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1.  How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information? 
BACKGROUND
Average real variability (ARV) is a recently proposed index for short-term blood pressure (BP) variability. We aimed to determine the minimum number of BP readings required to compute ARV without loss of prognostic information.
METHODS
ARV was calculated from a discovery dataset that included 24-hour ambulatory BP measurements for 1,254 residents (mean age = 56.6 years; 43.5% women) of Copenhagen, Denmark. Concordance between ARV from full (≥80 BP readings) and randomly reduced 24-hour BP recordings was examined, as was prognostic accuracy. A test dataset that included 5,353 subjects (mean age = 54.0 years; 45.6% women) with at least 48 BP measurements from 11 randomly recruited population cohorts was used to validate the results.
RESULTS
In the discovery dataset, a minimum of 48 BP readings allowed an accurate assessment of the association between cardiovascular risk and ARV. In the test dataset, over 10.2 years (median), 806 participants died (335 cardiovascular deaths, 206 cardiac deaths) and 696 experienced a major fatal or nonfatal cardiovascular event. Standardized multivariable-adjusted hazard ratios (HRs) were computed for associations between outcome and BP variability. Higher diastolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.19), and cardiac (HR = 1.19) mortality and fatal combined with nonfatal cerebrovascular events (HR = 1.16). Higher systolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.17), and cardiac (HR = 1.24) mortality.
CONCLUSIONS
Forty-eight BP readings over 24 hours were observed to be adequate to compute ARV without meaningful loss of prognostic information.
doi:10.1093/ajh/hpt142
PMCID: PMC3848629  PMID: 23955605
ambulatory blood pressure; blood pressure; blood pressure variability; epidemiology; hypertension; population science; risk factors.
2.  Left ventricular diastolic function in relation to the urinary proteome: A proof-of-concept study in a general population 
International Journal of Cardiology  2014;176(1):158-165.
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.
Highlights
•Aim: to validate urinary proteomic markers for LV dysfunction in a population.•Result: LV diastolic dysfunction was associated with the urinary proteome.•Perspective: Screening for subclinical LV dysfunction becomes possible.
doi:10.1016/j.ijcard.2014.07.014
PMCID: PMC4155932  PMID: 25065337
Diastolic dysfunction; Urinary proteomics; Population science
3.  Heart ‘omics’ in AGEing (HOMAGE): design, research objectives and characteristics of the common database 
Journal of Biomedical Research  2014;28(5):349-359.
Abstract
Heart failure is common in older people and its prevalence is increasing. The Heart ‘omics’ in AGEing (HOMAGE) project aims to provide a biomarker approach that will improve the early diagnosis of heart failure. A large clinical database, based on (1) prospective population studies or (2) cross-sectional, prospective studies or randomized controlled trials (RCTs) of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ‘omics’-based biomarkers to identify the risk of developing heart failure and/or comorbidities. Population studies, patient cohorts and RCTs are eligible for inclusion in the common database, if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors. Currently, the HOMAGE database includes 43,065 subjects, from 20 studies in eight European countries, including healthy subjects from three population studies in France, Belgium and Italy (n  =  7,124), patients with heart failure (n  =  4,312) from four cohorts in the UK, Spain and Switzerland and patients at high risk for cardiovascular disease (n  =  31,629) in 13 cohorts. It is anticipated that more partners will join the consortium and enlarge the pooled data. This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.
doi:10.7555/JBR.28.20140045
PMCID: PMC4197385  PMID: 25332706
left ventricle; heart failure; heart failure with reduced ejection fraction; heart failure with preserved ejection fraction; population science; morbidity; mortality
4.  Nigerian Population Research on Environment, Gene and Health (NIPREGH) – objectives and protocol 
Journal of Biomedical Research  2014;28(5):360-367.
Abstract
Sub-Saharan Africa is currently undergoing an epidemiological transition from a disease burden largely attributable to communicable diseases to that resulting from a combination of both communicable and chronic non-communicable diseases. Data on chronic disease incidence, lifestyle, environmental and genetic risk factors are sparse in this region. This report aimed at providing relevant information in respect to risk factors that increase blood pressure and lead to development of intermediate cardiovascular phenotypes. We presented the rationale, objectives and key methodological features of the Nigerian Population Research on Environment, Gene and Health (NIPREGH) study. The challenges encountered in carrying out population study in this part of the world and the approaches at surmounting them were also presented. The preliminary data as at 20 November 2013 showed that out of the 205 individuals invited starting from early April 2013, 160 (72 women) consented and were enrolled; giving a response rate of 78%. Participants' age ranged from 18 to 80 years, with a mean (SD) of 39.8 (12.4) years and they were of 34 different ethnic groups spread over 24 states out of the 36 states that constitute Nigeria. The mean (SD) of office and home blood pressures were 113.0 (15.2) mm Hg systolic, 73.5 (12.5) mm Hg diastolic and 117.3 (15.0) mm Hg systolic, and 76.0 (9.6) mm Hg diastolic, respectively. Forty-three (26.8%) participants were hypertensive and 8 (5.0%) were diabetic. In addition to having the unique potential of recruiting a cohort that is a true representative of the entire Nigerian population, NIPREGH is feasible and the objectives realisable.
doi:10.7555/JBR.28.20130199
PMCID: PMC4197386  PMID: 25332707
Africa, black populations, blood pressure, hypertension, population science
5.  Estimation of Glomerular Filtration Rate Based on Serum Cystatin C versus Creatinine in a Uruguayan Population 
Background. Estimation of glomerular filtration rate (eGFR) from biomarkers has evolved and multiple equations are available to estimate renal function at bedside. Methods. In a random sample of 119 Uruguayans (54.5% women; 56.2 years (mean)), we used Bland and Altman's method and Cohen's kappa statistic to assess concordance on a continuous or categorical (eGFR < 60 versus ≥60 mL/min/1.73 m2) scale between eGFRcys (reference) and eGFR derived from serum creatinine according to the Modification of Diet in Renal Disease (eGFRmdrd) or the Chronic Kidney Disease Epidemiology Collaboration equations (eGFRepi) or from both serum cystatin C and creatinine (eGFRmix). Results. In all participants, eGFRmdrd, eGFRepi, and eGFRmix were, respectively, 9.7, 11.5, and 5.6 mL/min/1.73 m2 higher (P < 0.0001) than eGFRcys. The prevalence of eGFR <60 mL/min/1.73 m2 was the highest for eGFRcys (21.8%), intermediate for eGFRmix (11.8%), and the lowest for eGFRmdrd (5.9%) and eGFRepi (3.4%). Using eGFRcys as reference, we found only fair agreement with the equations based on creatinine (Cohen's kappa statistic 0.15 to 0.23). Conclusion. Using different equations we reached clinically significant differences in the estimation of renal function. eGFRcys provides lower estimates, resulting in higher prevalence of eGFR <60 mL/min/1.73 m2.
doi:10.1155/2014/837106
PMCID: PMC4158300  PMID: 25215234
6.  Randomised Double-Blind Comparison of Placebo and Active Drugs for Effects on Risks Associated with Blood Pressure Variability in the Systolic Hypertension in Europe Trial 
PLoS ONE  2014;9(8):e103169.
Background
In the Systolic Hypertension in Europe trial (NCT02088450), we investigated whether systolic blood pressure variability determines prognosis over and beyond level.
Methods
Using a computerised random function and a double-blind design, we randomly allocated 4695 patients (≥60 years) with isolated systolic hypertension (160–219/<95 mm Hg) to active treatment or matching placebo. Active treatment consisted of nitrendipine (10–40 mg/day) with possible addition of enalapril (5–20 mg/day) and/or hydrochlorothiazide (12.5–25.0 mg/day). We assessed whether on-treatment systolic blood pressure level (SBP), visit-to-visit variability independent of the mean (VIM) or within-visit variability (WVV) predicted total (n = 286) or cardiovascular (n = 150) mortality or cardiovascular (n = 347), cerebrovascular (n = 133) or cardiac (n = 217) endpoints.
Findings
At 2 years, mean between-group differences were 10.5 mm Hg (p<0.0001) for SBP, 0.29 units (p = 0.20) for VIM, and 0.07 mm Hg (p = 0.47) for WVV. Active treatment reduced (p≤0.048) cardiovascular (−28%), cerebrovascular (−40%) and cardiac (−24%) endpoints. In analyses dichotomised by the median, patients with low vs. high VIM had similar event rates (p≥0.14). Low vs. high WVV was not associated with event rates (p≥0.095), except for total and cardiovascular mortality on active treatment, which were higher with low WVV (p≤0.0003). In multivariable-adjusted Cox models, SBP predicted all endpoints (p≤0.0043), whereas VIM did not predict any (p≥0.058). Except for an inverse association with total mortality (p = 0.042), WVV was not predictive (p≥0.15). Sensitivity analyses, from which we excluded blood pressure readings within 6 months after randomisation, 6 months prior to an event or both were confirmatory.
Conclusions
The double-blind placebo-controlled Syst-Eur trial demonstrated that blood-pressure lowering treatment reduces cardiovascular complications by decreasing level but not variability of SBP. Higher blood pressure level, but not higher variability, predicted risk.
Trial Registration
ClinicalTrials.gov NCT02088450
doi:10.1371/journal.pone.0103169
PMCID: PMC4121168  PMID: 25090617
8.  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.
doi:10.1161/JAHA.114.000789
PMCID: PMC4309065  PMID: 24780207
diastole; echocardiography; epidemiology; survival; tissue Doppler imaging
9.  Heritability and Clinical Determinants of Serum Indoxyl Sulfate and p-Cresyl Sulfate, Candidate Biomarkers of the Human Microbiome Enterotype 
PLoS ONE  2014;9(5):e79682.
Background
Indoxyl sulfate and p-cresyl sulfate are unique microbial co-metabolites. Both co-metabolites have been involved in the pathogenesis of accelerated cardiovascular disease and renal disease progression. Available evidence suggests that indoxyl sulfate and p-cresyl sulfate may be considered candidate biomarkers of the human enterotype and may help to explain the link between diet and cardiovascular disease burden.
Objective and Design
Information on clinical determinants and heritability of indoxyl sulfate and p-cresyl sulfate serum is non-existing. To clarify this issue, the authors determined serum levels of indoxyl sulfate and p-cresyl sulfate in 773 individuals, recruited in the frame of the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO study).
Results
Serum levels of indoxyl sulfate and p-cresyl sulfate amounted to 3.1 (2.4–4.3) and 13.0 (7.4–21.5) μM, respectively. Regression analysis identified renal function, age and sex as independent determinants of both co-metabolites. Both serum indoxyl sulfate (h2 = 0.17) and p-cresyl sulfate (h2 = 0.18) concentrations showed moderate but significant heritability after adjustment for covariables, with significant genetic and environmental correlations for both co-metabolites.
Limitations
Family studies cannot provide conclusive evidence for a genetic contribution, as confounding by shared environmental effects can never be excluded.
Conclusions
The heritability of indoxyl sulfate and p-cresyl sulfate is moderate. Besides genetic host factors and environmental factors, also renal function, sex and age influence the serum levels of these co-metabolites.
doi:10.1371/journal.pone.0079682
PMCID: PMC4029585  PMID: 24850265
10.  Epidemiology of Masked and White-Coat Hypertension: The Family-Based SKIPOGH Study 
PLoS ONE  2014;9(3):e92522.
Objective
We investigated factors associated with masked and white-coat hypertension in a Swiss population-based sample.
Methods
The Swiss Kidney Project on Genes in Hypertension is a family-based cross-sectional study. Office and 24-hour ambulatory blood pressure were measured using validated devices. Masked hypertension was defined as office blood pressure<140/90 mmHg and daytime ambulatory blood pressure≥135/85 mmHg. White-coat hypertension was defined as office blood pressure≥140/90 mmHg and daytime ambulatory blood pressure<135/85 mmHg. Mixed-effect logistic regression was used to examine the relationship of masked and white-coat hypertension with associated factors, while taking familial correlations into account. High-normal office blood pressure was defined as systolic/diastolic blood pressure within the 130–139/85–89 mmHg range.
Results
Among the 652 participants included in this analysis, 51% were female. Mean age (±SD) was 48 (±18) years. The proportion of participants with masked and white coat hypertension was respectively 15.8% and 2.6%. Masked hypertension was associated with age (odds ratio (OR) = 1.02, p = 0.012), high-normal office blood pressure (OR = 6.68, p<0.001), and obesity (OR = 3.63, p = 0.001). White-coat hypertension was significantly associated with age (OR = 1.07, p<0.001) but not with education, family history of hypertension, or physical activity.
Conclusions
Our findings suggest that physicians should consider ambulatory blood pressure monitoring for older individuals with high-normal office blood pressure and/or who are obese.
doi:10.1371/journal.pone.0092522
PMCID: PMC3963885  PMID: 24663506
11.  Association of digital vascular function with cardiovascular risk factors: a population study 
BMJ Open  2014;4(3):e004399.
Objectives
Vasodilation of the peripheral arteries during reactive hyperaemia depends in part on release of nitric oxide from endothelial cells. Previous studies mainly employed a fingertip tonometric device to derive pulse wave amplitude (PWA) and PWA hyperaemic changes. An alternative approach is based on photoplethysmography (PPG). We sought to evaluate the correlates of digital PPG PWA hyperaemic responses as a measure of peripheral vascular function.
Design
The Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) is a population-based cohort study.
Setting
Respondents were examined at one centre in northern Belgium.
Participants
For this analysis, our sample consisted of 311 former participants (53.5% women; mean age 52.6 years; 43.1% hypertensive), who were examined from January 2010 until March 2012 (response rate 85.1%).
Primary outcome measures
Using a fingertip PPG device, we measured digital PWA at baseline and at 30 s intervals for 4 min during reactive hyperaemia induced by a 5 min forearm cuff occlusion. We performed stepwise regression to identify correlates of the hyperaemic response ratio for each 30 s interval after cuff deflation.
Results
The maximal hyperaemic response was detected in the 30–60 s interval. The explained variance for the PPG PWA ratio ranged from 9.7% at 0–30 s interval to 22.5% at 60–90 s time interval. The hyperaemic response at each 30 s interval was significantly higher in women compared with men (p≤0.001). The PPG PWA changes at 0–90 s intervals decreased with current smoking (p≤0.0007) and at 0–240 s intervals decreased with higher body mass index (p≤0.035). These associations with sex, current smoking and body mass index were mutually independent.
Conclusions
Our study is the first to implement the new PPG technique to measure digital PWA hyperaemic changes in a general population. Hyperaemic response, as measured by PPG, is inversely associated with traditional cardiovascular risk factors such as male sex, smoking and obesity.
doi:10.1136/bmjopen-2013-004399
PMCID: PMC3975759  PMID: 24662447
population; endothelial function; vasodilation; photoplethysmography
12.  SYMPLICITY HTN-3 results to be announced: a mystery or a story foretold? 
Journal of Biomedical Research  2014;28(2):73-74.
doi:10.7555/JBR.28.20140026
PMCID: PMC3968276  PMID: 24683403
13.  Risk Stratification by Self-Measured Home Blood Pressure across Categories of Conventional Blood Pressure: A Participant-Level Meta-Analysis 
PLoS Medicine  2014;11(1):e1001591.
Jan Staessen and colleagues compare the risk of cardiovascular, cardiac, or cerebrovascular events in patients with elevated office blood pressure vs. self-measured home blood pressure.
Please see later in the article for the Editors' Summary
Background
The Global Burden of Diseases Study 2010 reported that hypertension is worldwide the leading risk factor for cardiovascular disease, causing 9.4 million deaths annually. We examined to what extent self-measurement of home blood pressure (HBP) refines risk stratification across increasing categories of conventional blood pressure (CBP).
Methods and Findings
This meta-analysis included 5,008 individuals randomly recruited from five populations (56.6% women; mean age, 57.1 y). All were not treated with antihypertensive drugs. In multivariable analyses, hazard ratios (HRs) associated with 10-mm Hg increases in systolic HBP were computed across CBP categories, using the following systolic/diastolic CBP thresholds (in mm Hg): optimal, <120/<80; normal, 120–129/80–84; high-normal, 130–139/85–89; mild hypertension, 140–159/90–99; and severe hypertension, ≥160/≥100.
Over 8.3 y, 522 participants died, and 414, 225, and 194 had cardiovascular, cardiac, and cerebrovascular events, respectively. In participants with optimal or normal CBP, HRs for a composite cardiovascular end point associated with a 10-mm Hg higher systolic HBP were 1.28 (1.01–1.62) and 1.22 (1.00–1.49), respectively. At high-normal CBP and in mild hypertension, the HRs were 1.24 (1.03–1.49) and 1.20 (1.06–1.37), respectively, for all cardiovascular events and 1.33 (1.07–1.65) and 1.30 (1.09–1.56), respectively, for stroke. In severe hypertension, the HRs were not significant (p≥0.20). Among people with optimal, normal, and high-normal CBP, 67 (5.0%), 187 (18.4%), and 315 (30.3%), respectively, had masked hypertension (HBP≥130 mm Hg systolic or ≥85 mm Hg diastolic). Compared to true optimal CBP, masked hypertension was associated with a 2.3-fold (1.5–3.5) higher cardiovascular risk. A limitation was few data from low- and middle-income countries.
Conclusions
HBP substantially refines risk stratification at CBP levels assumed to carry no or only mildly increased risk, in particular in the presence of masked hypertension. Randomized trials could help determine the best use of CBP vs. HBP in guiding BP management. Our study identified a novel indication for HBP, which, in view of its low cost and the increased availability of electronic communication, might be globally applicable, even in remote areas or in low-resource settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, hypertension (high blood pressure) is the leading risk factor for cardiovascular disease and is responsible for 9.4 million deaths annually from heart attacks, stroke, and other cardiovascular diseases. Hypertension, which rarely has any symptoms, is diagnosed by measuring blood pressure, the force that blood circulating in the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic blood pressure) and lowest when the heart is refilling (diastolic blood pressure). European guidelines define optimal blood pressure as a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) and a diastolic blood pressure of less than 80 mm Hg (a blood pressure of less than 120/80 mm Hg). Normal blood pressure, high-normal blood pressure, and mild hypertension are defined as blood pressures in the ranges 120–129/80–84 mm Hg, 130–139/85–89 mm Hg, and 140–159/90–99 mm Hg, respectively. A blood pressure of more than 160 mm Hg systolic or 100 mm Hg diastolic indicates severe hypertension. Many factors affect blood pressure; overweight people and individuals who eat salty or fatty food are at high risk of developing hypertension. Lifestyle changes and/or antihypertensive drugs can be used to control hypertension.
Why Was This Study Done?
The current guidelines for the diagnosis and management of hypertension recommend risk stratification based on conventionally measured blood pressure (CBP, the average of two consecutive measurements made at a clinic). However, self-measured home blood pressure (HBP) more accurately predicts outcomes because multiple HBP readings are taken and because HBP measurement avoids the “white-coat effect”—some individuals have a raised blood pressure in a clinical setting but not at home. Could risk stratification across increasing categories of CBP be refined through the use of self-measured HBP, particularly at CBP levels assumed to be associated with no or only mildly increased risk? Here, the researchers undertake a participant-level meta-analysis (a study that uses statistical approaches to pool results from individual participants in several independent studies) to answer this question.
What Did the Researchers Do and Find?
The researchers included 5,008 individuals recruited from five populations and enrolled in the International Database of Home Blood Pressure in Relation to Cardiovascular Outcome (IDHOCO) in their meta-analysis. CBP readings were available for all the participants, who measured their HBP using an oscillometric device (an electronic device for measuring blood pressure). The researchers used information on fatal and nonfatal cardiovascular, cardiac, and cerebrovascular (stroke) events to calculate the hazard ratios (HRs, indicators of increased risk) associated with a 10-mm Hg increase in systolic HBP across standard CBP categories. In participants with optimal CBP, an increase in systolic HBP of 10-mm Hg increased the risk of any cardiovascular event by nearly 30% (an HR of 1.28). Similar HRs were associated with a 10-mm Hg increase in systolic HBP for all cardiovascular events among people with normal and high-normal CBP and with mild hypertension, but for people with severe hypertension, systolic HBP did not significantly add to the prediction of any end point. Among people with optimal, normal, and high-normal CBP, 5%, 18.4%, and 30.4%, respectively, had a HBP of 130/85 or higher (“masked hypertension,” a higher blood pressure in daily life than in a clinical setting). Finally, compared to individuals with optimal CBP without masked hypertension, individuals with masked hypertension had more than double the risk of cardiovascular disease.
What Do These Findings Mean?
These findings indicate that HBP measurements, particularly in individuals with masked hypertension, refine risk stratification at CBP levels assumed to be associated with no or mildly elevated risk of cardiovascular disease. That is, HBP measurements can improve the prediction of cardiovascular complications or death among individuals with optimal, normal, and high-normal CBP but not among individuals with severe hypertension. Clinical trials are needed to test whether the identification and treatment of masked hypertension leads to a reduction of cardiovascular complications and is cost-effective compared to the current standard of care, which does not include HBP measurements and does not treat people with normal or high-normal CBP. Until then, these findings provide support for including HBP monitoring in primary prevention strategies for cardiovascular disease among individuals at risk for masked hypertension (for example, people with diabetes), and for carrying out HBP monitoring in people with a normal CBP but unexplained signs of hypertensive target organ damage.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001591.
This study is further discussed in a PLOS Medicine Perspective by Mark Caulfield
The US National Heart, Lung, and Blood Institute has patient information about high blood pressure (in English and Spanish) and a guide to lowering high blood pressure that includes personal stories
The American Heart Association provides information on high blood pressure and on cardiovascular diseases (in several languages); it also provides personal stories about dealing with high blood pressure
The UK National Health Service Choices website provides detailed information for patients about hypertension (including a personal story) and about cardiovascular disease
The World Health Organization provides information on cardiovascular disease and controlling blood pressure; its A Global Brief on Hypertension was published on World Health Day 2013
The UK charity Blood Pressure UK provides information about white-coat hypertension and about home blood pressure monitoring
MedlinePlus provides links to further information about high blood pressure, heart disease, and stroke (in English and Spanish)
doi:10.1371/journal.pmed.1001591
PMCID: PMC3897370  PMID: 24465187
14.  Double Product Reflects the Predictive Power of Systolic Pressure in the General Population: Evidence from 9,937 Participants 
American journal of hypertension  2013;26(5):665-672.
BACKGROUND
The double product (DP), consisting of the systolic blood pressure (SBP) multiplied by the pulse rate (PR), is an index of myocardial oxygen consumption, but its prognostic value in the general population remains unknown.
METHODS
We recorded health outcomes in 9,937 subjects (median age, 53.2 years; 47.3% women) randomly recruited from 11 populations and enrolled in the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) study. We obtained the SBP, PR, and DP for these subjects as determined through 24-hour ambulatory monitoring.
RESULTS
Over a median period of 11.0 years, 1,388 of the 9,937 study subjects died, of whom 536 and 794, respectively, died of cardiovascular (CV) and non-CV causes, and a further 1,161, 658, 494, and 465 subjects, respectively, experienced a CV, cardiac, coronary, or cerebrovascular event. In multivariate-adjusted Cox models, not including SBP and PR, DP predicted total, CV, and non-CV mortality (standardized hazard ratio [HR], ≥ 1.10; P ≤ 0.02), and all CV, cardiac, coronary, and stroke events (HR, ≥ 1.21; P < 0.0001). For CV mortality (HR, 1.34 vs. 1.30; P = 0.71) and coronary events (1.28 vs. 1.21; P = 0.26), SBP and the DP were equally predictive. As compared with DP, SBP was a stronger predictor of all CV events (1.39 vs. 1.27; P = 0.002) and stroke (1.61 vs. 1.36; P < 0.0001), and a slightly stronger predictor of cardiac events (1.32 vs. 1.22; P = 0.06). In fully adjusted models, including both SBP and PR, the predictive value of DP disappeared for fatal endpoints (P ≥ 0.07), coronary events (P = 0.06), and stroke (P = 0.12), or DP was even inversely associated with the risk of all CV and cardiac events (both P ≤ 0.01).
CONCLUSION
In the general population, we did not observe DP to add to risk stratification over and beyond SBP and PR.
doi:10.1093/ajh/hps119
PMCID: PMC3792705  PMID: 23391621
blood pressure; double product; systolic blood pressure; cardiovascular risk; hypertension; general population
15.  Association of left ventricular diastolic function with systolic dyssynchrony: a population study 
Aims
Left ventricular (LV) (dys)synchrony has an important impact on LV function and structure. Our study aimed to describe the distribution and determinants of LV mechanical delay indexes in the general population and to assess an association of different Doppler indexes reflecting LV diastolic function with LV mechanical delay indexes.
Methods and results
In 200 subjects enrolled in a family-based population study (46.5% women; mean age, 57.9; 48% hypertensive), we performed echocardiography with tissue synchronization imaging (TSI) and two-dimensional speckle tracking. We measured the maximum difference in time to peak systolic velocity between any 2 of 12 LV segments (Ts-max); the standard deviation of time to peak systolic velocity of 12 segments (Ts-sd); the difference in time to peak systolic velocity and strain between septal and lateral LV walls and the strain delay index in septal and lateral walls [septal and lateral (SDI)]. In univariable and multivariable regression analyses, TSI indexes and lateral SDI independently increased with age (P ≤ 0.027) and body mass index (P ≤ 0.010). Ts-max and Ts-sd also increased with female sex (P ≤ 0.0002) and decreased with heart rate (P ≤ 0.0004). Septal SDI only increased with female sex (P < 0.0001). Among the Doppler indexes of LV diastolic function, only E/e′ was significantly and positively associated with TSI indexes (P ≤ 0.037) and lateral SDI (P = 0.0026), but not with septal SDI (P = 0.69). In participants with advanced stage of LV diastolic dysfunction, TSI indexes were prolonged compare with subjects with normal LV diastolic function (P ≤ 0.002).
Conclusion
We demonstrated that in unselected subjects LV diastolic dysfunction was associated with mechanical LV dyssynchrony as assessed by echocardiography.
doi:10.1093/ehjci/jes189
PMCID: PMC3792706  PMID: 23002213
Population; Left ventricular dyssynchrony; Tissue synchronization imaging; Strain; Diastolic dysfunction
16.  A family-based association test to detect gene–gene interactions in the presence of linkage 
For many complex diseases, quantitative traits contain more information than dichotomous traits. One of the approaches used to analyse these traits in family-based association studies is the quantitative transmission disequilibrium test (QTDT). The QTDT is a regression-based approach that models simultaneously linkage and association. It splits up the association effect in a between- and a within-family genetic component to adjust and test for population stratification and includes a variance components method to model linkage. We extend this approach to detect gene–gene interactions between two unlinked QTLs by adjusting the definition of the between- and within-family component and the variance components included in the model. We simulate data to investigate the influence of the epistasis model, linkage disequilibrium patterns between the markers and the QTLs, and allele frequencies on the power and type I error rates of the approach. Results show that for some of the investigated settings, power gains are obtained in comparison with FAM-MDR. We conclude that our approach shows promising results for candidate-gene studies where too few markers are available to correct for population stratification using standard methods (for example EIGENSTRAT). The proposed method is applied to real-life data on hypertension from the FLEMENGHO study.
doi:10.1038/ejhg.2012.45
PMCID: PMC3421128  PMID: 22419171
QTDT; epistasis; association; linkage
17.  Associations of Urinary Cadmium with Age and Urinary Proteins: Further Evidence of Physiological Variations Unrelated to Metal Accumulation and Toxicity 
Environmental Health Perspectives  2013;121(9):1047-1053.
Background: The current risk assessment for environmental cadmium (Cd) largely relies on the assumption that urinary Cd (U-Cd) is a reliable biomarker of the Cd body burden. Recent studies have questioned the validity of this assumption.
Objectives: We studied the lifetime trend of U-Cd as a function of diuresis, gender, smoking status, and protein tubular reabsorption. We also analyzed the associations between U-Cd and urinary proteins.
Methods: Cd, retinol-binding protein, and albumin were measured in the urine of six cohorts of the general population of Belgium, with a mean age ranging from 5.7 to 88.1 years (n = 1,567). Variations of U-Cd with age were modeled using natural cubic splines.
Results: In both genders, U-Cd decreased to a minimum (~ 0.20 μg/L) at the end of adolescence, then increased until 60–70 years of age (~ 0.60 μg/L in never-smokers) before leveling off or decreasing. When U-Cd was expressed in micrograms per gram of creatinine, these variations were amplified (minimum, 0.15 µg/g creatinine; maximum, 0.70 µg/g creatinine) and much higher U-Cd values were observed in women. We observed no difference in U-Cd levels between never-smokers and former smokers, and the difference with current smokers did not increase over time. Lifetime curves of U-Cd were higher with increasing urinary retinol-binding protein or albumin, a consequence of the coexcretion of Cd with proteins.
Conclusions: At low Cd exposure levels, U-Cd and age are associated through nonlinear and nonmonotonic relationships that appear to be driven mainly by recent Cd intake and physiological variations in the excretion of creatinine and proteins.
Citation: Chaumont A, Voisin C, Deumer G, Haufroid V, Annesi-Maesano I, Roels H, Thijs L, Staessen J, Bernard A. 2013. Associations of urinary cadmium with age and urinary proteins: further evidence of physiological variations unrelated to metal accumulation and toxicity. Environ Health Perspect 121:1047–1053; http://dx.doi.org/10.1289/ehp.1306607
doi:10.1289/ehp.1306607
PMCID: PMC3764089  PMID: 23774576
18.  Urinary proteome analysis in hypertensive patients with left ventricular diastolic dysfunction 
European heart journal  2012;33(18):2342-2350.
Aims
Despite the significant heart failure (HF) burden on society, easily applicable screening techniques, particularly for the early detection of asymptomatic left ventricular (LV) dysfunction, are lacking. The present study aimed to identify and test a set of urinary polypeptides that may indicate early LV diastolic dysfunction as defined by echocardiography in hypertensive patients in a cross-sectional case–control study nested within the FLEMish study on ENvironment, Genes and Health Outcome (FLEMENGHO).
Methods and results
To identify potentially discriminating urinary biomarkers for LV diastolic dysfunction, we applied capillary electrophoresis coupled to mass spectrometry. In the discovery set, we compared 19 hypertensive patients with asymptomatic LV diastolic dysfunction with 19 healthy controls. In the absence of adjustment for multiple testing, 85 urinary peptides were different between cases and controls at a P-value of <0.033. With adjustment for multiple testing, three potential biomarkers remained significantly different between cases and controls (P ≤ 0.02). We combined the 85 potential biomarkers in a high-dimensional model (classifier), which we applied in a blinded manner to an independent test set of 16 hypertensive patients with symptomatic HF and 16 healthy controls. Upon unblinding, the area under the receiver operating characteristic curve (AUC) of the HF classification was 0.84 (95% CI: 0.70–0.98; P = 0.001).
Conclusion
In asymptomatic hypertensive patients with LV diastolic dysfunction, we identified a set of urinary polypeptides specific for essential hypertension with LV diastolic dysfunction that subsequently distinguished hypertensive patients with overt HF from healthy controls.
doi:10.1093/eurheartj/ehs185
PMCID: PMC3705161  PMID: 22789915
Diastolic dysfunction; Urinary proteomics
19.  Central Systolic Augmentation Indexes and Urinary Sodium in a White Population 
American journal of hypertension  2013;26(1):95-103.
BACKGROUND
The association between cardiovascular health and salt intake remains controversial. The objective of our study was to assess the association between arterial stiffness and urinary sodium, both cross-sectionally and prospectively.
METHODS
In 630 participants (mean age 40.6 years; 51% women), randomly recruited from a Flemish population, we measured sodium and creatinine in 24-hour urine samples at baseline and follow-up (median, 9.7 years) and the carotid and aortic augmentation indexes (AIs) standardized to heart rate at follow-up only.
RESULTS
From baseline to follow-up, the urinary sodium concentration decreased (117.1 vs. 105.2 mmol/L; P < 0.0001), whereas 24-hour urinary sodium did not change significantly (166.5 vs. 171.5 mmol/L; P = 0.12). In multivariable-adjusted longitudinal analyses, a 40 mmol/L (~1 SD) increase in the urinary sodium concentration was independently and inversely associated with the carotid AI (effect size, −1.38 ± 0.66%; P = 0.04) and aortic AI (−1.54 ± 0.72%; P = 0.02). In cross-sectional analyses of follow-up data, these estimates were −1.26 ± 0.70% (P = 0.07) and −1.52 ± 0.76% (P = 0.04), respectively. In the longitudinal and cross-sectional analyses, the carotid and aortic AIs were unrelated to the 24-hour urinary excretion of sodium.
CONCLUSIONS
Our study showed an inverse association between the central arterial AIs and the urinary sodium concentration. Further research is required to consolidate our findings, to unravel the underlying mechanism, and to establish the role of renal vasodilatation in the maintenance of sodium balance.
doi:10.1093/ajh/hps023
PMCID: PMC3705162  PMID: 23382332
artery stiffness; blood pressure; cross-sectional; hypertension; prospective; urinary sodium; white population
20.  Heritability and intrafamilial aggregation of arterial characteristics 
Journal of hypertension  2008;26(4):721-728.
Background
We investigated the heritability and familial aggregation of various indexes of arterial stiffness and wave reflection and we partitioned the phenotypic correlation between these traits into shared genetic and environmental components.
Methods
Using a family-based population sample, we recruited 204 parents (mean age, 51.7 years) and 290 offspring (29.4 years) from the population in Cracow, Poland (62 families), Hechtel-Eksel, Belgium (36), and Pilsen, the Czech Republic (50). We measured peripheral pulse pressure (PPp) sphygmomanometrically at the brachial artery; central pulse pressure (PPc), the peripheral augmentation indexes (PAIxs) and central augmentation indexes (CAIxs) by applanation tonometry at the radial artery; and aortic pulse wave velocity (PWV) by tonometry or ultrasound. In multivariate-adjusted analyses, we used the ASSOC and PROC GENMOD procedures as implemented in SAGE and SAS, respectively.
Results
We found significant heritability for PAIx, CAIx, PPc and mean arterial pressure ranging from 0.37 to 0.41; P ≤ 0.0001. The method of intrafamilial concordance confirmed these results; intrafamilial correlation coefficients were significant for all arterial indexes (r > ≥ 0.12; P < ≤ 0.02) with the exception of PPc (r = −0.007; P = 0.90) in parent–offspring pairs. The sib–sib correlations were also significant for CAIx (r = 0.22; P = 0.001). The genetic correlation between PWV and the other arterial indexes were significant (ρG ≥ 0.29; P < 0.0001). The corresponding environmental correlations were only significantly positive for PPp (ρE = 0.10, P = 0.03).
Conclusion
The observation of significant intrafamilial concordance and heritability of various indexes of arterial stiffness as well as the genetic correlations among arterial phenotypes strongly support the search for shared genetic determinants underlying these traits.
doi:10.1097/HJH.0b013e3282f4d1e7
PMCID: PMC3693934  PMID: 18327082
arterial stiffness; familial aggregation; heritability; pulse pressure; systolic augmentation
21.  Ethnic differences in proximal and distal tubular sodium reabsorption are heritable in black and white populations 
Journal of hypertension  2009;27(3):606-612.
Background
Segmental handling of sodium along the proximal and distal nephron might be heritable and different between black and white participants.
Methods
We randomly recruited 95 nuclear families of black South African ancestry and 103 nuclear families of white Belgian ancestry. We measured the (FENa) and estimated the fractional renal sodium reabsorption in the proximal (RNaprox) and distal (RNadist) tubules from the clearances of endogenous lithium and creatinine. In multivariable analyses, we studied the relation of RNaprox and RNadist with FENa and estimated the heritability (h2) of RNaprox and RNadist.
Results
Independent of urinary sodium excretion, South Africans (n =240) had higher RNaprox (unadjusted median, 93.9% vs. 81.0%; P < 0.001) than Belgians (n =737), but lower RNadist (91.2% vs. 95.1%; P < 0.001). The slope of RNaprox on FENa was steeper in Belgians than in South Africans (−5.40 ±0.58 vs. −0.78 ±0.58 units; P < 0.001), whereas the opposite was true for the slope of RNadist on FENa (−3.84 ± 0.19 vs. −13.71 ± 1.30 units; P < 0.001). h2 of RNaprox and RNadist was high and significant (P < 0.001) in both countries. h2 was higher in South Africans than in Belgians for RNaprox (0.82 vs. 0.56; P < 0.001), but was similar for RNadist (0.68 vs. 0.50; P = 0.17). Of the filtered sodium load, black participants reabsorb more than white participants in the proximal nephron and less postproximally.
Conclusion
Segmental sodium reabsorption along the nephron is highly heritable, but the capacity for regulation in the proximal and postproximal tubules differs between whites and blacks.
doi:10.1097/HJH.0b013e32832104b1
PMCID: PMC3683574  PMID: 19262228
clinical genetics; epidemiology; kidney; lithium clearance; salt sensitivity; segmental tubular sodium transport
22.  Masked Hypertension in Diabetes Mellitus 
Hypertension  2013;61(5):964-971.
Although distinguishing features of masked hypertension in diabetics are well known, the significance of antihypertensive treatment on clinical practice decisions has not been fully explored. We analyzed 9691 subjects from the population-based 11-country International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes. Prevalence of masked hypertension in untreated normotensive participants was higher (P<0.0001) among 229 diabetics (29.3%, n=67) than among 5486 nondiabetics (18.8%, n=1031). Over a median of 11.0 years of follow-up, the adjusted risk for a composite cardiovascular end point in untreated diabetic-masked hypertensives tended to be higher than in normotensives (hazard rate [HR], 1.96; 95% confidence interval [CI], 0.97–3.97; P=0.059), similar to untreated stage 1 hypertensives (HR, 1.07; CI, 0.58–1.98; P=0.82), but less than stage 2 hypertensives (HR, 0.53; CI, 0.29–0.99; P=0.048). In contrast, cardiovascular risk was not significantly different in antihypertensive-treated diabetic-masked hypertensives, as compared with the normotensive comparator group (HR, 1.13; CI, 0.54–2.35; P=0.75), stage 1 hypertensives (HR, 0.91; CI, 0.49–1.69; P=0.76), and stage 2 hypertensives (HR, 0.65; CI, 0.35–1.20; P=0.17). In the untreated diabetic-masked hypertensive population, mean conventional systolic/diastolic blood pressure was 129.2±8.0/76.0±7.3 mm Hg, and mean daytime systolic/diastolic blood pressure 141.5±9.1/83.7±6.5 mm Hg. In conclusion, masked hypertension occurred in 29% of untreated diabetics, had comparable cardiovascular risk as stage 1 hypertension, and would require considerable reduction in conventional blood pressure to reach daytime ambulatory treatment goal. Importantly, many hypertensive diabetics when receiving antihypertensive therapy can present with normalized conventional and elevated ambulatory blood pressure that mimics masked hypertension.
doi:10.1161/HYPERTENSIONAHA.111.00289
PMCID: PMC3631136  PMID: 23478096
ambulatory blood pressure; conventional blood pressure; diabetes mellitus; masked hypertension; population study
23.  FTO genotype is associated with phenotypic variability of body mass index 
Yang, Jian | Loos, Ruth J. F. | Powell, Joseph E. | Medland, Sarah E. | Speliotes, Elizabeth K. | Chasman, Daniel I. | Rose, Lynda M. | Thorleifsson, Gudmar | Steinthorsdottir, Valgerdur | Mägi, Reedik | Waite, Lindsay | Smith, Albert Vernon | Yerges-Armstrong, Laura M. | Monda, Keri L. | Hadley, David | Mahajan, Anubha | Li, Guo | Kapur, Karen | Vitart, Veronique | Huffman, Jennifer E. | Wang, Sophie R. | Palmer, Cameron | Esko, Tõnu | Fischer, Krista | Zhao, Jing Hua | Demirkan, Ayşe | Isaacs, Aaron | Feitosa, Mary F. | Luan, Jian’an | Heard-Costa, Nancy L. | White, Charles | Jackson, Anne U. | Preuss, Michael | Ziegler, Andreas | Eriksson, Joel | Kutalik, Zoltán | Frau, Francesca | Nolte, Ilja M. | Van Vliet-Ostaptchouk, Jana V. | Hottenga, Jouke-Jan | Jacobs, Kevin B. | Verweij, Niek | Goel, Anuj | Medina-Gomez, Carolina | Estrada, Karol | Bragg-Gresham, Jennifer Lynn | Sanna, Serena | Sidore, Carlo | Tyrer, Jonathan | Teumer, Alexander | Prokopenko, Inga | Mangino, Massimo | Lindgren, Cecilia M. | Assimes, Themistocles L. | Shuldiner, Alan R. | Hui, Jennie | Beilby, John P. | McArdle, Wendy L. | Hall, Per | Haritunians, Talin | Zgaga, Lina | Kolcic, Ivana | Polasek, Ozren | Zemunik, Tatijana | Oostra, Ben A. | Junttila, M. Juhani | Grönberg, Henrik | Schreiber, Stefan | Peters, Annette | Hicks, Andrew A. | Stephens, Jonathan | Foad, Nicola S. | Laitinen, Jaana | Pouta, Anneli | Kaakinen, Marika | Willemsen, Gonneke | Vink, Jacqueline M. | Wild, Sarah H. | Navis, Gerjan | Asselbergs, Folkert W. | Homuth, Georg | John, Ulrich | Iribarren, Carlos | Harris, Tamara | Launer, Lenore | Gudnason, Vilmundur | O’Connell, Jeffrey R. | Boerwinkle, Eric | Cadby, Gemma | Palmer, Lyle J. | James, Alan L. | Musk, Arthur W. | Ingelsson, Erik | Psaty, Bruce M. | Beckmann, Jacques S. | Waeber, Gerard | Vollenweider, Peter | Hayward, Caroline | Wright, Alan F. | Rudan, Igor | Groop, Leif C. | Metspalu, Andres | Khaw, Kay Tee | van Duijn, Cornelia M. | Borecki, Ingrid B. | Province, Michael A. | Wareham, Nicholas J. | Tardif, Jean-Claude | Huikuri, Heikki V. | Cupples, L. Adrienne | Atwood, Larry D. | Fox, Caroline S. | Boehnke, Michael | Collins, Francis S. | Mohlke, Karen L. | Erdmann, Jeanette | Schunkert, Heribert | Hengstenberg, Christian | Stark, Klaus | Lorentzon, Mattias | Ohlsson, Claes | Cusi, Daniele | Staessen, Jan A. | Van der Klauw, Melanie M. | Pramstaller, Peter P. | Kathiresan, Sekar | Jolley, Jennifer D. | Ripatti, Samuli | Jarvelin, Marjo-Riitta | de Geus, Eco J. C. | Boomsma, Dorret I. | Penninx, Brenda | Wilson, James F. | Campbell, Harry | Chanock, Stephen J. | van der Harst, Pim | Hamsten, Anders | Watkins, Hugh | Hofman, Albert | Witteman, Jacqueline C. | Zillikens, M. Carola | Uitterlinden, André G. | Rivadeneira, Fernando | Zillikens, M. Carola | Kiemeney, Lambertus A. | Vermeulen, Sita H. | Abecasis, Goncalo R. | Schlessinger, David | Schipf, Sabine | Stumvoll, Michael | Tönjes, Anke | Spector, Tim D. | North, Kari E. | Lettre, Guillaume | McCarthy, Mark I. | Berndt, Sonja I. | Heath, Andrew C. | Madden, Pamela A. F. | Nyholt, Dale R. | Montgomery, Grant W. | Martin, Nicholas G. | McKnight, Barbara | Strachan, David P. | Hill, William G. | Snieder, Harold | Ridker, Paul M. | Thorsteinsdottir, Unnur | Stefansson, Kari | Frayling, Timothy M. | Hirschhorn, Joel N. | Goddard, Michael E. | Visscher, Peter M.
Nature  2012;490(7419):267-272.
There is evidence across several species for genetic control of phenotypic variation of complex traits1–4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5–7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9,10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
doi:10.1038/nature11401
PMCID: PMC3564953  PMID: 22982992
24.  Impact of Hypertension on Ventricular-Arterial Coupling and Regional Myocardial Work at Rest and during Isometric Exercise 
Background
To understand better the mechanism of left ventricular (LV) remodeling related to hypertension, it is important to evaluate LV function in relation to the changes in loading conditions. The aim of this study was to investigate changes in conventional ventricular-arterial coupling indexes, LV strain, and a new index reflecting regional myocardial work assessed noninvasively at rest and during isometric exercise in a random sample including participants with normal blood pressure and those with hypertension.
Methods
A total of 148 participants (53.4% women; mean age, 52.0 years; 39.2% with hypertension) underwent simultaneous echocardiographic and arterial data acquisition at rest and during increased afterload (handgrip exercise). End-systolic pressure was determined from the carotid pulse wave. Arterial elastance (Ea) and LV elastance (Ees) were calculated as end-systolic pressure/stroke volume and end-systolic pressure/end-systolic volume. Doppler tissue imaging and two-dimensional speckle tracking were used to derive LV longitudinal strain. Regional myocardial work (ejection work density [EWD]) was the area of the pressure-strain loop during ejection.
Results
At rest, with adjustments applied, Ees (3.06 vs 3.71 mmHg/mL,P = .0003), Ea/Ees (0.54 vs 0.47,P=.002) and EWD (670 vs 802 Pa/m2, P = .0001) differed significantly between participants with normal blood pressure and those with hypertension. During handgrip exercise, Ea and Ea/Ees significantly increased (P < .0001) in both groups. Doppler tissue imaging and two-dimensional LV strain decreased in participants with hypertension (P ≤ .008). Only in subjects with normal blood pressure EWD significantly increased (+14.7%, P = .0009).
Conclusions
Although patients with hypertension compared with those with normal blood pressure have increased LV systolic stiffness and regional myocardial work to match arterial load at rest, they might have diminished cardiac reserve to increase myocardial performance, as estimated by EWD during isometric exercise.
doi:10.1016/j.echo.2012.04.018
PMCID: PMC3607228  PMID: 22622108
Echocardiography; Hypertension; Ventricular-arterial coupling; Strain
25.  Within-Subject Blood Pressure Level—Not Variability—Predicts Fatal and Nonfatal Outcomes in a General Population 
Hypertension  2012;60(5):1138-1147.
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) mm Hg, and 4.08 (2.05) mm Hg 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 β-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.
doi:10.1161/HYPERTENSIONAHA.112.202143
PMCID: PMC3607229  PMID: 23071126
blood pressure variability; cardiovascular disease; population science; risk factors; epidemiology

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