[Clinicopathological Features of Primary Small Cell Neuroendocrine Carcinoma of the Bladder].

Objective To investigate the clinicopathological features,immunohistochemical features,diagnosis,and relationship with sporadic prostate cancer in primary small cell neuroendocrine carcinoma of the bladder. Methods We retrospectively analyzed the clinical characteristics of 12 patients with primary small cell neuroendocrine carcinoma of the bladder diagnosed at Beijing Chao-Yang Hospital affiliated to Capital Medical University from January 2013 to September 2022.The histological features of primary small cell neuroendocrine carcinoma of the bladder were re-evaluated by two pathologists according to the 2022 revision of the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs.Electronic medical records were retrieved,and telephone follow-up was conducted from the time of histopathological diagnosis to the death or the end of the last follow-up until January 31,2023. Results The 12 patients include 7 patients in pT3 stage and 1 patient in pT4 stage.Eight patients were complicated with other types of tumors,such as high-grade urothelial carcinoma of the bladder and squamous cell carcinoma.Five patients had sporadic prostate cancer.Immunohistochemical staining showed that 12 (100.0%),10 (83.3%),and 8 (66.7%) patients were tested positive for CD56,Syn,and CgA,respectively.The Ki67 proliferation index ranged from 80% to 90%.Five patients with urothelial carcinoma were tested positive for CK20,GATA3,and CK7.P504S was positive in all the 5 patients with prostate cancer,while P63 and 34ßE12 were negative.The follow-up of the 12 patients lasted for 3-60 months.Eight of these patients died during follow-up,with the median survival of 15.5 months.Four patients survived. Conclusions Primary small cell neuroendocrine carcinoma of the bladder is a rare urological tumor with high aggressiveness and poor prognosis.In male patients with bladder prostatectomy,all prostate tissue should be sampled.If prostate cancer is detected,the prostate-specific antigen level should be monitored.

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.

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.

Retinal microvascular diameter, a hypertension-related trait, in ECG-gated vs. non-gated images analyzed by IVAN and SIVA.

The diameters of the retinal microvasculature reflect intermediate target organ damage and predict adverse health outcomes. In view of the pulsatility of the cerebral blood flow and refinement of software used for off-line analysis, we assessed the repeatability of retinal microvascular diameters in ECG-gated vs. non-gated images using nonmydriatic retinal photographs (Canon Cr-DGi visualization system) postprocessed by IVAN (Vasculomatic ala Nicola, version 1.1) or SIVA (Singapore I Vessel Assessment, version 3.6). Using these algorithms, we determined the central retinal arteriolar (CRAE) and venular (CRVE) equivalents and their ratio (arteriole-to-venule ratio (AVR)). The estimates of CRAE (mean, 158.5 µm), CRVE (222.5 µm) and AVR (0.71) in 10 volunteers were unaffected (P⩾0.059) by ECG gating. We assessed intragrader repeatability by the Bland and Altman approach in 30 participants with non-gated images and 30 with ECG-gated photographs. Repeatability, which was expressed as the percentage of near maximal variability (4-s.d. range), did not improve with ECG gating. Using SIVA, CRAE and CRVE were systematically larger (P⩽0.031), and the AVR estimates were similar (P⩾0.15) compared with IVAN. The differences (IVAN-SIVA) averaged -5.4 µm for CRAE, -3.9 µm for CRVE and -0.012 for AVR in the non-gated images and -3.3 µm, -6.9 µm and 0.006, respectively, in the ECG-gated photographs. In conclusion, ECG gating does not affect estimates of the retinal microvascular diameters or improve intragrader repeatability. SIVA yields slightly but significantly larger estimates of the retinal arteriolar and venular diameters. Combining historical readings analyzed by IVAN with more recent readings by SIVA is possible only for AVR and is not recommended for either CRAE or CRVE.

Urinary Proteomics Pilot Study for Biomarker Discovery and Diagnosis in Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Biomarker discovery and new insights into the pathophysiology of heart failure with reduced ejection fraction (HFrEF) may emerge from recent advances in high-throughput urinary proteomics. This could lead to improved diagnosis, risk stratification and management of HFrEF. METHODS AND RESULTS: Urine samples were analyzed by on-line capillary electrophoresis coupled to electrospray ionization micro time-of-flight mass spectrometry (CE-MS) to generate individual urinary proteome profiles. In an initial biomarker discovery cohort, analysis of urinary proteome profiles from 33 HFrEF patients and 29 age- and sex-matched individuals without HFrEF resulted in identification of 103 peptides that were significantly differentially excreted in HFrEF. These 103 peptides were used to establish the support vector machine-based HFrEF classifier HFrEF103. In a subsequent validation cohort, HFrEF103 very accurately (area under the curve, AUC = 0.972) discriminated between HFrEF patients (N = 94, sensitivity = 93.6%) and control individuals with and without impaired renal function and hypertension (N = 552, specificity = 92.9%). Interestingly, HFrEF103 showed low sensitivity (12.6%) in individuals with diastolic left ventricular dysfunction (N = 176). The HFrEF-related peptide biomarkers mainly included fragments of fibrillar type I and III collagen but also, e.g., of fibrinogen beta and alpha-1-antitrypsin. CONCLUSION: CE-MS based urine proteome analysis served as a sensitive tool to determine a vast array of HFrEF-related urinary peptide biomarkers which might help improving our understanding and diagnosis of heart failure.

Conventional and Ambulatory Blood Pressure as Predictors of Retinal Arteriolar Narrowing.

At variance with the long established paradigm that retinal arteriolar narrowing trails hypertension, several longitudinal studies, all based on conventional blood pressure (CBP) measurement, proposed that retinal arteriolar narrowing indicates heightened microvascular resistance and precedes hypertension. In 783 randomly recruited Flemish (mean age, 38.2 years; 51.3% women), we investigated to what extent CBP and daytime (10 am to 8 pm) ambulatory blood pressure (ABP) measured at baseline (1989-2008) predicted the central retinal arteriolar equivalent (CRAE) in retinal photographs obtained at follow-up (2008-2015). Systolic/diastolic hypertension thresholds were 140/90 mm Hg for CBP and 135/85 mm Hg for ABP. In multivariable-adjusted models including both baseline CBP and ABP, CRAE after 10.3 years (median) of follow-up was unrelated to CBP (P≥0.14), whereas ABP predicted CRAE narrowing (P≤0.011). Per 1-SD increment in systolic/diastolic blood pressure, the association sizes were -0.95 µm (95% confidence interval, -2.20 to 0.30)/-0.75 µm (-1.93 to 0.42) for CBP and -1.76 µm (-2.95 to -0.58)/-1.48 µm (-2.61 to -0.34) for ABP. Patients with ambulatory hypertension at baseline (17.0%) had smaller CRAE (146.5 versus 152.6 µm; P<0.001) at follow-up. CRAE was not different (P≥0.31) between true normotension (normal CBP and ABP; prevalence, 77.6%) and white-coat hypertension (elevated CBP and normal ABP, 5.4%) and between masked hypertension (normal CBP and elevated ABP, 10.2%) and hypertension (elevated CBP and ABP, 6.8%). In conclusion, the paradigm that retinal arteriolar narrowing precedes hypertension can be explained by the limitations of CBP measurement, including nonidentification of masked and white-coat hypertension.

Vitamin K Dependent Protection of Renal Function in Multi-ethnic Population Studies.

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 m(2)), 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 < 0.0001) mL/min/1.73 m(2) in Flemish, white Africans, black Africans and all participants combined; the odds ratios for moving up one CKD stage were 1.17 (P = 0.033), 1.03 (P = 0.87), 1.29 (P = 0.12) and 1.17 (P = 0.011), respectively. INTERPRETATION: In the general population, eGFR decreases and CKD risk increases with higher dp-ucMGP, a marker of VK deficiency. These findings highlight the possibility that VK supplementation might promote renal health.

Renal glomerular dysfunction in relation to retinal arteriolar narrowing and high pulse pressure in seniors.

Retinal arteriolar narrowing and high pulse pressure (PP) are associated with macrovascular complications and microvascular renal disease. Few studies addressed whether in seniors (⩾60 years) estimated glomerular filtration rate (eGFR) is independently related to central retinal arteriolar equivalent (CRAE) and PP. In 292 randomly recruited seniors (49.3% women; mean, 68.2 years), we measured PP by standard sphygmomanometry, CRAE (IVAN software), eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) and stage of chronic kidney disease (CKD (Kidney Disease Outcomes Quality Initiative guideline)). Statistical methods included linear and logistic regression. PP, CRAE and eGFR averaged 59.2 mm Hg, 146.3 µm and 79.9 ml min(-1) per 1.73 m(2). Decline in eGFR (-2.27 ml min(-1) per 1.73 m(2) per 15 µm; P=0.011) occurred in parallel with CRAE narrowing. CRAE (effect size per 1-s.d. increment, -1.85 µm; P=0.032) and eGFR (-2.68 ml min(-1) per 1.73 m(2); P=0.003) both declined with higher PP. With PP increasing from 63 to 73 mm Hg (threshold for macrovascular complications), CRAE dropped by -4.70 µm (P⩽0.037). A 70-mm Hg PP threshold corresponded with a 150-µm CRAE cutoff. The risk of CKD (stage ⩾2 vs. 1; n=203 vs. 89) rose with CRAE <150 µm (odds ratio, 2.81; P<0.0001), but not with PP ⩾70 mm Hg (1.47; P=0.20). Additionally, CRAE added to PP increased the area under the curve from 0.58 to 0.64 (P=0.047) for identifying stage ⩾2 CKD. In seniors, CRAE and eGFR decline in parallel with higher PP. CRAE <150 µm identifies early decline in eGFR.

Incidence of nephrolithiasis in relation to environmental exposure to lead and cadmium in a population study.

Whether environmental exposure to nephrotoxic agents that potentially interfere with calcium homeostasis, such as lead and cadmium, contribute to the incidence of nephrolithiasis needs further clarification. We investigated the relation between nephrolithiasis incidence and environmental lead and cadmium exposure in a general population. In 1302 participants randomly recruited from a Flemish population (50.9% women; mean age, 47.9 years), we obtained baseline measurements (1985-2005) of blood lead (BPb), blood cadmium (BCd), 24-h urinary cadmium (UCd) and covariables. We monitored the incidence of kidney stones until October 6, 2014. We used Cox regression to calculate multivariable-adjusted hazard ratios for nephrolithiasis. At baseline, geometric mean BPb, BCd and UCd was 0.29µmol/L, 9.0nmol/L, and 8.5nmol per 24h, respectively. Over 11.5 years (median), nephrolithiasis occurred in 40 people. Contrasting the low and top tertiles of the distributions, the sex- and age-standardized rates of nephrolithiasis expressed as events per 1000 person-years were 0.68 vs. 3.36 (p=0.0016) for BPb, 1.80 vs. 3.28 (p=0.11) for BCd, and 1.65 vs. 2.95 (p=0.28) for UCd. In continuous analysis, with adjustments applied for sex, age, serum magnesium, and 24-h urinary volume and calcium, the hazard ratios expressing the risk associated with a doubling of the exposure biomarkers were 1.35 (p=0.015) for BPb, 1.13 (p=0.22) for BCd, and 1.23 (p=0.070) for UCd. In conclusion, our results suggest that environmental lead exposure is a risk factor for nephrolithiasis in the general population.

Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study.

Detecting left ventricular (LV) dysfunction at an early stage is key in addressing the heart failure epidemic. In proteome profiling experiments in mice subjected either to aortic banding or sham, the circulating CXCR3 ligands monokine induced by interferon-γ (MIG) and interferon-γ inducible protein 10 (IP10) were 5 to 40 fold up-regulated at eight weeks. We assessed the diagnostic value of circulating NT-pro BNP and CXCR3 ligands (MIG, IP10, Interferon-inducible T-cell alpha chemo-attractant [I-TAC]) in patients with hypertension (≥140/90 mm Hg) associated with subclinical (n = 19) or symptomatic (n = 16) diastolic LV dysfunction on echocardiography and healthy controls. NT-pro BNP, MIG, IP10, I-TAC all increased (p ≤ 0.014) across the categories of worsening left ventricular dysfunction. In patients with symptomatic disease, MIG, IP10, and I-TAC increased 210% (p = 0.015), 140% (p = 0.007) and 120% (p = 0.035) more than NT-pro BNP. The optimal discrimination limits, obtained by maximizing Youden's index were 246 pmol/L, 65 pg/mL, 93 pg/mL, and 24 pg/mL, respectively. The odds ratios associated with the four biomarkers were significant (p ≤ 0.010), ranging from 4.00 for IP10 to 9.69 for MIG. With adjustment for NT-pro BNP, the CXCR3 ligands retained significance (p ≤ 0.028). Adding optimized thresholds for the CXCR3 ligands to NT-pro BNP enhanced (p ≤ 0.014) the integrated discrimination improvement and the net reclassification improvement. In conclusion, congruent with the concept that inflammation plays a key role in the pathogenesis of LV dysfunction, MIG, IP10 and I-TAC add diagnostic accuracy over and beyond NT-pro BNP.

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

BACKGROUND: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). RESULTS: In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype 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: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

Urinary Proteome and Systolic Blood Pressure as Predictors of 5-Year Cardiovascular and Cardiac Outcomes in a General Population.

In a previous cross-sectional study, we identified a multidimensional urinary classifier (HF1), which was associated with left ventricular dysfunction. We investigated whether HF1 predicts cardiovascular end points over and beyond traditional risk factors. In 791 randomly recruited Flemish (mean age, 51.2 years; 50.6% women), we quantified HF1 by capillary electrophoresis coupled with mass spectrometry. In addition, we measured cardiovascular risk factors. HF1 averaged -0.97 U (range, -3.26 to 2.60). Over 6.1 years (median), 35 participants died and 63, 45, and 22 experienced fatal or nonfatal cardiovascular, cardiac, or coronary events, respectively. The incidence of fatal combined with nonfatal cardiovascular and cardiac end points, standardized for sex and age, increased across thirds of the HF1 distribution (P≤0.014), whereas trends for all-cause mortality and coronary events were nonsignificant (P≥0.10). The multivariable-adjusted hazard ratios (+1-SD) were 1.30 (95% confidence interval, 1.03-1.65; P=0.029) and 1.39 (1.06-1.84; P=0.018) for cardiovascular and cardiac events in relation to HF1. For systolic pressure, the corresponding estimates were 0.97 (0.74-1.28; P=0.85) and 0.93 (0.67-1.29; P=0.66), respectively. The HF1 upper thresholds optimized by maximizing Younden's index were -0.50 and -0.36 U for cardiovascular and cardiac end points, respectively. Prognostic accuracy significantly (P≤0.006) improved by adding HF1 to Cox models already including the other baseline predictors. Sensitivity analyses, from which we excluded 71 participants with previous cardiovascular disease, were confirmatory. In conclusion, over a 6-year period, the urinary proteome, but not systolic pressure, predicted cardiovascular and cardiac disease.

Longitudinal changes in left ventricular diastolic function in a general population.

BACKGROUND: Data on changes in left ventricular diastolic function (LVDF) over time in the general population are sparse. We, therefore, investigated in the population cohort clinical correlates of longitudinal changes in Doppler diastolic indexes analyzed as continuous measures and assessed factors predictive of the changes in LVDF grades over time. METHODS AND RESULTS: We measured 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 in 650 participants (mean age, 50.7 years) at baseline and after 4.7 years (5th to 95th percentile, 3.7-5.4). In stepwise regression, the multivariable-adjusted correlates of the change in the transmitral and tissue Doppler imaging diastolic indexes included sex, age, baseline serum insulin, blood pressure, and heart rate. During follow-up, LVDF grades remained unchanged in 87.2% (95% confidence interval, 84.6%-89.8%), improved in 3.7% (95% confidence interval, 2.25%-5.15%), and worsened in 9.1% (95% confidence interval, 6.9%-11.3%). Baseline age was a strong predictor of worsening of LVDF from normal/mild grade to more advanced grade (odds ratio, 3.22; P<0.0001). A doubling of baseline insulin was associated with a 184% increase in the odds of worsening of LVDF (P<0.0001). Moreover, baseline diastolic blood pressure and the change in systolic blood pressure over time predicted worsening of LVDF (P≤0.014). CONCLUSIONS: The key findings of this study are that LVDF tended to worsen over time and was associated with advanced age, higher baseline insulin level, and hemodynamic parameters, such as heart rate and blood pressure.

Characteristics and determinants of the sublingual microcirculation in populations of different ethnicity.

No previous population study assessed sublingual capillary density (CD) or perfused boundary region (PBR). Lower PBR indicates greater glycocalyx width. In 252 Han and 220 She Chinese and 254 Flemish people (mean age, 51.1 years; 54.7% women), representing random population samples, we measured total and perfused CD and PBR in the sublingual capillary bed, using oblique profiled epi-illumination, and cardiovascular risk factors. In multivariable analyses, we modeled ethnicity as random effect. Significance level was α ≤ 0.05. Compared with Chinese, Flemish had lower total (577 versus 546 n°/mm(2)) and perfused (338 versus 320 n°/mm(2)) CD, but similar perfused-to-total CD ratio (mean, 0.59). Perfused-to-total CD ratio increased with age (effect size per 1-SD increase, +0.015 per year), body mass index (+0.008 per kg/m(2)), total cholesterol (+0.012 per mmol/L), and Framingham risk score (+0.018 per point) with no ethnic differences in these associations. For age and Framingham risk score, associations with perfused-to-total CD ratio were driven by positive relationships with perfused CD, whereas associations with total CD were nonsignificant. Chinese when compared with Flemish had higher hematocrit (43.0 versus 41.1%), PBR (2010 versus 1876 nm), and pulse rate (72.6 versus 63.3 bpm). PBR standardized for hematocrit, perfused CD, and pulse rate decreased with body mass index (-26.7 nm/kg/m2), mean arterial pressure (-30.6 nm/mm Hg), and diastolic pressure (-28.5 nm/mm Hg) with no ethnic differences in these associations. In conclusion, a higher cardiovascular risk profile is associated with functional recruitment of capillaries with preserved glycocalyx that protects the endothelial lining.

Study for Promotion of Health in Recycling Lead - Rationale and design.

BACKGROUND: The level at which low-level lead exposure produces subclinical adverse health effects in adults remains to be established. METHODS: The Study for Promotion of Health in Recycling Lead (SPHERL) will enroll 500 newly hired workers, whose blood lead during 2 years of follow-up is expected to increase from levels less than 2 µg/dl, as currently observed in the US population, to 20-30 µg/dl. The main outcome variables to be studied are (i) blood pressure (BP) analyzed as a continuous or categorical variable, both cross-sectionally and longitudinally, and using conventional and ambulatory BP measurement; (ii) indexes of glomerular and tubular renal function, (iii) heart rate variability analyzed in the frequency domain as measure of autonomous sympathetic modulation, (iv) peripheral nerve conductivity velocity, (v) neurocognitive performance, and (vi) quality of life. Expected outcomes. Assuming a 10-fold increase in blood lead, SPHERL will have sufficient statistical power to detect over 2 years a steepening of the age-related rise in systolic BP from 1 to 5 mmHg and a doubling of the age-related decline in the estimated glomerular filtration rate from 3.5 to 7.0 ml/min/1.73 m(2). The longitudinal design of our study complies with the temporality principle of the Bradford-Hill criteria for assessing possible causality between outcomes and exposure. SPHERL will attempt to resolve the apparent contradiction between general population studies showing associations between adverse health effects and low lead exposure with blood lead levels below 5 µg/dl and studies conducted in occupational cohorts indicating that adverse effects of lead exposure occur at much higher blood lead levels.

Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population.

Matrix Gla-protein is a vitamin K-dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP). The risk associated with dp-ucMGP in the population is unknown. In a Flemish population study, we measured circulating dp-ucMGP at baseline (1996-2011), genotyped MGP, recorded adverse health outcomes until December 31, 2012, and assessed the multivariable-adjusted associations of adverse health outcomes with dp-ucMGP. We applied a Mendelian randomization analysis using MGP genotypes as instrumental variables. Among 2318 participants, baseline dp-ucMGP averaged 3.61 µg/L. Over 14.1 years (median), 197 deaths occurred, 58 from cancer and 70 from cardiovascular disease; 85 participants experienced a coronary event. The risk of death and non-cancer mortality curvilinearly increased (P≤0.008) by 15.0% (95% confidence interval, 6.9-25.3) and by 21.5% (11.1-32.9) for a doubling of the nadir (1.43 and 0.97 µg/L, respectively). With higher dp-ucMGP, cardiovascular mortality log-linearly increased (hazard ratio for dp-ucMGP doubling, 1.14 [1.01-1.28]; P=0.027), but coronary events log-linearly decreased (0.93 [0.88-0.99]; P=0.021). dp-ucMGP levels were associated (P≤0.001) with MGP variants rs2098435, rs4236, and rs2430692. For non-cancer mortality and coronary events (P≤0.022), but not for total and cardiovascular mortality (P≥0.13), the Mendelian randomization analysis suggested causality. Higher dp-ucMGP predicts total, non-cancer and cardiovascular mortality, but lower coronary risk. For non-cancer mortality and coronary events, these associations are likely causal.

Blood pressure in relation to environmental lead exposure in the national health and nutrition examination survey 2003 to 2010.

In view of the declining environmental lead exposure in the United States, we analyzed the National Health and Nutrition Examination Survey (2003-2010) for association of blood pressure and hypertension with blood lead. The 12 725 participants included 21.1% blacks, 20.5% Hispanics, 58.4% whites, and 48.7% women. Blacks compared with non-Blacks had higher systolic and diastolic pressures (126.5 versus 123.9 and 71.9 versus 69.6 mm Hg) and higher hypertension prevalence (44.7 versus 36.8%). Blood lead was lower in whites than in non-whites (1.46 versus 1.57 µg/dL) and in women than in men (1.25 versus 1.80 µg/dL). In multivariable analyses of all participants, blood lead doubling was associated with higher (P≤0.0007) systolic and diastolic pressure (+0.76 mm Hg; 95% confidence interval, 0.38-1.13 and +0.43 mm Hg; 0.18-0.68), but not with the odds of hypertension (0.95; 0.90-1.01; P=0.11). Associations with blood lead were nonsignificant (P≥0.09) for systolic pressure in women and for diastolic pressure in non-whites. Among men, systolic pressure increased with blood lead (P≤0.060) with effect sizes associated with blood lead doubling ranging from +0.65 mm Hg in whites to +1.61 mm Hg in blacks. For systolic pressure, interactions of ethnicity and sex with blood lead were all significant (P≤0.019). In conclusion, small and inconsistent effect sizes in the associations of blood pressure with blood lead likely exclude current environmental lead exposure as a major hypertension cause in the United States.

Does blood pressure variability contribute to risk stratification? Methodological issues and a review of outcome studies based on home blood pressure.

This review addresses methodological issues in the assessment of blood pressure variability and the predictive value of blood pressure variability derived from blood pressure readings obtained in the relaxed home environment. Preference should be given to indexes of blood pressure variability that are independent of the mean because we should evaluate the impact of blood pressure variability by eliminating the effect of blood pressure levels. Beat-to-beat blood pressure recordings outperform home blood pressure measurement in the assessment of blood pressure variability in longitudinal Belgian and Japanese population studies, whereas blood pressure variability did not incrementally predict outcome beyond blood pressure level and other cardiovascular risk factors. In conclusion, clinicians should focus on blood pressure level, given that it is the predominant risk factor and is manageable by lifestyle modifications and adequate antihypertensive drug treatment. Blood pressure variability remains a research tool that requires further prospective studies with hard end points to define its potential application, as it may be potentially useful in daily clinical practice.

PEAR1 is not a human hypertension-susceptibility gene.

OBJECTIVE: Platelet endothelial aggregation receptor 1 (PEAR1) is a membrane protein involved in platelet contact-induced activation and sustained platelet aggregation. Experimental studies identified PEAR1, as a candidate gene that may be linked to the blood-pressure driven kidney injury in salt-sensitive Dahl rats. AIM: In a family-based European population study (mean age 39.7 years; 52.2% women), we searched for association of changes in blood pressure or incidence of hypertension with genetic variation in PEAR1. METHODS: Among 1973 randomly recruited people, genotyped for PEAR1, we measured blood pressure at baseline and follow-up. RESULTS: Median follow-up was 10.0 years. While accounting for family clusters and blood pressure at baseline and with adjustments applied for sex, age, body mass index, smoking and drinking, total cholesterol, and antihypertensive drug treatment, all associations of systolic and diastolic blood pressure changes with nine single nucleotide polymorphisms (SNPs) in PEAR1 were all non-significant (p ≥ 0.059). With similar adjustments, the incidence of hypertension (397 cases among 1532 participants were normotensive at baseline [25.9%]) was not related to the SNPs in PEAR1 (hazard ratios ≤ 1.09; p ≥ 0.09). CONCLUSION: Our study suggests that PEAR1 is not a hypertension susceptibility gene in humans.

Doppler indexes of left ventricular systolic and diastolic flow and central pulse pressure in relation to renal resistive index.

BACKGROUND: The cardio-renal interaction occurs via hemodynamic and humoral factors. Noninvasive assessment of renal hemodynamics is currently possible by assessment of renal resistive index (RRI) derived from intrarenal Doppler arterial waveforms as ((peak systolic velocity - end-diastolic velocity)/peak systolic velocity). Limited information is available regarding the relationship between RRI and cardiac hemodynamics. We investigated these associations in randomly recruited subjects from a general population. METHODS: In 171 participants (48.5% women; mean age, 52.2 years), using pulsed wave Doppler, we measured RRI (mean, 0.60) and left ventricular outflow tract (LVOT) and transmitral (E and A) blood flow peak velocities and its velocity time integrals (VTI). Using carotid applanation tonometry, we measured central pulse pressure and arterial stiffness indexes such as augmentation pressure and carotid-femoral pulse wave velocity. RESULTS: In stepwise regression analysis, RRI independently and significantly increased with female sex, age, body weight, brachial pulse pressure, and use of ß-blockers, whereas it decreased with body height and mean arterial pressure. In multivariable-adjusted models with central pulse pressure and arterial stiffness indexes as the explanatory variables, we observed a significant and positive correlation of RRI only with central pulse pressure (P < 0.0001). Among the Doppler indexes of left ventricular blood flow, RRI was significantly and positively associated with LVOT and E peak velocities (P ≤ 0.012) and VTIs (P ≤ 0.010). CONCLUSIONS: We demonstrated that in unselected subjects RRI was significantly associated with central pulse pressure and left ventricular systolic and diastolic Doppler blood flow indexes. Our findings imply that in addition to the anthropometric characteristics, cardiac hemodynamic factors influence the intrarenal arterial Doppler waveform patterns.