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Background: The metabolic signature associated with subclinical diastolic left ventricular (LV) dysfunction in the general population is unknown. Objectives: This population study aimed at identifying a specific profile of circulating me-tabolites associated with asymptomatic diastolic LV dysfunction. Methods: In 711 randomly recruited Flemish (50.8% women; mean age, 50.8 years), we assessed echocardiographic indexes of diastolic LV function in relation to 44 circulating metabolites determined by nuclear magnetic resonance spectroscopy. Statistical methods included multivariable-adjusted regression analyses and partial least square discriminant analysis (PLS DA). Results: In multivariable analyses with Bonferroni correction, a′ was inversely and e′/a′ was positively correlated (p ≤ 0.048) with circulating tyrosine, HDL apolipoproteins, glucose + glutamine, and an unidentified molecule, while a′ was also inversely associated with glucose + 2 aminobutyrate and glucose + 2 phosphoglycerate (p ≤ 0.031). PLS-DA identified three latent factors accounting for 54.4% of the variance. The metabolites associated with better diastolic LV function included, amongst others, glucose + glutamine (variable importance in projection score, 1.201), glucose + 2 aminobutyrate (1.185), and glucose + 2 phosphoglycerate (1.172). The three latent factors, compared with N-terminal prohormone brain natriuretic peptide, increased (p < 0.0001) the area under the curve from 0.64 to 0.73. Conclusions: In the general population, diastolic LV function is associated with a profile of circulating metabolites indicative of energy substrate utilization and protection against oxidative stress. These metabolic markers might lead to the discovery of new targets for prevention and treatment of diastolic LV dysfunction at a subclinical and still reversible stage.

Abstract Background Epicardial adipose tissue (EAT) has been suggested to exert deleterious effects on myocardium and cardiovascular disease (CVD) consequence. We evaluated the associations of EAT thickness with adverse outcomes and its potential mediators in the community. Methods Participants without heart failure (HF) who had undergone cardiac magnetic resonance (CMR) to measure EAT thickness over the right ventricular free wall from the Framingham Heart Study were included. The correlation of EAT thickness with 85 circulating biomarkers and cardiometric parameters was assessed in linear regression models. The occurrence of HF, atrial fibrillation, coronary heart disease (CHD), and other adverse events was tracked since CMR was implemented. Their associations with EAT thickness and the mediators were evaluated using Cox regression and causal mediation analysis. Results Of 1554 participants, 53.0% were females. Mean age, body mass index, and EAT thickness were 63.3 years, 28.1 kg/m2, and 9.8 mm, respectively. After fully adjusting, EAT thickness positively correlated with CRP, LEP, GDF15, MMP8, MMP9, ORM1, ANGPTL3, and SERPINE1 and negatively correlated with N-terminal pro-B-type natriuretic peptide (NT-proBNP), IGFBP1, IGFBP2, AGER, CNTN1, and MCAM. Increasing EAT thickness was associated with smaller left ventricular end-diastolic dimension, thicker left ventricular wall thickness, and worse global longitudinal strain (GLS). During a median follow-up of 12.7 years, 101 incident HF occurred. Per 1-standard deviation increment of EAT thickness was associated with a higher risk of HF (adjusted hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.19–1.72, P

Abstract It remains unknown whether systolic (SBP) and diastolic (DBP) pressure on admission are associated with short‐ and long‐term mortality in Chinese patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction. In 2706 HF patients (39.1% women; mean age, 68.8 years), we assessed the risk of 30‐day, 1‐year, and long‐term (> 1 year) mortality with 1‐SD increment in SBP and DBP, using multivariable logistic and Cox regression, respectively. During a median follow‐up of 4.1 years, 1341 patients died. The 30‐day, 1‐year, and long‐term mortality were 3.5%, 16.7%, and 39.4%, respectively. In multivariable‐adjusted analyses additionally accounted for DBP or SBP, a higher SBP conferred a higher risk of long‐term mortality (hazard ratio, 1.11; 95% CI, 1.02‐1.22; p = .017) and a lower DBP was associated with a higher risk of all types of mortality (p ≤ .011) in all HF patients. Independent of potential confounders including DBP or SBP, in patients with HFpEF, higher SBP and lower DBP levels predicted a higher risk of long‐term mortality with hazard ratios amounting to 1.16 (95% CI, 1.04–1.29; p = .007) and .89 (95% CI, .80–.99; p = .028), respectively. In patients with HFmrEF and HFrEF, irrespective of adjustments of potential confounders, DBP was associated with 1‐year mortality with odds ratios ranging from .49 to .62 (p ≤ .006). In conclusion, lower DBP and higher SBP levels on admission were associated with a higher risk of different types of all‐cause mortality in Chinese patients with different HF subtypes. Our observations highlight that admission BP may help to improve risk stratification.

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

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.

Background: Heart failure with preserved ejection fraction (HFpEF) affects women more frequently than men. However, data on sex-specific associations of adverse health outcomes and left ventricular structure and function and with microalbuminuria in patients with HFpEF are scarce.Methods: In 1,334 participants enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial, we estimated the sex-specific multivariable-adjusted risk and LV traits with urine microalbumin/creatine ratio (ACR), using Cox or linear regression.Results: In total, 604 (45.3%) were women. In multivariable-adjusted analyses, a doubling of ACR in both men and women was associated with higher posterior (+0.014 cm, p = 0.012/+0.012 cm, p = 0.033) wall thickness and left ventricular mass index (+2.55 mg/m2, p = 0.004/+2.45 mg/m2, p = 0.009), whereas was also associated with higher septal (+0.018 cm, p = 0.002) and left atrial volume index (+1.44 mL/m2, p = 0.001) in men. ACR was a key predictor of all-cause (HR, 1.11; p = 0.006) and cardiovascular (HR, 1.17; p = 0.002) death in women, whereas in men ACR was associated with HF hospitalization (HR, 1.23; p < 0.001), any hospitalization (HR, 1.06; p = 0.006), and myocardial infarction (HR, 1.19; p = 0.017). The interactions of sex with ACR were significant for hospitalization for heart failure and any hospitalization (p ≤ 0.034).Conclusions: Outcomes and cardiac structure and function in patients with HFpEF appear to be influenced by ACR that vary according to sex. In men, ACR was significant associated with LV diastolic function, hospitalization, and myocardial infarction, whereas in women was associated with mortality.

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

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

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

Background Increased renal resistive index (RRI) has been associated with target organ damage as well as renal and cardiovascular outcomes. Matrix Gla (γ‐carboxyglutamate) protein (MGP) is a strong inhibitor of soft tissue calcification. Its inactive form (dephospho‐uncarboxylated MGP [dp‐ucMGP]) has been associated with vascular stiffness, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp‐ucMGP were associated with increased RRI. Methods and Results We recruited participants via a multicenter family‐based cross‐sectional study in Switzerland. Levels of dp‐ucMGP were measured in plasma by sandwich ELISA. RRI was measured by Doppler ultrasound in 3 segmental arteries in both kidneys. We used mixed regression models to assess the relationship between dp‐ucMGP and RRI. We adjusted for common determinants of RRI as well as renal function and cardiovascular risk factors. We included 1006 participants in our analyses: 526 women and 480 men. Mean values were 0.44±0.20 nmol/L for dp‐ucMGP and 64±5% for RRI. After multivariable adjustment, dp‐ucMGP was positively associated with RRI (P=0.001). In subgroup analysis by age tertiles, this association was not significant in the youngest age group (55 years; P=0.016 and P

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: A recently developed urinary peptidomics biological aging clock can be used to study accelerated human aging. From 1990 to 2019, exposure to airborne particulate matter (PM) became the leading environmental risk factor worldwide. OBJECTIVES: This study investigated whether air pollution exposure is associated with accelerated urinary peptidomic aging, independent of calendar age, and whether this association is modified by other risk factors. METHODS: In a Flemish population, the urinary peptidomic profile (UPP) age (UPP-age) was derived from the urinary peptidomic profile measured by capillary electrophoresis coupled with mass spectrometry. UPP-age-R was calculated as the residual of the regression of UPP-age on chronological age, which reflects accelerated aging predicted by UPP-age, independent of chronological age. A high-resolution spatial-temporal interpolation method was used to assess each individual’s exposure to PM10, PM2.5, black carbon (BC), and nitrogen dioxide (NO2). Associations of UPP-age-R with these pollutants were investigated by mixed models, accounting for clustering by residential address and confounders. Effect modifiers of the associations between UPP-age-R and air pollutants that included 18 factors reflecting vascular function, renal function, insulin resistance, lipid metabolism, or inflammation were evaluated. Direct and indirect (via UPP-age-R) effects of air pollution on mortality were evaluated by multivariable adjusted Cox models. RESULTS: Among 660 participants (50.2% women; mean age: 50.7 y), higher exposure to PM10, PM2.5, BC, and NO2 was associated with a higher UPP-age-R. Studying effect modifiers showed that higher plasma levels of desphospho-uncarboxylated matrix Gla protein (dpucMGP), signifying poorer vitamin K status, steepened the slopes of UPP-age-R on the air pollutants. In further analyses among participants with dpucMGP =4.26 μg/L (median), an interquartile range (IQR) higher level in PM10, PM2.5, BC, and NO2 was associated with a higher UPP-age- R of 2.03 [95% confidence interval (CI): 0.60, 3.46], 2.22 (95% CI: 0.71, 3.74), 2.00 (95% CI: 0.56, 3.43), and 2.09 (95% CI: 0.77, 3.41) y, respectively. UPP-age-R was an indirect mediator of the associations of mortality with the air pollutants [multivariable-adjusted hazard ratios from 1.094 (95% CI: 1.000, 1.196) to 1.110 (95% CI: 1.007, 1.224)] in participants with a high dpucMGP, whereas no direct associations were observed. DISCUSSION: Ambient air pollution was associated with accelerated urinary peptidomics aging, and high vitamin K status showed a potential protective effect in this population. Current guidelines are insufficient to decrease the adverse health effects of airborne pollutants, including healthy aging trajectories. [ABSTRACT FROM AUTHOR]

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

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: Aortic pulse wave velocity (PWV) predicts cardiovascular events (CVEs) and total mortality (TM), but previous studies proposing actionable PWV thresholds have limited generalizability. This individual-participant meta-analysis is aimed at defining, testing calibration, and validating an outcome-driven threshold for PWV, using 2 populations studies, respectively, for derivation IDCARS (International Database of Central Arterial Properties for Risk Stratification) and replication MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease Health Survey - Copenhagen). METHODS: A risk-carrying PWV threshold for CVE and TM was defined by multivariable Cox regression, using stepwise increasing PWV thresholds and by determining the threshold yielding a 5-year risk equivalent with systolic blood pressure of 140 mm Hg. The predictive performance of the PWV threshold was assessed by computing the integrated discrimination improvement and the net reclassification improvement. RESULTS: In well-calibrated models in IDCARS, the risk-carrying PWV thresholds converged at 9 m/s (10 m/s considering the anatomic pulse wave travel distance). With full adjustments applied, the threshold predicted CVE (hazard ratio [CI]: 1.68 [1.15-2.45]) and TM (1.61 [1.01-2.55]) in IDCARS and in MONICA (1.40 [1.09-1.79] and 1.55 [1.23-1.95]). In IDCARS and MONICA, the predictive accuracy of the threshold for both end points was ≈-0.75. Integrated discrimination improvement was significant for TM in IDCARS and for both TM and CVE in MONICA, whereas net reclassification improvement was not for any outcome. CONCLUSIONS: PWV integrates multiple risk factors into a single variable and might replace a large panel of traditional risk factors. Exceeding the outcome-driven PWV threshold should motivate clinicians to stringent management of risk factors, in particular hypertension, which over a person's lifetime causes stiffening of the elastic arteries as waypoint to CVE and death. [ABSTRACT FROM AUTHOR]

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 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.

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.

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

Introduction: Matrix Gla Protein (MGP) is highly expressed in cardiomyocytes and is upregulated after acute and chronic pressure overload and in myocardial hypertrophy in mice and humans. However, no study addressed the relation between cardiac function and MGP in humans. Methods and results: In 767 participants randomly recruited from the Flemish population (51.5% women, mean age 50.6 years), we measured circulating levels of nonphosphorylated and uncarboxylated MGP (dp-ucMGP) and recorded early and late diastolic peak velocities of mitral inflow (E and A) by conventional Doppler and the mitral annular velocities (e′ and a′) by tissue Doppler imaging. Using principal component analysis, we summarized 7 Doppler indexes - namely, E, A, e′ and a′ velocities, and their ratios (E/A, e′/a′, and E/e′) - into a single diastolic score. According to published definitions, 73 (9.5%) participants had impaired relaxation and 114 (14.9%) had elevated LV filling pressure. In the continuous analysis, a doubling of dp-ucMGP is associated with a 6.9% increase in the diastolic score (95% CI 2.7–10.6, P < 0.001). No association was seen between systolic function and dp_ucMGP. Multivariable-adjusted odds ratio for a doubling of dp-ucMGP was 0.70 (95% CI 0.50–0.98; P = 0.038) for having elevated LV filling pressure. No significant association was seen between impaired relaxation and dp-ucMGP. Conclusion: Higher circulating levels of dp-ucMGP are associated with better LV diastolic function. Pending confirmation in other cohorts and further experimental studies are required to translate our epidemiological findings into underlying molecular mechanisms.