation were the top pathways associated with increased PWV. Potential drug targets included collagen type IV α 3 and transforming growth factor β 3. Angiotensin-converting enzyme inhibitors, which are widely used for vascular protection, were among the possible therapeutic agents. Conclusions: We suggest that stiffening of large elastic arteries involves changes of the extracellular matrix, as reflected by collagen turnover and regulation of myoblast differentiation. Pathway analysis identified potential drug targets, possibly amenable by angiotensin-converting enzyme inhibition.

Background: The retinal microvasculature can be visualized noninvasively and mirrors the status of the cerebral vasculature. We therefore investigated in 93 prematurely born infants (birth weight < 1000 g) and 87 controls born at term whether neurocognitive performance at ∼11 years is associated with the diameter of retinal microvessels. Methods: We post-processed retinal photographs by a semi-automated software (Singapore I Vessel Assessment, version 3.6) and administered the Wechsler Non-Verbal test, Dutch version (Pearson, The Netherlands) to estimate the intelligence quotient (IQ) by combining matrix reasoning and spatial span. Results: Compared with the controls, cases had lower IQ (92.5 vs. 108.7; P < 0.001), smaller central retinal arteriolar (CRAE; 162.7 vs. 174.0 mm; P < 0.001) and venular (CRVE; 234.7 vs. 242.7 mm; P = 0.003) diameters and CRAE/CRVE ratio (AVR; 0.70 vs. 0.72; P = 0.002) and lower body mass index (17.0 vs. 17.7 kg/m2; P = 0.044), but higher mean arterial pressure (82.7 vs. 77.7 mmHg; P < 0.001). In all children, the effect sizes associated with a 1-SD increase in CRAE were +3.87 (P < 0.001), +1.80 (P = 0.004) and +2.26 (P = 0.003) for total IQ, matrix reasoning, and spatial span, respectively. In models adjusted for body mass index and mean arterial pressure, these estimates were +3.21 (P = 0.009), +1.57 (P = 0.020), and +1.84 (P = 0.024), respectively. The associations of IQ and matrix reasoning with AVR also attained significance (P ≤ 0.031). Conclusions: In conclusion, our findings suggest that underdevelopment of the microcirculation in prematurely born children might have lasting effects on their cognitive performance.

Background: The heart ejects in the central elastic arteries. No previous study addressed the question whether ECG voltages are more closely associated with central than with peripheral blood pressure (BP). Methods: Using the oscillometric Mobil-O-Graph 24 h PWA monitor, we measured brachial, central BP and central hemodynamics over 24 hours in 177 men (mean age, 29.1 years), and linked to ECG voltages. Results: From wakefulness to sleep, as documented by diaries, systolic/diastolic BP decreased by 11.7/13.1 mmHg peripherally and by 9.3/13.6 mmHg centrally, whereas pulse pressure (PP) increased by 4.3 mmHg. Over 24 hours and the awake and asleep periods, the peripheral-minus-central differences in systolic/diastolic BPs and pulse pressure averaged 11.8/–1.6, 12.7/–1.8 and 10.3/–1.2 mmHg and 13.4, 14.4 and 11.5 mmHg, respectively (P < 0.0001). Cornel voltage and index averaged 1.18 mV and 114.8 mV×ms. The Cornell voltages were 0.104/0.086 and 0.082/0.105 mV higher in relation to brachial 24-h and asleep systolic/diastolic BP (per 1-SD), respectively, and 0.088/0.90 mV and 0.087/0.107 mV higher in relation to central BP. The corresponding estimates for the Cornel indexes were 9.6/8.6 and 8.2/105 mV×ms peripherally and 8.6/8.9 and 8.8/10.7 mV×ms centrally. The regression slopes were similar for brachial and central BP (P≥0.054). Associations of the ECG measurements with awake BP, PP, the augmentation ratio and pressure amplification did not reach significance. Cornell voltage (SV3 + RaVL, mV) Cornell index (Cornell voltage × QRS duration, mV·ms) Peripheral BP Central BP Peripheral BP Central BP Estimate (95% CI) P Estimate (95% CI) P Estimate (95% CI) P Estimate (95% CI) P Systolic BP 24-h 0.104 (0.016 to 0.191) 0.021 0.088 (0.0003 to 0.177) 0.049 9.61 (0.65 to 18.57) 0.036 8.58 (−0.40 to 17.56) 0.061 Awake 0.086 (−0.001 to 0.175) 0.054 0.062 (−0.026 to 0.151) 0.17 7.69 (−1.30 to 16.69) 0.093 5.80 (−3.23 to 14.82) 0.21 Asleep 0.082 (−0.006 to 0.170) 0.068 0.087 (−0.001 to 0.175) 0.053 8.17 (−0.82 to 17.16) 0.075 8.76 (−0.217 to 17.74) 0.056 Diastolic BP 24-h 0.086 (−0.002 to 0.174) 0.056 0.090 (0.002 to 0.178) 0.045 8.57 (−0.41 to 17.55) 0.061 8.93 (−0.04 to 17.90) 0.051 Awake 0.056 (−0.032 to 0.145) 0.21 0.060 (−0.029 to 0.149) 0.18 5.62 (−3.42 to 14.65) 0.22 5.97 (−3.06 to 15.00) 0.19 Asleep BP 0.105 (0.017 to 0.192) 0.020 0.107 (0.019 to 0.194) 0.017 10.53 (1.60 to 19.47) 0.021 10.71 (1.78 to 19.64) 0.019 Pulse pressure 24-h 0.040 (−0.049 to 0.129) 0.38 0.016 (−0.073 to 0.105) 0.72 3.07 (−5.99 to 12.13) 0.50 1.31 (−7.76 to 10.38) 0.77 Awake 0.048 (−0.041 to 0.137) 0.29 0.012 (−0.077 to 0.101) 0.78 3.63 (−5.43 to 12.68) 0.43 0.68 (−8.40 to 9.74) 0.88 Asleep 0.001 (−0.091 to 0.088) 0.98 0.001 (−0.087 to 0.090) 0.98 −0.29 (−9.37 to 8.78) 0.95 0.21 (−8.86 to 9.28) 0.96 ECG refers to electrocardiography. BP stands for blood pressure. Cornell voltage is the voltage sum of S wave in precordial V3 lead (SV3) and R wave in limb aVL lead (ReVL), while Cornell index is the product of QRS duration multiplied by the Cornell voltage. The estimate (95% Confidence Interval, CI) of the association was unadjusted and expressed as 1-SD increase of BP. P value is for significance of the estimate. The association estimates of Cornell voltage (P ≥ 0.054) and index (P ≥ 0.079) with central BP were not significantly different from those estimates with peripheral measurements. TableAssociation of ECG Cornell voltage and indexes with peripheral and central BP. Conclusions: The diurnal rhythm of peripheral and central BP run in parallel. Central BP does not improve the association of Cornell voltage or index with peripheral BP.

Introduction: Common carotid artery (CCA) intima-media thickness (IMT), lumen diameter, and maximum plaque thickness were assessed on ultrasound images. The objective of the study was to evaluate the intra- and inter-reader reproducibility of the measurements following a standardised protocol. Methods: Two readers performed the off-line measurements on B-mode ultrasound images of the distal CCA, in a randomly selected subset (n = 60) from a Flemish population cohort (FLEMENGHO). We calculated the coefficient of variation, the interclass correlation coefficient (ICC) and reproducibility according to the Bland–Altman method. Results: The intra-reader bias for the measurements of left and right side CCA IMT were −0.003 ± 0.04 mm (p = 0.55) and 0.01 ± 0.04 mm (p = 0.03), respectively. The intra-reader bias of the lumen diameter was −0.04 ± 0.25 mm (p = 0.27) for the left and 0.02 ± 0.22 mm (p = 0.45) for the right side. The measurements for the maximum plaque thickness showed no intra-reader differences with bias 0.07 ± 0.2 mm (p = 0.26) for the left and −0.03 ± 0.2 mm (p = 0.55) for the right side. The inter-reader analysis showed good reproducibility for the left and right side CCA IMT with bias 0.004 ± 0.06 mm (p = 0.57) and −0.008 ± 0.05 mm (p = 0.19), respectively, but the lumen diameter measurements showed inter-reader differences, with bias 0.17 ± 0.27 mm (p < 0.0001) for the left and 0.10 ± 0.21 mm (p = 0.0006) for the right side. The inter-reader bias for the maximum plaque thickness were 0.07 ± 0.2 mm (p = 0.21) and −0.1 ± 0.4 mm (p = 0.26) for the left and right side, respectively. Conclusion: The results demonstrated a reliable reproducibility of carotid wall structural measurements, allowing for an adequate further analysis of the entire population cohort.

BackgroundTo address the need for personalized prevention, we conducted a subject‐level meta‐analysis within the framework of the Heart “OMics” in AGEing (HOMAGE) study to develop a risk prediction model for heart failure (HF) based on routinely available clinical measurements. Methods and ResultsThree studies with elderly persons (Health Aging and Body Composition [Health ABC], Valutazione della PREvalenza di DIsfunzione Cardiaca asinTOmatica e di scompenso cardiaco [PREDICTOR], and Prospective Study of Pravastatin in the Elderly at Risk [PROSPER]) were included to develop the HF risk function, while a fourth study (Anglo‐Scandinavian Cardiac Outcomes Trial [ASCOT]) was used as a validation cohort. Time‐to‐event analysis was conducted using the Cox proportional hazard model. Incident HF was defined as HF hospitalization. The Cox regression model was evaluated for its discriminatory performance (area under the receiver operating characteristic curve) and calibration (Grønnesby‐Borgan χ2 statistic). During a follow‐up of 3.5 years, 470 of 10 236 elderly persons (mean age, 74.5 years; 51.3% women) developed HF. Higher age, BMI, systolic blood pressure, heart rate, serum creatinine, smoking, diabetes mellitus, history of coronary artery disease, and use of antihypertensive medication were associated with increased HF risk. The area under the receiver operating characteristic curve of the model was 0.71, with a good calibration (χ2 7.9, P=0.54). A web‐based calculator was developed to allow easy calculations of the HF risk. ConclusionsSimple measurements allow reliable estimation of the short‐term HF risk in populations and patients. The risk model may aid in risk stratification and future HF prevention strategies.

BackgroundExperimental studies have demonstrated that lead and cadmium have direct toxic effects on the myocardium, but the few human studies are limited by design, assessment of exposure, and use of heart failure as a late‐stage endpoint. Methods and ResultsIn a prospective population study, we studied the association of left ventricular (LV) function with blood lead (BPb) and 24‐hour urinary cadmium (UCd). In 179 participants randomly recruited from a Flemish population (50.3% women; mean age 39.1 years), geometric mean BPb and UCd at enrollment (1985‐2000) were 0.20 μmol/L and 6.1 nmol, respectively. We assessed systolic and diastolic LV function 11.9 years (median) later (2005‐2010) by using Doppler imaging of the transmitral blood flow and the mitral annular movement and speckle tracking. In multivariable‐adjusted linear regression, LV systolic function decreased with BPb. For a doubling of exposure, estimates were −0.392% for global longitudinal strain (P=0.034), −0.618% and −0.113 s−1 for regional longitudinal strain (P=0.028) and strain rate (P=0.008), and −0.056 s−1 for regional radial strain rate (P=0.050). Regional longitudinal strain rate (−0.066 s−1, P=0.009) and regional radial strain (−2.848%, P=0.015) also decreased with UCd. Models including both exposure indexes did not allow differentiating whether LV dysfunction was predominately related to BPb or UCd. Diastolic LV function was not associated with BPb or UCd (P≥0.159). ConclusionsAlthough effect sizes were small, our results suggest that environmental exposure to lead, cadmium, or both might be a risk factor for systolic LV dysfunction, a condition often proceeding to heart failure.

Mitochondrial DNA (mtDNA) content might undergo significant changes caused by metabolic derangements, oxidative stress and inflammation that lead to development and progression of cardiovascular diseases. We, therefore, investigated in a general population the association of peripheral blood mtDNA content with circulating metabolites and inflammatory markers. We examined 310 subjects (50.6% women; mean age, 53.3 years) randomly selected from a Flemish population. Relative mtDNA content was measured by quantitative real-time PCR in peripheral blood cells. Peak circulating metabolites were quantified using nuclear magnetic resonance spectroscopy. The level of inflammation was assessed via established inflammatory markers. Using Partial Least Squares analysis, we constructed 3 latent factors from the 44 measured metabolites that explained 62.5% and 8.5% of the variance in the contributing metabolites and the mtDNA content, respectively. With adjustments applied, mtDNA content was positively associated with the first latent factor (P = 0.002). We identified 6 metabolites with a major impact on the construction of this latent factor including HDL3 apolipoproteins, tyrosine, fatty acid with αCH2, creatinine, β-glucose and valine. We summarized them into a single composite metabolite score. We observed a negative association between the composite metabolic score and mtDNA content (P = 0.001). We also found that mtDNA content was inversely associated with inflammatory markers including hs-CRP, hs-IL6, white blood cell and neutrophil counts as well as neutrophil-to-lymphocyte ratio (P≤0.0024). We demonstrated that in a general population relative peripheral blood mtDNA content was associated with circulating metabolites indicative of perturbed lipid metabolism and with inflammatory biomarkers.

OBJECTIVES:Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET; NCT03152422) aims: (i) to construct new multidimensional urinary proteomic (UP) classifiers that after heart transplantation (HTx) help in detecting graft vasculopathy, monitoring immune system activity and graft performance, and in adjusting immunosuppression; (ii) to sequence UP peptide fragments and to identify key proteins mediating HTx-related complications; (iii) to validate UP classifiers by demonstrating analogy between UP profiles and tissue proteomic signatures (TP) in diseased explanted hearts, to be compared with normal donor hearts; (iv) and to identify new drug targets. This article describes the uPROPHET database construction, follow-up strategies and baseline characteristics of the HTx patients. METHODS:HTx patients enrolled at the University Hospital Gasthuisberg (Leuven) collected mid-morning urine samples. Cardiac biopsies were obtained at HTx. UP and TP methods and the statistical work flow in pursuit of the research objectives are described in detail in the Data supplement. RESULTS:Of 352 participants in the UP study (24.4% women), 38.9%, 40.3%, 5.7% and 15.1% had ischemic, dilated, hypertrophic or other cardiomyopathy. The median interval between HTx and first UP assessment (baseline) was 7.8 years. At baseline, mean values were 56.5 years for age, 25.2 kg/m2 for body mass index, 142.3/84.8 mm Hg and 124.2/79.8 mm Hg for office and 24-h ambulatory systolic/diastolic pressure, and 58.6 mL/min/1.73 m2 for the estimated glomerular filtration rate. Of all patients, 37.2% and 6.5% had a history of mild (grade = 1B) or severe (grade ≥ 2) cellular rejection. Anti-body mediated rejection had occurred in 6.2% patients. The number of follow-up urine samples available for future analyses totals over 950. The TP study currently includes biopsies from 7 healthy donors and 15, 14, and 3 patients with ischemic, dilated, and hypertrophic cardiomyopathy. CONCLUSIONS:uPROPHET constitutes a solid resources for UP and TP research in the field of HTx and has the ambition to lay the foundation for the clinical application of UP in risk stratification in HTx patients.

BackgroundThe metabolic signature associated with subclinical diastolic left ventricular (LV) dysfunction in the population remains ill defined. Methods and ResultsIn 711 randomly recruited Flemish (50.8% women; mean age, 50.8 years), we assessed echocardiographic Doppler indexes of diastolic LV function in relation to 44 circulating metabolites determined by nuclear magnetic resonance spectroscopy. In multivariable‐adjusted regression analysis with Bonferroni correction of significance levels applied, peak a’ decreased (P≤0.048) and e’/a’ increased (P≤0.044) with circulating tyrosine, high‐density lipoprotein apolipoproteins, glucose+glutamine, and an unidentified molecule. Effect sizes expressed per 1‐SD increment in the metabolite ranged from −0.277 to −0.203 cm/s for peak a’ and from +0.047 to +0.054 for e’/a’. In addition, peak a’ decreased (P≤0.031) with glucose+2‐aminobutyrate (−0.261 cm/s) and glucose+2‐phosphoglycerate (−0.209 cm/s). In partial least square discriminant analysis (PLS‐DA), metabolites associated with normal diastolic LV function (n=538) included glucose+glutamine, glucose+2‐aminobutyrate, and glucose+2‐phosphoglycerate, whereas those siding with abnormal function encompassed 4‐aminobutyrate, 4‐hydroxybutyrate, creatinine, and phosphocholine. In receiver operating characteristics plots, adding 3 latent factors identified by PLS‐DA to prohormone brain natriuretic peptide increased (P