Yu-Mei Gu

Within-Subject Blood Pressure Level—Not Variability—Predicts Fatal and Nonfatal Outcomes in a General Population

To assess the prognostic significance of blood pressure (BP) variability, we followed health outcomes in a family-based random population sample representative of the general population (n=2944; mean age: 44.9 years; 50.7% women). At baseline, BP was measured 5 times consecutively at each of 2 home visits 2 to 4 weeks apart. We assessed within-subject overall (10 readings), within- and between-visit systolic BP variability from variability independent of the mean, the difference between maximum and minimum BP, and average real variability. Over a median follow-up of 12 years, 401 deaths occurred and 311 participants experienced a fatal or nonfatal cardiovascular event. Overall systolic BP variability averaged (SD) 5.45 (2.82) units, 15.87 (8.36) mmHg, and 4.08 (2.05) mmHg for variability independent of the mean, difference between maximum and minimum BP, and average real variability, respectively. Female sex, older age, higher-mean systolic BP, lower body mass index, a history of peripheral arterial disease, and use of &bgr;-blockers were the main correlates of systolic BP variability. In multivariable-adjusted analyses, overall and within- and between-visit BP variability did not predict total or cardiovascular mortality or the composite of any fatal plus nonfatal cardiovascular end point. For instance, the hazard ratios for all cardiovascular events combined in relation to overall variability independent of the mean, difference between maximum and minimum BP, and average real variability were 1.05 (0.96–1.15), 1.06 (0.96–1.16), and 1.08 (0.98–1.19), respectively. By contrast, mean systolic BP was a significant predictor of all end points under study, independent of BP variability. In conclusion, in an unbiased population sample, BP variability did not contribute to risk stratification over and beyond mean systolic BP.

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.

Age-specific differences between conventional and ambulatory daytime blood pressure values.

Mean daytime ambulatory blood pressure (BP) values are considered to be lower than conventional BP values, but data on this relation among younger individuals <50 years are scarce. Conventional and 24-hour ambulatory BP were measured in 9550 individuals not taking antihypertensive treatment from 13 population-based cohorts. We compared individual differences between daytime ambulatory and conventional BP according to 10-year age categories. Age-specific prevalences of white coat and masked hypertension were calculated. Among individuals aged 18 to 30, 30 to 40, and 40 to 50 years, mean daytime BP was significantly higher than the corresponding conventional BP (6.0, 5.2, and 4.7 mm Hg for systolic; 2.5, 2.7, and 1.7 mm Hg for diastolic BP; all P<0.0001). In individuals aged 60 to 70 and ≥70 years, conventional BP was significantly higher than daytime ambulatory BP (5.0 and 13.0 mm Hg for systolic; 2.0 and 4.2 mm Hg for diastolic BP; all P<0.0001).The prevalence of white coat hypertension exponentially increased from 2.2% to 19.5% from those aged 18 to 30 years to those aged ≥70 years, with little variation between men and women (8.0% versus 6.1%; P=0.0003). Masked hypertension was more prevalent among men (21.1% versus 11.4%; P<0.0001). The age-specific prevalences of masked hypertension were 18.2%, 27.3%, 27.8%, 20.1%, 13.6%, and 10.2% among men and 9.0%, 9.9%, 12.2%, 11.9%, 14.7%, and 12.1% among women. In conclusion, this large collaborative analysis showed that the relation between daytime ambulatory and conventional BP strongly varies by age. These findings may have implications for diagnosing hypertension and its subtypes in clinical practice.

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

BACKGROUND We investigate whether the urinary proteome refines the diagnosis of renal dysfunction, which affects over 10% of the adult population. METHODS We 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. RESULTS In 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). CONCLUSIONS The urinary proteome refines the diagnosis of existing or progressing renal dysfunction and predicts cardiovascular complications.

Correlates of Peripheral Blood Mitochondrial DNA Content in a General Population

Accumulation of mitochondrial DNA (mtDNA) mutations leads to alterations of mitochondrial biogenesis and function that might produce a decrease in mtDNA content within cells. This implies that mtDNA content might be a potential biomarker associated with oxidative stress and inflammation. However, data on correlates of mtDNA content in a general population are sparse. Our goal in the present study was to describe in a randomly recruited population sample the distribution and determinants of peripheral blood mtDNA content. From 2009 to 2013, we examined 689 persons (50.4% women; mean age = 54.4 years) randomly selected from a Flemish population (Flemish Study on Environment, Genes, and Health Outcomes). Relative mtDNA copy number as compared with nuclear DNA was measured by quantitative real-time polymerase chain reaction in peripheral blood. There was a curvilinear relationship between relative mtDNA copy number and age. mtDNA content slightly increased until the fifth decade of life and declined in older subjects (Page2 = 0.0002). mtDNA content was significantly higher in women (P = 0.007) and increased with platelet count (P < 0.0001), whereas it was inversely associated with white blood cell count (P < 0.0001). We also observed lower mtDNA content in women using estroprogestogens (P = 0.044). This study demonstrated in a general population that peripheral blood mtDNA content is significantly associated with sex and age. Blood mtDNA content is also influenced by platelet and white blood cell counts and estroprogestogen intake. Further studies are required to clarify the impact of chronic inflammation and hormone therapy on mitochondrial function.

Ambulatory Hypertension Subtypes and 24-Hour Systolic and Diastolic Blood Pressure as Distinct Outcome Predictors in 8341 Untreated People Recruited From 12 Populations

Background— Data on risk associated with 24-hour ambulatory diastolic (DBP24) versus systolic (SBP24) blood pressure are scarce. Methods and Results— We recorded 24-hour blood pressure and health outcomes in 8341 untreated people (mean age, 50.8 years; 46.6% women) randomly recruited from 12 populations. We computed hazard ratios (HRs) using multivariable-adjusted Cox regression. Over 11.2 years (median), 927 (11.1%) participants died, 356 (4.3%) from cardiovascular causes, and 744 (8.9%) experienced a fatal or nonfatal cardiovascular event. Isolated diastolic hypertension (DBP24≥80 mm Hg) did not increase the risk of total mortality, cardiovascular mortality, or stroke (HRs⩽1.54; P≥0.18), but was associated with a higher risk of fatal combined with nonfatal cardiovascular, cardiac, or coronary events (HRs≥1.75; P⩽0.0054). Isolated systolic hypertension (SBP24≥130 mm Hg) and mixed diastolic plus systolic hypertension were associated with increased risks of all aforementioned end points (P⩽0.0012). Below age 50, DBP24 was the main driver of risk, reaching significance for total (HR for 1-SD increase, 2.05; P=0.0039) and cardiovascular mortality (HR, 4.07; P=0.0032) and for all cardiovascular end points combined (HR, 1.74; P=0.039) with a nonsignificant contribution of SBP24 (HR⩽0.92; P≥0.068); above age 50, SBP24 predicted all end points (HR≥1.19; P⩽0.0002) with a nonsignificant contribution of DBP24 (0.96⩽HR⩽1.14; P≥0.10). The interactions of age with SBP24 and DBP24 were significant for all cardiovascular and coronary events (P⩽0.043). Conclusions— The risks conferred by DBP24 and SBP24 are age dependent. DBP24 and isolated diastolic hypertension drive coronary complications below age 50, whereas above age 50 SBP24 and isolated systolic and mixed hypertension are the predominant risk factors.

Risk stratification by ambulatory blood pressure monitoring across JNC classes of conventional blood pressure.

BACKGROUND Guidelines propose classification of conventional blood pressure (CBP) into normotension (<120/<80 mm Hg), prehypertension (120-139/80-89 mm Hg), and hypertension (≥140/≥90 mm Hg). METHODS To assess the potential differential contribution of ambulatory blood pressure (ABP) in predicting risk across CBP strata, we analyzed outcomes in 7,826 untreated people recruited from 11 populations. RESULTS During an 11.3-year period, 809 participants died (276 cardiovascular deaths) and 639, 383, and 225 experienced a cardiovascular, cardiac, or cerebrovascular event. Compared with normotension (n = 2,639), prehypertension (n = 3,076) carried higher risk (P ≤ 0.015) of cardiovascular (+41%) and cerebrovascular (+92%) endpoints; compared with hypertension (n = 2,111) prehypertension entailed lower risk (P ≤ 0.005) of total mortality (-14%) and cardiovascular mortality (-29%) and of cardiovascular (-34%), cardiac (-33%), or cerebrovascular (-47%) events. Multivariable-adjusted hazard ratios (HRs) for stroke associated with 24-hour and daytime diastolic ABP (+5 mm Hg) were higher (P ≤ 0.045) in normotension than in prehypertension and hypertension (1.98 vs.1.19 vs.1.28 and 1.73 vs.1.09 vs. 1.24, respectively) with similar trends (0.03 ≤ P ≤ 0.11) for systolic ABP (+10 mm Hg). However, HRs for fatal endpoints and cardiac events associated with ABP did not differ significantly (P ≥ 0.13) across CBP categories. Of normotensive and prehypertensive participants, 7.5% and 29.3% had masked hypertension (daytime ABP ≥135/≥85 mm Hg). Compared with true normotension (P ≤ 0.01), HRs for stroke were 3.02 in normotension and 2.97 in prehypertension associated with masked hypertension with no difference between the latter two conditions (P = 0.93). CONCLUSION ABP refines risk stratification in normotension and prehypertension mainly by enabling the diagnosis of masked hypertension.

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.

Outcome-Driven Thresholds for Ambulatory Pulse Pressure in 9938 Participants Recruited From 11 Populations

Evidence-based thresholds for risk stratification based on pulse pressure (PP) are currently unavailable. To derive outcome-driven thresholds for the 24-hour ambulatory PP, we analyzed 9938 participants randomly recruited from 11 populations (47.3% women). After age stratification (<60 versus ≥60 years) and using average risk as reference, we computed multivariable-adjusted hazard ratios (HRs) to assess risk by tenths of the PP distribution or risk associated with stepwise increasing (+1 mm Hg) PP levels. All adjustments included mean arterial pressure. Among 6028 younger participants (68 853 person-years), the risk of cardiovascular (HR, 1.58; P=0.011) or cardiac (HR, 1.52; P=0.056) events increased only in the top PP tenth (mean, 60.6 mm Hg). Using stepwise increasing PP levels, the lower boundary of the 95% confidence interval of the successive thresholds did not cross unity. Among 3910 older participants (39 923 person-years), risk increased (P⩽0.028) in the top PP tenth (mean, 76.1 mm Hg). HRs were 1.30 and 1.62 for total and cardiovascular mortality, and 1.52, 1.69, and 1.40 for all cardiovascular, cardiac, and cerebrovascular events. The lower boundary of the 95% confidence interval of the HRs associated with stepwise increasing PP levels crossed unity at 64 mm Hg. While accounting for all covariables, the top tenth of PP contributed less than 0.3% (generalized R2 statistic) to the overall risk among the elderly. Thus, in randomly recruited people, ambulatory PP does not add to risk stratification below age 60; in the elderly, PP is a weak risk factor with levels below 64 mm Hg probably being innocuous.

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.