Zhen-Yu Zhang

Setting thresholds to varying blood pressure monitoring intervals differentially affects risk estimates associated with white-coat and masked hypertension in the population

Outcome-driven recommendations about time intervals during which ambulatory blood pressure should be measured to diagnose white-coat or masked hypertension are lacking. We cross-classified 8237 untreated participants (mean age, 50.7 years; 48.4% women) enrolled in 12 population studies, using ≥140/≥90, ≥130/≥80, ≥135/≥85, and ≥120/≥70 mm Hg as hypertension thresholds for conventional, 24-hour, daytime, and nighttime blood pressure. White-coat hypertension was hypertension on conventional measurement with ambulatory normotension, the opposite condition being masked hypertension. Intervals used for classification of participants were daytime, nighttime, and 24 hours, first considered separately, and next combined as 24 hours plus daytime or plus nighttime, or plus both. Depending on time intervals chosen, white-coat and masked hypertension frequencies ranged from 6.3% to 12.5% and from 9.7% to 19.6%, respectively. During 91 046 person-years, 729 participants experienced a cardiovascular event. In multivariable analyses with normotension during all intervals of the day as reference, hazard ratios associated with white-coat hypertension progressively weakened considering daytime only (1.38; P=0.033), nighttime only (1.43; P=0.0074), 24 hours only (1.21; P=0.20), 24 hours plus daytime (1.24; P=0.18), 24 hours plus nighttime (1.15; P=0.39), and 24 hours plus daytime and nighttime (1.16; P=0.41). The hazard ratios comparing masked hypertension with normotension were all significant (P<0.0001), ranging from 1.76 to 2.03. In conclusion, identification of truly low-risk white-coat hypertension requires setting thresholds simultaneously to 24 hours, daytime, and nighttime blood pressure. Although any time interval suffices to diagnose masked hypertension, as proposed in current guidelines, full 24-hour recordings remain standard in clinical practice.

Prognostic Value of Left Ventricular Diastolic Dysfunction in a General Population

Background New techniques of Tissue Doppler Imaging (TDI) enable the measurement of myocardial velocities and provide information about left ventricular (LV) diastolic function. Recent studies explored the prognostic role of TDI‐derived indexes. However, these studies considered only total mortality and did not provide information on cardiovascular mortality and morbidity. Therefore, we investigated in continuous and categorical analyses whether Doppler diastolic indexes contained any prognostic information over and beyond traditional cardiovascular risk factors in a general population. 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 TDI in 793 participants (mean age 50.9 years). We calculated multivariable‐adjusted hazard ratios for conventional and TDI Doppler indexes, while accounting for family cluster and cardiovascular risk factors. Median follow‐up was 4.8 years (5th to 95th percentile, 3.0 to 5.4). With adjustments applied for covariables, e velocity was a significant predictor of fatal and nonfatal cardiovascular (n=59; P=0.004) and cardiac events (n=40; P=0.001). TDI e yielded a net reclassification improvement of 54.2% for cardiovascular and 64.0% for cardiac events. Hazard ratios of all cardiovascular (2.21; P=0.042) and cardiac (4.50; P=0.002) events were significantly elevated in participants with increased LV filling pressure compared with subjects with normal diastolic function. Conclusions TDI e velocity is a significant predictor of fatal and nonfatal cardiovascular events in a general population. Furthermore, we observed an increase in all cardiovascular events in the diastolic dysfunction group characterized by elevated LV filling pressure.

The urinary proteome as correlate and predictor of renal function in a population study.

BACKGROUNDnWe investigate whether the urinary proteome refines the diagnosis of renal dysfunction, which affects over 10% of the adult population.nnnMETHODSnWe measured serum creatinine, estimated glomerular filtration rate (eGFR) and 24-h albuminuria in 797 people randomly recruited from a population. We applied capillary electrophoresis coupled with mass spectrometry to measure multi-dimensional urinary proteomic classifiers developed for renal dysfunction (CKD273) or left ventricular dysfunction (HF1 and HF2). Renal function was followed up in 621 participants and the incidence of cardiovascular events in the whole study population.nnnRESULTSnIn multivariable-adjusted cross-sectional analyses, higher biomarker levels analysed separately or combined by principal component analysis into a single factor (SF), correlated (P ≤ 0.010) with worse renal function. Over 4.8 years, higher HF1 and SF predicted (P ≤ 0.014) lowering of eGFR; higher HF2 predicted (P ≤ 0.049) increase in serum creatinine and decrease eGFR. HF1, HF2 and SF predicted progression from CKD Stages 2 or ≤2 to Stage ≥3, with risk estimates for a 1-SD increment in the urinary biomarkers ranging from 38 to 71% (P ≤ 0.039). HF1, HF2 and SF yielded a net reclassification improvement of 31-51% (P ≤ 0.029). Over 6.1 years, 47 cardiovascular events occurred. HF2 and SF, independent of baseline eGFR, 24-h albuminuria and other covariables were significant predictors of cardiovascular complications with risk estimates for 1-SD increases ranging from 32 to 41% (P ≤ 0.047).nnnCONCLUSIONSnThe urinary proteome refines the diagnosis of existing or progressing renal dysfunction and predicts cardiovascular complications.

The Cardiovascular Risk of White-Coat Hypertension

BACKGROUNDnThe role of white-coat hypertension (WCH) and the white-coat-effect (WCE) in development of cardiovascular disease (CVD) risk remains poorly understood.nnnOBJECTIVESnUsing data from the population-based, 11-cohort IDACO (International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes), this study compared daytime ambulatory blood pressure monitoring with conventional blood pressure measurements in 653 untreated subjects with WCH and 653 normotensive control subjects.nnnMETHODSnEuropean Society Hypertension guidelines were used as a 5-stage risk score. Low risk was defined as 0 to 2 risk factors, and high risk was defined asxa0≥3 to 5 risk factors, diabetes, and/or history of prior CVD events. Age- and cohort-matching was done between 653 untreated subjects with WCH and 653 normotensive control subjects.nnnRESULTSnIn a stepwise linear regression model, systolic WCE increased by 3.8 mmxa0Hg (95% confidence interval [CI]: 3.1xa0to 4.6 mmxa0Hg) per 10-year increase in age, and was similar in low- and high-risk subjects with or without prior CVDxa0events. Over a median 10.6-year follow-up, incidence of new CVD events was higher in 159 high-risk subjects with WCH compared with 159 cohort- and age-matched high-risk normotensive subjects (adjusted hazard ratio [HR]: 2.06; 95% CI: 1.10 to 3.84; pxa0= 0.023). The HR was not significant for 494 participants with low-risk WCH and age-matched low-risk normotensive subjects. Subgroup analysis by age showed that an association between WCH and incident CVD events is limited to older (agexa0≥60 years) high-risk WCH subjects; the adjusted HR was 2.19 (95% CI: 1.09 to 4.37; pxa0=xa00.027) in the older high-risk group and 0.88 (95% CI: 0.51 to 1.53; pxa0= 0.66) in the older low-risk group (pxa0forxa0interactionxa0= 0.044).nnnCONCLUSIONSnWCE size is related to aging, not to CVD risk. CVD risk in most persons with WCH is comparable to age-xa0and risk-adjusted normotensive control subjects.

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 &mgr;g/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 &mgr;g/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.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.nn# Novelty and Significance {#article-title-44}

Left ventricular diastolic function in relation to the urinary proteome: a proof-of-concept study in a general population

Background In previous studies, we identified two urinary proteomic classifiers, termed HF1 and HF2, which discriminated subclinical diastolic left ventricular (LV) dysfunction from normal. HF1 and HF2 combine information from 85 and 671 urinary peptides, mainly up- or down-regulated collagen fragments. We sought to validate these classifiers in a population study. Methods In 745 people randomly recruited from a Flemish population (49.8 years; 51.3% women), we measured early and late diastolic peak velocities of mitral inflow (E and A) and mitral annular velocities (e and a) by conventional and tissue Doppler echocardiography, and the urinary proteome by capillary electrophoresis coupled with mass spectrometry. Results In the analyses adjusted for sex, age, body mass index, blood pressure, heart rate, LV mass index and intake of medications, we expressed effect sizes per 1-SD increment in the classifiers. HF1 was associated with 0.204 cm/s lower e peak velocity (95% confidence interval, 0.057–0.351; p = 0.007) and 0.145 higher E/e ratio (0.023–0.268; p = 0.020), while HF2 was associated with a 0.174 higher E/e ratio (0.046–0.302; p = 0.008). According to published definitions, 67 (9.0%) participants had impaired LV relaxation and 96 (12.9%) had elevated LV filling pressure. The odds of impaired relaxation associated with HF1 was 1.38 (1.01–1.88; p = 0.043) and that of increased LV filling pressure associated with HF2 was 1.38 (1.00–1.90; p = 0.052). Conclusions In a general population, the urinary proteome correlated with diastolic LV dysfunction, proving its utility for early diagnosis of this condition.

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 &mgr;g/dL) and in women than in men (1.25 versus 1.80 &mgr;g/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.

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 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 < 0.0001) mL/min/1.73 m2 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.

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.