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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.

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.

Aims: In mice, MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. We investigated whether coronary heart disease (CHD) in humans is associated with variation in these genes. Methods and results: In 2027 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.0% women; mean age 43.6 years), we genotyped SNPs in MEOX2 and TCF15, measured baseline cardiovascular risk factors, and recorded CHD incidence. Over 15.2 years (median), CHD occurred in 106 participants. For SNPs, we contrasted minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. Sex- and age-standardised CHD rates were higher in MEOX2 rs10777, rs12056299, rs7787043, rs4532497, rs1050290 variants, in MEOX2 GTCCGC haplotype carriers (prevalence, 16.5%), but lower in MEOX2 rs6959056 variants (P ≤ 0.04, adjusted for multiple testing). In multivariable-adjusted analyses, the corresponding hazard ratios were ≥1.50 (P ≤ 0.049), 1.77 (P = 0.0054) and 0.62 (P = 0.025), respectively. None of four TCF15 SNPs was associated with coronary risk (P ≥ 0.29). However, CHD risk associated with MEOX2 rs4532497 was confined to TCF15 rs12624577 variant allele carriers (P for interaction = 0.011). The MEOX2 GTCCGC hap-lotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7% vs. 16.2%). Conclusions: In randomly recruited Flemish, genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.