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1.  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
2.  The Promise of Prevention: The Effects of Four Preventable Risk Factors on National Life Expectancy and Life Expectancy Disparities by Race and County in the United States 
PLoS Medicine  2010;7(3):e1000248.
Majid Ezzati and colleagues examine the contribution of a set of risk factors (smoking, high blood pressure, elevated blood glucose, and adiposity) to socioeconomic disparities in life expectancy in the US population.
Background
There has been substantial research on psychosocial and health care determinants of health disparities in the United States (US) but less on the role of modifiable risk factors. We estimated the effects of smoking, high blood pressure, elevated blood glucose, and adiposity on national life expectancy and on disparities in life expectancy and disease-specific mortality among eight subgroups of the US population (the “Eight Americas”) defined on the basis of race and the location and socioeconomic characteristics of county of residence, in 2005.
Methods and Findings
We combined data from the National Health and Nutrition Examination Survey and the Behavioral Risk Factor Surveillance System to estimate unbiased risk factor levels for the Eight Americas. We used data from the National Center for Health Statistics to estimate age–sex–disease-specific number of deaths in 2005. We used systematic reviews and meta-analyses of epidemiologic studies to obtain risk factor effect sizes for disease-specific mortality. We used epidemiologic methods for multiple risk factors to estimate the effects of current exposure to these risk factors on death rates, and life table methods to estimate effects on life expectancy. Asians had the lowest mean body mass index, fasting plasma glucose, and smoking; whites had the lowest systolic blood pressure (SBP). SBP was highest in blacks, especially in the rural South—5–7 mmHg higher than whites. The other three risk factors were highest in Western Native Americans, Southern low-income rural blacks, and/or low-income whites in Appalachia and the Mississippi Valley. Nationally, these four risk factors reduced life expectancy at birth in 2005 by an estimated 4.9 y in men and 4.1 y in women. Life expectancy effects were smallest in Asians (M, 4.1 y; F, 3.6 y) and largest in Southern rural blacks (M, 6.7 y; F, 5.7 y). Standard deviation of life expectancies in the Eight Americas would decline by 0.50 y (18%) in men and 0.45 y (21%) in women if these risks had been reduced to optimal levels. Disparities in the probabilities of dying from cardiovascular diseases and diabetes at different ages would decline by 69%–80%; the corresponding reduction for probabilities of dying from cancers would be 29%–50%. Individually, smoking and high blood pressure had the largest effect on life expectancy disparities.
Conclusions
Disparities in smoking, blood pressure, blood glucose, and adiposity explain a significant proportion of disparities in mortality from cardiovascular diseases and cancers, and some of the life expectancy disparities in the US.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Life expectancy (a measure of longevity and premature death) and overall health have increased steadily in the United States over recent years. New drugs, new medical technologies, and better disease prevention have all helped Americans to lead longer, healthier lives. However, even now, some Americans live much longer and much healthier lives than others. Health disparities—differences in how often certain diseases occur and cause death in groups of people classified according to their ethnicity, geographical location, sex, or age—are extremely large and persistent in the US. On average, black men and women in the US live 6.3 and 4.5 years less, respectively, than their white counterparts; the gap between life expectancy in the US counties with the lowest and highest life expectancies is 18.4 years for men and 14.3 years for women. Disparities in deaths (mortality) from chronic diseases such as cardiovascular diseases (for example, heart attacks and stroke), cancers, and diabetes are known to be the main determinants of these life expectancy disparities.
Why Was This Study Done?
Preventable risk factors such as smoking, high blood pressure, excessive body fat (adiposity), and high blood sugar are responsible for many thousands of deaths from chronic diseases. Exposure to these risk factors varies widely by race, state of residence, and socioeconomic status. However, the effects of these observed disparities in exposure to modifiable risk factors on US life expectancy disparities have only been examined in selected groups of people and it is not known how multiple modifiable risk factors affect US health disparities. A better knowledge about how disparities in risk factor exposure contribute to health disparities is needed to ensure that prevention programs not only improve the average health status but also reduce health disparities. In this study, the researchers estimate the effects of smoking, high blood pressure, high blood sugar, and adiposity on US life expectancy and on disparities in life expectancy and disease-specific deaths among the “Eight Americas,” population groups defined by race and by the location and socioeconomic characteristics of their county of residence.
What Did the Researchers Do and Find?
The researchers extracted data on exposure to these risk factors from US national health surveys, information on deaths from different diseases in 2005 from the US National Center for Health Statistics, and estimates of how much each risk factor increases the risk of death from each disease from published studies. They then used modeling methods to estimate the effects of risk factor exposure on death rates and life expectancy. The Asian subgroup had the lowest adiposity, blood sugar, and smoking rates, they report, and the three white subgroups had the lowest blood pressure. Blood pressure was highest in the three black subgroups, whereas the other three risk factors were highest in Western Native Americans, Southern rural blacks, and whites living in Appalachia and the Mississippi Valley. The effects on life expectancy of these factors were smallest in Asians and largest in Southern rural blacks but, overall, these risk factors reduced the life expectancy for men and women born in 2005 by 4.9 and 4.1 years, respectively. Other calculations indicate that if these four risk factors were reduced to optimal levels, disparities among the subgroups in deaths from cardiovascular diseases and diabetes and from cancers would be reduced by up to 80% and 50%, respectively.
What Do These Findings Mean?
These findings suggest that disparities in smoking, blood pressure, blood sugar, and adiposity among US racial and geographical subgroups explain a substantial proportion of the disparities in deaths from cardiovascular diseases, diabetes, and cancers among these subgroups. The disparities in risk factor exposure also explain some of the disparities in life expectancy. The remaining disparities in deaths and life expectancy could be the result of preventable risk factors not included in this study—one of its limitations is that it does not consider the effect of dietary fat, alcohol use, and dietary salt, which are major contributors to different diseases. Thus, suggest the researchers, reduced exposure to preventable risk factors through the implementation of relevant policies and programs should reduce life expectancy and mortality disparities in the US and yield health benefits at a national scale.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000248.
The US Centers for Disease Control and Prevention, the US Office of Minority Health, and the US National Center on Minority Health and Health Disparities all provide information on health disparities in the US
MedlinePlus provides links to information on health disparities and on healthy living (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on all aspects of healthy living
The American Heart Association and the American Cancer Society provide information on modifiable risk factors for patients and caregivers
Healthy People 2010 is a national framework designed to improve the health of people living in the US
The US National Health and Nutrition Examination Survey (NHANES) and the Behavioral Risk Factor Surveillance System (BRFSS) collect information on risk factor exposures in the US
doi:10.1371/journal.pmed.1000248
PMCID: PMC2843596  PMID: 20351772
3.  Allostatic load amplifies the effect of blood lead levels on elevated blood pressure among middle-aged U.S. adults: a cross-sectional study 
Environmental Health  2013;12:64.
Background
Scientists and regulators have sought to understand whether and how physiologic dysregulation due to chronic stress exposure may enhance vulnerability to the adverse health effects of toxicant exposures. We conducted a cross-sectional study to determine whether allostatic load (AL), a composite measure of physiologic response to chronic exposure to stress, amplifies the effect of lead exposure on blood pressure among middle-aged adults.
Methods
We analyzed associations between blood lead levels and blood pressure in a nationally representative sample of 8,194 U.S. adults (aged 40-65 years) participating in the National Health and Nutritional Examination Survey, 1999--2008. Outcomes were elevated systolic (≥ 140 mm Hg) and diastolic (≥ 90 mm Hg) blood pressure. AL was defined as the aggregate score of seven components, reflecting dysregulation of the cardiovascular, inflammatory, and endocrine systems.
Results
Logistic regression models showed a linear dose-response relationship for quintiles of blood lead and elevated systolic blood pressure in the high AL group (p = 0.03) but not the low AL group (p = 0.24). Similarly, the relationship between lead exposure and elevated diastolic blood pressure was stronger among the high AL group than the low AL group. Within the high AL group, the fourth and fifth quintiles had significantly elevated odds of elevated blood pressure compared to lowest quintile [OR = 1.92, (95% CI, 1.07, 3.47) and OR =2.28 (95% CI, 1.33, 3.91), respectively]. In the low AL group, none of the quintile effects were significantly different than the referent group although there was evidence of a linear trend (p =0.03). The lead by AL interaction term was not statistically significant for either systolic or diastolic blood pressure models.
Conclusions
Results suggest that higher AL may amplify the adverse effects of lead on blood pressure. Future research should assess the implications of cumulative exposures to environmental and social stressors for regulatory decision-making.
doi:10.1186/1476-069X-12-64
PMCID: PMC3847858  PMID: 23953669
Blood pressure; Cumulative impacts; Environmental health; Lead; Stress
4.  Life Course Trajectories of Systolic Blood Pressure Using Longitudinal Data from Eight UK Cohorts 
PLoS Medicine  2011;8(6):e1000440.
Analysis of eight population-based and occupational cohorts from the UK reveals the patterns of change of blood pressure in the population through the life course.
Background
Much of our understanding of the age-related progression of systolic blood pressure (SBP) comes from cross-sectional data, which do not directly capture within-individual change. We estimated life course trajectories of SBP using longitudinal data from seven population-based cohorts and one predominantly white collar occupational cohort, each from the United Kingdom and with data covering different but overlapping age periods.
Methods and Findings
Data are from 30,372 individuals and comprise 102,583 SBP observations spanning from age 7 to 80+y. Multilevel models were fitted to each cohort. Four life course phases were evident in both sexes: a rapid increase in SBP coinciding with peak adolescent growth, a more gentle increase in early adulthood, a midlife acceleration beginning in the fourth decade, and a period of deceleration in late adulthood where increases in SBP slowed and SBP eventually declined. These phases were still present, although at lower levels, after adjusting for increases in body mass index though adulthood. The deceleration and decline in old age was less evident after excluding individuals who had taken antihypertensive medication. Compared to the population-based cohorts, the occupational cohort had a lower mean SBP, a shallower annual increase in midlife, and a later midlife acceleration. The maximum sex difference was found at age 26 (+8.2 mm Hg higher in men, 95% CI: 6.7, 9.8); women then experienced steeper rises and caught up by the seventh decade.
Conclusions
Our investigation shows a general pattern of SBP progression from childhood in the UK, and suggests possible differences in this pattern during adulthood between a general population and an occupational population.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About a third of US and UK adults have high blood pressure (hypertension). Although hypertension has no obvious symptoms, it can lead to life-threatening heart attacks, stroke, and other forms of cardiovascular disease (CVD). It is diagnosed by measuring blood pressure—the force that blood moving around the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic blood pressure [SBP]) and lowest when the heart is re-filling with blood (diastolic blood pressure [DBP]). Normal adult blood pressure is defined as an SBP of less than 130 millimeters of mercury (mm Hg) and a DBP of less than 85 mm Hg (a blood pressure of 130/85). A reading of more than 140/90 indicates hypertension. Many factors affect blood pressure, but overweight people and individuals who eat fatty or salty food are at high risk of developing hypertension. Moreover, blood pressure tends to increase with age. Mild hypertension can often be corrected by making lifestyle changes, but many people take antihypertensive drugs to reduce their blood pressure.
Why Was This Study Done?
Several trials have indicated that SBP is an important, modifiable risk factor for CVD. But, to determine the best way to prevent CVD, it is important to understand how SBP changes through life and how lifestyle factors affect this age-related progression. Textbook descriptions of age-related changes in SBP are based on studies that measured SBP at a single time point in groups (cohorts) of people of different ages. However, such “cross-sectional” studies do not capture within-individual changes in SBP and may be affected by environmental effects related to specific historical periods. The best way to measure age-related changes in SBP is through longitudinal studies in which SBP is repeatedly measured over many years in a single cohort. Such studies are underway, but it will be some decades before individuals in these studies reach old age. In this study, therefore, the researchers use data from multiple UK cohorts that had repeated SBP measurements taken over different but overlapping periods of life to investigate the life course trajectory of SBP.
What Did the Researchers Do and Find?
The researchers used statistical models to analyze data from longitudinal studies of SBP in seven population-based cohorts (the participants were randomly chosen from the general population) and in one occupational cohort (civil servants). SBP measurements were available for 30,372 individuals with ages spanning from seven years to more than 80 years. The researchers' analysis revealed four phases of SBP change in both sexes: a rapid increase in SBP during adolescent growth, a gentler increase in early adulthood, a midlife acceleration beginning in the fourth decade of life, and a period in late adulthood when SBP increases slowed and then reversed. This last phase was less marked when people taking antihypertensive drugs were excluded from the analysis. After adjusting for increases in body mass index (a measure of body fat) during adulthood, the magnitude of the SBP age-related changes was similar but the average SBP at each age was lower. Compared to the population-based cohorts, the occupational cohort had a lower average SBP, a shallower annual increase in SBP, and a later midlife acceleration, possibly because of socially determined modifiable SBP-related factors such as diet and lifestyle. Finally, although women had lower SBPs in early adulthood than men, they experienced steeper midlife SBP rises (probably because of a menopause-related effect on salt sensitivity) so that by the seventh decade of life, men and women had similar average SBPs.
What Do These Findings Mean?
These findings describe the general pattern of age-related progression of SBP from early childhood in the UK. The findings may not be generalizable because other populations may be exposed to different distributions of modifiable factors. In addition, their accuracy may be affected by differences between cohorts in how SBP was measured. Nevertheless, these findings—in particular, the slower midlife increase in SBP in the occupational cohort than in the population-based cohorts—suggest that the key determinants of age-related increases in blood pressure are modifiable and could be targeted for CVD prevention. Further research is now needed to identify exactly which factors affect the life course trajectory of SBP and to discover when these factors have their greatest influence on SBP.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000440.
The US National Heart Lung and Blood Institute has patient information about high blood pressure (in English and Spanish)
The American Heart Association provides information on high blood pressure and on cardiovascular diseases (in several languages)
The UK National Health Service Choices Web site also provides detailed information for patients about hypertension and about cardiovascular disease
MedlinePlus provides links to further information about high blood pressure, heart disease, and stroke (in English and Spanish)
doi:10.1371/journal.pmed.1000440
PMCID: PMC3114857  PMID: 21695075
5.  Low-Level Lead Exposure and Elevations in Blood Pressure during Pregnancy 
Environmental Health Perspectives  2011;119(5):664-669.
Background
Lead exposure is associated with elevated blood pressure during pregnancy; however, the magnitude of this relationship at low exposure levels is unclear.
Objectives
Our goal was to determine the association between low-level lead exposure and blood pressure during late pregnancy.
Methods
We collected admission and maximum (based on systolic) blood pressures during labor and delivery among 285 women in Baltimore, Maryland. We measured umbilical cord blood lead using inductively coupled plasma mass spectrometry. Multivariable models were adjusted for age, race, median household income, parity, smoking during pregnancy, prepregnancy body mass index, and anemia. These models were used to calculate benchmark dose values.
Results
Geometric mean cord blood lead was 0.66 μg/dL (95% confidence interval, 0.61–0.70). Comparing blood pressure measurements between those in the highest and those in the lowest quartile of lead exposure, we observed a 6.87-mmHg (1.51–12.21 mmHg) increase in admission systolic blood pressure and a 4.40-mmHg (0.21–8.59 mmHg) increase in admission diastolic blood pressure after adjustment for confounders. Corresponding values for maximum blood pressure increase were 7.72 (1.83–13.60) and 8.33 (1.14–15.53) mmHg. Benchmark dose lower limit values for a 1-SD increase in blood pressure were < 2 μg/dL blood lead for all blood pressure end points.
Conclusions
A significant association between low-level lead exposures and elevations in maternal blood pressure during labor and delivery can be observed at umbilical blood lead levels < 2 μg/dL.
doi:10.1289/ehp.1002666
PMCID: PMC3094418  PMID: 21292600
benchmark dose; blood pressure; hypertension; lead; pregnancy; risk assessment; umbilical cord
6.  The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis 
Fall, Tove | Hägg, Sara | Mägi, Reedik | Ploner, Alexander | Fischer, Krista | Horikoshi, Momoko | Sarin, Antti-Pekka | Thorleifsson, Gudmar | Ladenvall, Claes | Kals, Mart | Kuningas, Maris | Draisma, Harmen H. M. | Ried, Janina S. | van Zuydam, Natalie R. | Huikari, Ville | Mangino, Massimo | Sonestedt, Emily | Benyamin, Beben | Nelson, Christopher P. | Rivera, Natalia V. | Kristiansson, Kati | Shen, Huei-yi | Havulinna, Aki S. | Dehghan, Abbas | Donnelly, Louise A. | Kaakinen, Marika | Nuotio, Marja-Liisa | Robertson, Neil | de Bruijn, Renée F. A. G. | Ikram, M. Arfan | Amin, Najaf | Balmforth, Anthony J. | Braund, Peter S. | Doney, Alexander S. F. | Döring, Angela | Elliott, Paul | Esko, Tõnu | Franco, Oscar H. | Gretarsdottir, Solveig | Hartikainen, Anna-Liisa | Heikkilä, Kauko | Herzig, Karl-Heinz | Holm, Hilma | Hottenga, Jouke Jan | Hyppönen, Elina | Illig, Thomas | Isaacs, Aaron | Isomaa, Bo | Karssen, Lennart C. | Kettunen, Johannes | Koenig, Wolfgang | Kuulasmaa, Kari | Laatikainen, Tiina | Laitinen, Jaana | Lindgren, Cecilia | Lyssenko, Valeriya | Läärä, Esa | Rayner, Nigel W. | Männistö, Satu | Pouta, Anneli | Rathmann, Wolfgang | Rivadeneira, Fernando | Ruokonen, Aimo | Savolainen, Markku J. | Sijbrands, Eric J. G. | Small, Kerrin S. | Smit, Jan H. | Steinthorsdottir, Valgerdur | Syvänen, Ann-Christine | Taanila, Anja | Tobin, Martin D. | Uitterlinden, Andre G. | Willems, Sara M. | Willemsen, Gonneke | Witteman, Jacqueline | Perola, Markus | Evans, Alun | Ferrières, Jean | Virtamo, Jarmo | Kee, Frank | Tregouet, David-Alexandre | Arveiler, Dominique | Amouyel, Philippe | Ferrario, Marco M. | Brambilla, Paolo | Hall, Alistair S. | Heath, Andrew C. | Madden, Pamela A. F. | Martin, Nicholas G. | Montgomery, Grant W. | Whitfield, John B. | Jula, Antti | Knekt, Paul | Oostra, Ben | van Duijn, Cornelia M. | Penninx, Brenda W. J. H. | Davey Smith, George | Kaprio, Jaakko | Samani, Nilesh J. | Gieger, Christian | Peters, Annette | Wichmann, H.-Erich | Boomsma, Dorret I. | de Geus, Eco J. C. | Tuomi, TiinaMaija | Power, Chris | Hammond, Christopher J. | Spector, Tim D. | Lind, Lars | Orho-Melander, Marju | Palmer, Colin Neil Alexander | Morris, Andrew D. | Groop, Leif | Järvelin, Marjo-Riitta | Salomaa, Veikko | Vartiainen, Erkki | Hofman, Albert | Ripatti, Samuli | Metspalu, Andres | Thorsteinsdottir, Unnur | Stefansson, Kari | Pedersen, Nancy L. | McCarthy, Mark I. | Ingelsson, Erik | Prokopenko, Inga
PLoS Medicine  2013;10(6):e1001474.
In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Please see later in the article for the Editors' Summary
Background
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
Methods and Findings
We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.
Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).
Conclusions
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Globally, both the incidence of CVD (the number of new cases in a population every year) and its prevalence (the proportion of the population with CVD) are increasing, particularly in low- and middle-income countries. This increasing burden of CVD is occurring in parallel with a global increase in the incidence and prevalence of obesity—having an unhealthy amount of body fat (adiposity)—and of metabolic diseases—conditions such as diabetes in which metabolism (the processes that the body uses to make energy from food) is disrupted, with resulting high blood sugar and damage to the blood vessels.
Why Was This Study Done?
Epidemiological studies—investigations that record the patterns and causes of disease in populations—have reported an association between adiposity (indicated by an increased body mass index [BMI], which is calculated by dividing body weight in kilograms by height in meters squared) and cardiometabolic traits such as coronary heart disease, stroke, heart failure (a condition in which the heart is incapable of pumping sufficient amounts of blood around the body), diabetes, high blood pressure (hypertension), and high blood cholesterol (dyslipidemia). However, observational studies cannot prove that adiposity causes any particular cardiometabolic trait because overweight individuals may share other characteristics (confounding factors) that are the real causes of both obesity and the cardiometabolic disease. Moreover, it is possible that having CVD or a metabolic disease causes obesity (reverse causation). For example, individuals with heart failure cannot do much exercise, so heart failure may cause obesity rather than vice versa. Here, the researchers use “Mendelian randomization” to examine whether adiposity is causally related to various cardiometabolic traits. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Thus, an investigation of the associations between rs9939609 and cardiometabolic traits can indicate whether obesity is causally related to these traits.
What Did the Researchers Do and Find?
The researchers analyzed the association between rs9939609 (the “instrumental variable,” or IV) and BMI, between rs9939609 and 24 cardiometabolic traits, and between BMI and the same traits using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent. They then quantified the strength of the causal association between BMI and the cardiometabolic traits by calculating “IV estimators.” Higher BMI showed a causal relationship with heart failure, metabolic syndrome (a combination of medical disorders that increases the risk of developing CVD), type 2 diabetes, dyslipidemia, hypertension, increased blood levels of liver enzymes (an indicator of liver damage; some metabolic disorders involve liver damage), and several other cardiometabolic traits. All the IV estimators were similar to the BMI–cardiovascular trait associations (observational estimates) derived from the same individuals, with the exception of diabetes, where the causal estimate was higher than the observational estimate, probably because the observational estimate is based on a single BMI measurement, whereas the causal estimate considers lifetime changes in BMI.
What Do These Findings Mean?
Like all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. Nevertheless, these findings provide support for many previously suspected and biologically plausible causal relationships, such as that between adiposity and hypertension. They also provide new insights into the causal effect of obesity on liver enzyme levels and on heart failure. In the latter case, these findings suggest that a one-unit increase in BMI might increase the incidence of heart failure by 17%. In the US, this corresponds to 113,000 additional cases of heart failure for every unit increase in BMI at the population level. Although additional studies are needed to confirm and extend these findings, these results suggest that global efforts to reduce the burden of obesity will likely also reduce the occurrence of CVD and metabolic disorders.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001474.
The American Heart Association provides information on all aspects of cardiovascular disease and tips on keeping the heart healthy, including weight management (in several languages); its website includes personal stories about stroke and heart attacks
The US Centers for Disease Control and Prevention has information on heart disease, stroke, and all aspects of overweight and obesity (in English and Spanish)
The UK National Health Service Choices website provides information about cardiovascular disease and obesity, including a personal story about losing weight
The World Health Organization provides information on obesity (in several languages)
The International Obesity Taskforce provides information about the global obesity epidemic
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides links to other sources of information on heart disease, on vascular disease, on obesity, and on metabolic disorders (in English and Spanish)
The International Association for the Study of Obesity provides maps and information about obesity worldwide
The International Diabetes Federation has a web page that describes types, complications, and risk factors of diabetes
doi:10.1371/journal.pmed.1001474
PMCID: PMC3692470  PMID: 23824655
7.  Alcohol Intake and Blood Pressure: A Systematic Review Implementing a Mendelian Randomization Approach 
PLoS Medicine  2008;5(3):e52.
Background
Alcohol has been reported to be a common and modifiable risk factor for hypertension. However, observational studies are subject to confounding by other behavioural and sociodemographic factors, while clinical trials are difficult to implement and have limited follow-up time. Mendelian randomization can provide robust evidence on the nature of this association by use of a common polymorphism in aldehyde dehydrogenase 2 (ALDH2) as a surrogate for measuring alcohol consumption. ALDH2 encodes a major enzyme involved in alcohol metabolism. Individuals homozygous for the null variant (*2*2) experience adverse symptoms when drinking alcohol and consequently drink considerably less alcohol than wild-type homozygotes (*1*1) or heterozygotes. We hypothesise that this polymorphism may influence the risk of hypertension by affecting alcohol drinking behaviour.
Methods and Findings
We carried out fixed effect meta-analyses of the ALDH2 genotype with blood pressure (five studies, n = 7,658) and hypertension (three studies, n = 4,219) using studies identified via systematic review. In males, we obtained an overall odds ratio of 2.42 (95% confidence interval [CI] 1.66–3.55, p = 4.8 × 10−6) for hypertension comparing *1*1 with *2*2 homozygotes and an odds ratio of 1.72 (95% CI 1.17–2.52, p = 0.006) comparing heterozygotes (surrogate for moderate drinkers) with *2*2 homozygotes. Systolic blood pressure was 7.44 mmHg (95% CI 5.39–9.49, p = 1.1 × 10−12) greater among *1*1 than among *2*2 homozygotes, and 4.24 mmHg (95% CI 2.18–6.31, p = 0.00005) greater among heterozygotes than among *2*2 homozygotes.
Conclusions
These findings support the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.
Using a mendelian randomization approach Sarah Lewis and colleagues find strong support for the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.
Editors' Summary
Background.
High blood pressure (hypertension) is a common medical condition that affects nearly a third of US and UK adults. Hypertension has no symptoms but can lead to heart attacks or strokes. It is diagnosed by measuring blood pressure—the force that blood moving around the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic pressure) and lowest when it is filling up with blood (diastolic pressure). Normal blood pressure is defined as a systolic pressure of less than 130 millimeters of mercury (mmHg) and a diastolic pressure of less than 85 mmHg (a blood pressure of 130/85). A reading of more than 140/90 indicates hypertension. Many factors affect blood pressure, but overweight people and individuals who eat too much salty or fatty foods are at high risk of developing hypertension. Mild hypertension can often be corrected by lifestyle changes, but many people also take antihypertensive drugs to reduce their blood pressure.
Why Was This Study Done?
Another modifiable lifestyle factor thought to affect blood pressure is alcohol intake. Observational studies that ask people about their drinking habits and measure their blood pressure suggest that alcohol intake correlates with blood pressure, but they cannot prove a causal link because of “confounding”—other risk factors associated with alcohol drinking, such as diet, might also affect the study participant's blood pressures. A trial that randomly assigns people to different alcohol intakes could provide this proof of causality, but such a trial is impractical. In this study, therefore, the researchers have used “Mendelian randomization” to investigate whether alcohol intake affects blood pressure. An inactive variant of aldehyde dehydrogenase 2 (ALDH2; the enzyme that removes alcohol from the body) has been identified. People who inherit the variant form of this gene from both parents have an ALDH2 *2*2 genotype (genetic makeup) and become flushed and nauseated after drinking. Consequently, they drink less than people with a *1*2 genotype and much less than those with a *1*1 genotype. Because inheritance of these genetic variants does not affect lifestyle factors other than alcohol intake, an association between ALDH2 genotypes and blood pressure would indicate that alcohol intake has an effect on blood pressure without any confounding.
What Did the Researchers Do and Find?
The researchers identified ten published studies (mainly done in Japan where the ALDH2 gene variant is common) on associations between ALDH2 genotype and blood pressure or hypertension using a detailed search protocol (a “systematic review”). A meta-analysis (a statistical method for combining the results of independent studies) of the studies that had investigated the association between ALDH2 genotype and hypertension showed that men with the *1*1 genotype (highest alcohol intake) and those with the *1*2 genotype (intermediate alcohol intake) were 2.42 and 1.72 times more likely, respectively, to have hypertension than those with the *2*2 genotype (lowest alcohol intake). There was no association between ALDH2 genotype and hypertension among the women in these studies because they drank very little. Systolic and diastolic blood pressures showed a similar relationship to ALDH2 genotype in a second meta-analysis of relevant studies. Finally, the researchers estimated that for men the lifetime effect of drinking 1 g of alcohol a day (one unit of alcohol contains 8 g of alcohol in the UK and 14 g in the US; recommended daily limits in these countries are 3–4 and 1–2 units, respectively) would be an increase in systolic blood pressure of 0.24 mmHg.
What Do These Findings Mean?
These findings support the suggestion that alcohol has a marked effect on blood pressure and hypertension. Consequently, some cases of hypertension could be prevented by encouraging people to reduce their daily alcohol intake. Although the Mendelian randomization approach avoids most of the confounding intrinsic to observational studies, it is possible that a gene near ALDH2 that has no effect on alcohol intake affects blood pressure, since genes are often inherited in blocks. Alternatively, ALDH2 could affect blood pressure independent of alcohol intake. The possibility that ALDH2 could effect blood pressure independently of alcohol is intake made unlikely by the fact that no effect of genotype on blood pressure is seen among women who drink very little. Additional large-scale studies are needed to address these possibilities, to confirm the current finding in more people, and to improve the estimates of the effect that alcohol intake has on blood pressure.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050052.
The MedlinePlus encyclopedia has a page on hypertension (in English and Spanish)
The American Heart Association provides information for patients and health professionals about hypertension
The UK Blood Pressure Association provides information for patients and health professionals on all aspects of hypertension, including information about alcohol affects blood pressure
The Explore@Bristol science center (a UK charity) provides an alcohol unit calculator and information on the effects of alcohol
The International Center for Alcohol Policies provides drinking guidelines for countries around the world
doi:10.1371/journal.pmed.0050052
PMCID: PMC2265305  PMID: 18318597
8.  The relation between occupational exposure to lead and blood pressure among employed normotensive men 
Background:
Lead is a pollutant with numerous adverse effects on health. Since it can affect blood pressure, peripheral blood vessels, and the heart, the present study aimed to evaluate the relation between occupational exposure to lead and blood pressure.
Materials and Methods:
This cross-sectional study included male individuals working in battery firms in Isfahan. A questionnaire covering demographic characteristics and the history of different diseases and occupational exposure to lead was completed. Each participant's blood pressure was also measured and recorded. After obtaining blood samples and determining lead levels, mean and frequency analyses were performed. In addition, Pearson's correlation test and linear regression were used to assess the relation between blood lead levels (BLLs) and systolic and diastolic blood pressure. All analyses were performed in SPSS.19
Results:
The mean age of the 182 studied workers was 42.85 ± 13.65 years. They had worked in battery firms for a mean period of 23.67 ± 14.72 years. Moreover, the mean value of BLLs among the participants was 7.92 ± 3.44 μg/dL. Correlation between BLL and systolic and diastolic blood pressure was not significant. The effects of lead on systolic and diastolic blood pressure after stepwise regression were B = –0.327 [confidence interval (CI) 95%: –0.877 to 0.223] and B = –0.094 (CI 95%: –0.495 to 0.307), respectively.
Conclusion:
This study revealed that BLLs in battery firm workers to be normal. Additionally, BLLs were not significantly related with either systolic or diastolic blood pressure which might have been the result of normal BLLs.
PMCID: PMC4155701  PMID: 25197288
Hypertension; lead; occupational exposure
9.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Objective
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Design
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Results
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Conclusions
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
doi:10.1542/peds.2006-0092
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
10.  Noise exposure as a risk factor of cardiovascular diseases in workers 
Introduction:
Workers in different jobs are exposed to noise, which can affect hearing loss and sleep disturbance in the long term. Excessive noise exposure may lead to increased blood pressure, reduced efficiency, and increased absenteeism.
Materials and Methods:
In this case-control study, 80 workers were studied in terms of noise exposure and blood pressure. Noise exposure was measured by SEL 440 sound level meters according to ISO 1996 standard. Blood pressure of the case and control groups was measured in workplace, under standard circumstances, using ALPK2 mercury sphygmomanometer during physical examination. Data were analyzed by t-test and Pearson's correlation coefficient.
Results:
Mean level of noise was 95.21 ± 2.56 db, which was significantly higher than permitted limit of 85 db (ACGIH 2009) (P < 0.01). Diastolic blood pressure was normal in 28.8% and high in 50.1%, and between these in 21.1% of workers. Mean difference of systolic blood pressure in two studied groups (P < 0.01) was meaningful. However, mean difference of diastolic blood pressure was not significant in two studied groups (P > 0.05). There was a positive and weak relationship between noise and systolic blood pressure (r = 0.28, P < 0.006).
Conclusion:
Prolonged exposure to industrial noise is related with high blood pressure as a risk factor of cardiovascular diseases. Therefore, it is recommended that training programs be held for workers, preventive measures for noise exposure at workplace be taken, blood pressure of workers be attended to and special care be given to workers with a history of hypertension.
doi:10.4103/2277-9531.112683
PMCID: PMC3778583  PMID: 24083264
Cardiovascular diseases; hypertension; Isfahan industry; noise; occupational exposure; workers
11.  Conventional versus automated measurement of blood pressure in primary care patients with systolic hypertension: randomised parallel design controlled trial 
Objective To compare the quality and accuracy of manual office blood pressure and automated office blood pressure using the awake ambulatory blood pressure as a gold standard.
Design Multi-site cluster randomised controlled trial.
Setting Primary care practices in five cities in eastern Canada.
Participants 555 patients with systolic hypertension and no serious comorbidities under the care of 88 primary care physicians in 67 practices in the community.
Interventions Practices were randomly allocated to either ongoing use of manual office blood pressure (control group) or automated office blood pressure (intervention group) using the BpTRU device. The last routine manual office blood pressure (mm Hg) was obtained from each patient’s medical record before enrolment. Office blood pressure readings were compared before and after enrolment in the intervention and control groups; all readings were also compared with the awake ambulatory blood pressure.
Main outcome measure Difference in systolic blood pressure between awake ambulatory blood pressure minus automated office blood pressure and awake ambulatory blood pressure minus manual office blood pressure.
Results Cluster randomisation allocated 31 practices (252 patients) to manual office blood pressure and 36 practices (303 patients) to automated office blood pressure measurement. The most recent routine manual office blood pressure (149.5 (SD 10.8)/81.4 (8.3)) was higher than automated office blood pressure (135.6 (17.3)/77.7 (10.9)) (P<0.001). In the control group, routine manual office blood pressure before enrolment (149.9 (10.7)/81.8 (8.5)) was reduced to 141.4 (14.6)/80.2 (9.5) after enrolment (P<0.001/P=0.01), but the reduction in the intervention group from manual office to automated office blood pressure was significantly greater (P<0.001/P=0.02). On the first study visit after enrolment, the estimated mean difference for the intervention group between the awake ambulatory systolic/diastolic blood pressure and automated office blood pressure (−2.3 (95% confidence interval −0.31 to −4.3)/−3.3 (−2.7 to −4.4)) was less (P=0.006/P=0.26) than the difference in the control group between the awake ambulatory blood pressure and the manual office blood pressure (−6.5 (−4.3 to −8.6)/−4.3 (−2.9 to −5.8)). Systolic/diastolic automated office blood pressure showed a stronger (P<0.001) within group correlation (r=0.34/r=0.56) with awake ambulatory blood pressure after enrolment compared with manual office blood pressure versus awake ambulatory blood pressure before enrolment (r=0.10/r= 0.40); the mean difference in r was 0.24 (0.12 to 0.36)/0.16 (0.07 to 0.25)). The between group correlation comparing diastolic automated office blood pressure and awake ambulatory blood pressure (r=0.56) was stronger (P<0.001) than that for manual office blood pressure versus awake ambulatory blood pressure (r=0.30); the mean difference in r was 0.26 (0.09 to 0.41). Digit preference with readings ending in zero was substantially reduced by use of automated office blood pressure.
Conclusion In compliant, otherwise healthy, primary care patients with systolic hypertension, introduction of automated office blood pressure into routine primary care significantly reduced the white coat response compared with the ongoing use of manual office blood pressure measurement. The quality and accuracy of automated office blood pressure in relation to the awake ambulatory blood pressure was also significantly better when compared with manual office blood pressure.
Trial registration Clinical trials NCT 00214053.
doi:10.1136/bmj.d286
PMCID: PMC3034423  PMID: 21300709
12.  Plasma lipid profile in Nigerians with high - normal blood pressure 
BMC Research Notes  2014;7(1):930.
Background
High blood pressure levels have been associated with elevated atherogenic blood lipid fraction, but epidemiological surveys often give inconsistent results across population sub-groups. To determine the extent to which there are differences in lipid profile based on blood pressure levels, we assessed lipid profile of subjects with high-normal blood pressure and compared with those of hypertensives and optimally normal blood pressure.
Methods
The study was a cross–sectional comparative study conducted at Aminu Kano Teaching Hospital, Kano, Nigeria. Fasting lipid levels were examined among randomly selected patients with optimally normal blood pressure (group 1), high – normal blood pressure (group 2) and those with hypertension (group 3). Optimal blood pressure was defined as systolic blood pressure (SBP) of < 120 mmHg/or diastolic blood pressure (DBP) of < 80 mmHg; and high- normal blood pressure as SBP of 130 – 139 mmHg and/or DBP of 85 – 89 mmHg.
Results
A total of 300 subjects were studied, 100 in each group. The mean age of subjects in group 1 was 27.32 ± 8.20 years and 60% were female, while that of group 2 was 34.04 ± 6.25 years, and 53% were female, and that for group 3 was 52.81 ± 13.3 years and 56% were female. The mean total cholesterol (TC) for subjects in group1 (3.96 ± 0.40 mmol/L) was significantly lower than levels in group2 (4.55 ± 1.01 mmol/L); P = <0.001. Subjects in group 3 (5.20 ± 1.88 mmol/L), however had statistically significant higher mean TC when compared with group 2; (P = 0.03). The difference between the groups for low density lipoprotein cholesterol (LDL-C) and triglycerides (TG) followed the same pattern as that of TC, with statistically significant increasing trend across the blood pressure categories. Levels of high density lipoprotein cholesterol (HDL-C) were however similar across the three groups (group 2 versus group 1; P = 0.49, group 2 versus group 3; P = 0.9). Increased TC (>5.2 mmol/L) was absent in group1, but found among 11% of group2 subjects and 40% of those in group 3 (P-value for trend <0.001). Mean fasting plasma glucose (FPG) was 3.8 ± 0.4 mmol/L, 4.7 ± 1.1 mmol/L, 5.1 ± 1.9 mmol/L and for subjects in groups 1, 2 and 3 respectively (p > 0.05 for groups 2 Vs 1 and p <0.001 for groups 2 Vs 3). The differences in mean body mass index (BMI) between the groups followed a similar trend as that of FPG. Multivariate logistic regression analysis showed that FPG, TG and BMI were the strongest predictors of prehypertension [odds ratio (OR) 10.14, 95% CI (confidence interval) 3.63 – 28.33, P = 0.000; OR 5.75, 95% CI 2.20 – 15.05, P = 0.000; and OR 2.03, 95% CI 1.57 – 2.62, P = 0.000 respectively].
Conclusion
The study has shown a significant increase in plasma TC, LDL-C and TG values as blood pressure levels increased from optimally normal, across high-normal to hypertensive levels. There was a similar trend for FPG and BMI, demonstrating the central role that blood pressure plays in these metabolic disorders in Nigerians. These findings are relevant in terms of both prevention and treatment of cardiovascular morbidities and mortality.
doi:10.1186/1756-0500-7-930
PMCID: PMC4301796  PMID: 25522744
High-normal blood pressure; Plasma lipids; Nigerians
13.  Urinary cadmium and blood pressure: results from the NHANES II survey. 
Relationships between urinary cadmium levels and blood pressure were examined in a sample of 951 adult men and women who participated in the Second National Health and Nutritional Examination Survey (NHANES II). Among all participants, positive relationships were seen between urinary cadmium levels and both systolic and diastolic blood pressure (p less than 0.05 and p less than 0.01, respectively), after adjusting for age, sex, race, relative body weight, smoking status, and hypertensive medication use. However, analyses for subgroups determined by sex and smoking status were inconsistent. Among current smokers, urinary cadmium levels were significantly positively associated with both systolic and diastolic blood pressure for women, and with diastolic blood pressure for men. Yet among former smokers and lifelong nonsmokers of both sexes, urinary cadmium was not significantly associated with either systolic or diastolic blood pressure. Evidence that some hypertensive medications increase urinary cadmium excretion suggests that the positive associations seen among current smokers may reflect high urinary cadmium levels among hypertensives induced by hypertensive treatment. After treated hypertensives were removed from the analysis, regression coefficients relating blood pressure to cadmium dropped by a factor of two and lost statistical significance. We conclude that the present data provide little support for a causal association between systemic cadmium and hypertension at nonoccupational exposure levels. Further, conflicting results of previous studies may reflect failure to control adequately for age, smoking status, and hypertensive treatment.
PMCID: PMC1519365  PMID: 2040243
14.  Effects of exposure to carbon disulphide on low density lipoprotein cholesterol concentration and diastolic blood pressure. 
The relation of carbon disulphide (CS2) exposure to risk factors for ischaemic heart disease was recently examined using data from a 1979 cross sectional study of 410 male textile workers, of whom 165 were exposed and 245 were unexposed to CS2. Average eight hour CS2 exposure concentrations ranged from 0.6 to 11.8 ppm by job title category among the exposed workers. A significant and positive linear trend in low density lipoprotein cholesterol concentration (LDLc) and diastolic blood pressure with increasing CS2 exposure was found after adjustment for potential confounders. When exposure was examined as a categorical variable (none, low, moderate, and high), the high exposure group had an adjusted mean LDLc that was 0.32 mmol/l greater than the non-exposed group (p = 0.02), and an adjusted mean diastolic blood pressure that was 3.16 mm Hg greater than the non-exposed group (p = 0.09). The effect of CS2 on diastolic blood pressure was strengthened in analyses limited to exposed workers: the high exposure group had an adjusted mean diastolic blood pressure that was 5 mm Hg greater than that of the low exposed group (p = 0.03). Triglyceride, high density lipoprotein cholesterol, and fasting glucose concentration, and systolic blood pressure were not affected by exposure. Blood lead concentration was positively associated with systolic and diastolic blood pressure. The results indicate that relatively modest exposure to CS2 may raise LDLc concentration and diastolic blood pressure and suggest mechanisms by which exposure to CS2 may influence risk of ischaemic heart disease. Also the results provide further support for the hypothesis of a possible association between blood lead concentration and blood pressure.
PMCID: PMC1012112  PMID: 1571299
15.  The Effect of Chelation on Blood Pressure in Lead-Exposed Children: A Randomized Study 
Environmental Health Perspectives  2006;114(4):579-583.
Studies in children suggest a weak association between blood lead concentration and blood pressure. To understand this better, we tested the strength of the association in children with elevated blood lead concentrations and whether succimer chelation changed blood pressure as it did blood lead. In a randomized clinical trial of 780 children with blood lead concentrations of 20–44 μg/dL at 12–33 months of age, we compared the systolic and diastolic blood pressure in the succimer-treated group and placebo group for up to 5 years of follow-up. We also analyzed the relation of blood lead to blood pressure. Children in the succimer group had lower blood lead concentrations for 9–10 months during and after treatment, but their blood pressure did not differ from those in the placebo group during this period. During 1–5 years of follow-up, children in the succimer group had systolic blood pressure 1.09 (95% confidence interval, 0.27–1.90) mmHg higher than did untreated children in a model with repeated measurements, but the difference in diastolic blood pressure was not statistically significant. No association between blood lead and blood pressure was found. Overall, there is no association between blood lead and blood pressure in these children with moderately high lead exposure, nor does chelation with succimer change blood pressure.
doi:10.1289/ehp.8634
PMCID: PMC1440784  PMID: 16581549
blood pressure; chelation; child; lead; succimer
16.  Alcohol and blood pressure: the INTERSALT study. 
BMJ : British Medical Journal  1994;308(6939):1263-1267.
OBJECTIVES--To assess the relation between alcohol intake and blood pressure in men and women and in men at younger and older ages; to examine the influence of amount and pattern of alcohol consumption, as well as of acute effects, taking into account body mass index, smoking, and urinary sodium and potassium excretion. DESIGN--Subjects reported alcohol consumption for each of seven days before standardised blood pressure measurement, and whether they had consumed any alcohol in the 24 hours before measurement. SETTING--50 centres worldwide. SUBJECTS--4844 men and 4837 women aged 20-59. MAIN OUTCOME MEASURES--Effect of alcohol on blood pressure estimated by taking a weighted average of regression coefficients from centres. Acute effect assessed by examining mean differences in blood pressure of non-drinkers and of heavy drinkers who had and had not consumed alcohol in the 24 hours before measurement. Effect of pattern of consumption assessed by examining mean differences in blood pressure of non-drinkers compared with drinkers (i) whose intake was concentrated in fewer days or who were drinking more frequently, and (ii) whose alcohol intake varied little over the seven days or varied more substantially, as indicated by the standard deviation of daily consumption. RESULTS--Of the 48 centres in which some people reported consuming at least 300 ml/week of alcohol, 35 had positive regression coefficients linking heavy alcohol consumption to blood pressure. Overall, alcohol consumption was associated with blood pressure, significantly at the highest intake. After account was taken of key confounders, men who drank 300-499 ml alcohol/week had systolic/diastolic blood pressure on average 2.7/1.6 mmHg higher than non-drinkers, and men who drank > or = 500 ml alcohol/week had pressures of 4.6/3.0 mmHg higher. For women, heavy drinkers (> or = 300 ml/week) had blood pressures higher by 3.9/3.1 mmHg than non-drinkers. Heavy drinking and blood pressure were strongly associated in both sexes, and in men at both younger (20-39 years) and older (40-59 years) ages. In men who were heavy drinkers, episodic drinkers (those with great variation in daily alcohol consumption) had greater differences in blood pressure compared with non-drinkers than did regular drinkers of relatively constant amounts. CONCLUSION--The significant relation of heavy drinking (3-4 or more drinks/day) to blood pressure, observed in both men and women, and in younger and older men, was independent of and added to the effect on blood pressure of body mass index and urinary excretion of sodium and potassium. The findings indicate the usefulness of targeting those at high risk as well as the general population to reduce the adverse effects of alcohol on blood pressure.
PMCID: PMC2540174  PMID: 7802765
17.  Blood lead concentration, renal function, and blood pressure in London civil servants. 
Blood lead concentration was measured in 398 male and 133 female London civil servants not subject to industrial exposure to heavy metals. The relation between blood lead and serum creatinine concentrations and blood pressure were examined. Blood lead concentration ranged from 0.20 to 1.70 mumol/l with a geometric mean concentrations of 0.58 mumol/l in men and 0.46 mumol/l in women (p less than 0.001). In women blood lead concentration increased with age (r = +0.27; p = 0.002). In the two sexes blood lead concentration was positively correlated with the number of cigarettes smoked a day (men r = +0.17 and women r = +0.22; p less than or equal to 0.01), with the reported number of alcoholic beverages consumed a day (men r = +0.34 and women r = 0.23; p less than 0.01), and with serum gamma-glutamyltranspeptidase (men r = +0.23 and women r = +0.14; for men p less than 0.01). Blood lead concentration was not correlated with body weight, body mass index, and employment grade. In men 14% of the variance of blood lead concentration was explained by the significant and independent contributions of smoking and alcohol intake and in women 16% by age, smoking, and alcohol consumption. In men serum creatinine concentration tended to rise by 0.6 mumol/l (95% confidence interval from -0.2 to +1.36 mumol/l) for each 25% increment in blood lead concentration. In men and women the correlations between blood lead concentration and systolic and diastolic blood did not approach statistical significance. In conclusion, in subjects not exposed to heavy metals at work gender, age, smoking, and alcohol intake are determinants of blood lead concentration. At a low level of exposure, lead accumulation may slightly impair renal function, whereas blood pressure does not seem to be importantly influenced. Alternatively, a slight impairment of renal function may give rise to an increase in blood lead concentration.
PMCID: PMC1035204  PMID: 1974456
18.  Lifestyle modifications to prevent and control hypertension. 5. Recommendations on dietary salt. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada 
OBJECTIVE: To provide updated, evidence-based recommendations concerning the effects of dietary salt intake on the prevention and control of hypertension in adults (except pregnant women). The guidelines are intended for use in clinical practice and public education campaigns. OPTIONS: Restriction of dietary salt intake may be an alternative to antihypertensive medications or may supplement such medications. Other options include other nonpharmacologic treatments for hypertension and no treatment. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: A MEDLINE search was conducted for the period 1966-1996 using the terms hypertension, blood pressure, vascular resistance, sodium chloride, sodium, diet, sodium or sodium chloride dietary, sodium restricted/reducing diet, clinical trials, controlled clinical trial, randomized controlled trial and random allocation. Both trials and review articles were obtained, and other relevant evidence was obtained from the reference lists of the articles identified, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design and graded according to level of evidence. In addition, a systematic review of all published randomized controlled trials relating to dietary salt intake and hypertension was conducted. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS, HARMS AND COSTS: For normotensive people, a marked change in sodium intake is required to achieve a modest reduction in blood pressure (there is a decrease of 1 mm Hg in systolic blood pressure for every 100 mmol decrease in daily sodium intake). For hypertensive patients, the effects of dietary salt restriction are most pronounced if age is greater than 44 years. A decrease of 6.3 mm Hg in systolic blood pressure and 2.2 mm Hg in diastolic blood pressure per 100 mmol decrease in daily sodium intake was observed in people of this age group. For hypertensive patients 44 years of age and younger, the decreases were 2.4 mm Hg for systolic blood pressure and negligible for diastolic blood pressure. A diet in which salt is moderately restricted appears not to be associated with health risks. RECOMMENDATIONS: (1) Restriction of salt intake for the normotensive population is not recommended at present, because of insufficient evidence demonstrating that this would lead to a reduced incidence of hypertension. (2) To avoid excessive intake of salt, people should be counselled to choose foods low in salt (e.g., fresh fruits and vegetables), to avoid foods high in salt (e.g., pre-prepared foods), to refrain from adding salt at the table and minimize the amount of salt used in cooking, and to increase awareness of the salt content of food choices in restaurants. (3) For hypertensive patients, particularly those over the age of 44 years, it is recommended that the intake of dietary sodium be moderately restricted, to a target range of 90-130 mmol per day (which corresponds to 3-7 g of salt per day). (4) The salt consumption of hypertensive patients should be determined by interview. VALIDATION: These recommendations were reviewed by all of the sponsoring organizations and by participants in a satellite symposium of the fourth International Conference on Preventive Cardiology. They have not been clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada.
PMCID: PMC1230337  PMID: 10333851
19.  Trust in Physicians and Blood Pressure Control in Blacks and Whites Being Treated for Hypertension in the Regards Study 
Ethnicity & disease  2010;20(3):282-289.
Objectives
Among persons treated for hypertension, Blacks are more likely to have uncontrolled blood pressure compared to Whites. Few studies have focused on trust in physicians as a potential contributor to this disparity in blood pressure (BP) control. The primary objective of this study was to assess the relationship between trust in physicians and blood pressure control among Blacks and Whites being treated for hypertension.
Design
Cross-sectional analysis of baseline data collected from the REasons for Geographic And Racial Differences in Stroke cohort, a US national, population-based cohort study. Participants were recruited by telephone from 2003–2007, completed a telephone survey, and had BP measured during an in-home visit.
Participants
2843 Black and White adults aged >45 years with treated hypertension.
Main Outcome Measures
Uncontrolled blood pressure was defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg. For participants with diabetes, renal disease, or self-reported previous myocardial infarction, uncontrolled blood pressure was defined as systolic blood pressure >130 mm Hg or diastolic blood pressure >80 mm Hg.
Results
Trust in physicians was not associated with uncontrolled blood pressure in either unadjusted (odd ratio [OR] 1.07; 95% confidence interval [CI] 0.92, 1.25) or adjusted analyses (OR 0.97; 0.83, 1.14). Both Black race (OR 1.58; 1.36, 1.84) and imperfect medication adherence (OR 1.56; 1.31, 1.86) were associated with higher odds of uncontrolled blood pressure.
Conclusions
Trust in physicians was not related to blood pressure control among Blacks and Whites with treated hypertension in this sample. The racial disparity in blood pressure control was not completely explained by trust in physicians or medication adherence, and a better understanding of the mechanisms leading to this disparity is needed.
PMCID: PMC3049916  PMID: 20828103
Hypertension; Trust; Disparities
20.  The Influence of Health Systems on Hypertension Awareness, Treatment, and Control: A Systematic Literature Review 
PLoS Medicine  2013;10(7):e1001490.
Will Maimaris and colleagues systematically review the evidence that national or regional health systems, including place of care and medication co-pays, influence hypertension awareness, treatment, and control.
Please see later in the article for the Editors' Summary
Background
Hypertension (HT) affects an estimated one billion people worldwide, nearly three-quarters of whom live in low- or middle-income countries (LMICs). In both developed and developing countries, only a minority of individuals with HT are adequately treated. The reasons are many but, as with other chronic diseases, they include weaknesses in health systems. We conducted a systematic review of the influence of national or regional health systems on HT awareness, treatment, and control.
Methods and Findings
Eligible studies were those that analyzed the impact of health systems arrangements at the regional or national level on HT awareness, treatment, control, or antihypertensive medication adherence. The following databases were searched on 13th May 2013: Medline, Embase, Global Health, LILACS, Africa-Wide Information, IMSEAR, IMEMR, and WPRIM. There were no date or language restrictions. Two authors independently assessed papers for inclusion, extracted data, and assessed risk of bias. A narrative synthesis of the findings was conducted. Meta-analysis was not conducted due to substantial methodological heterogeneity in included studies. 53 studies were included, 11 of which were carried out in LMICs. Most studies evaluated health system financing and only four evaluated the effect of either human, physical, social, or intellectual resources on HT outcomes. Reduced medication co-payments were associated with improved HT control and treatment adherence, mainly evaluated in US settings. On balance, health insurance coverage was associated with improved outcomes of HT care in US settings. Having a routine place of care or physician was associated with improved HT care.
Conclusions
This review supports the minimization of medication co-payments in health insurance plans, and although studies were largely conducted in the US, the principle is likely to apply more generally. Studies that identify and analyze complexities and links between health systems arrangements and their effects on HT management are required, particularly in LMICs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, one billion people, three-quarters of whom were living in low- and middle-income countries, had high blood pressure (hypertension). Worldwide, hypertension, which rarely has any symptoms, leads to about 7.5 million deaths annually from heart attacks, stroke, other cardiovascular diseases, and kidney disease. Hypertension, selected by the World Health Organization as the theme for World Health Day 2013, 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 contracts to pump blood out (systolic blood pressure) and lowest when the heart relaxes and refills (diastolic blood pressure). Normal adult blood pressure is defined as a systolic blood pressure of less than 120 millimeters of mercury (mmHg) and a diastolic blood pressure of less than 80 mmHg (a blood pressure of less than 120/80 mmHg). A blood pressure reading of more than 140/90 mmHg indicates hypertension. Many factors affect blood pressure, but overweight people and individuals who eat fatty or salty foods are at high risk of developing hypertension.
Why Was This Study Done?
Most individuals can achieve good hypertension control, which reduces death and disability from cardiovascular and kidney disease, by making lifestyle changes (mild hypertension) and/or by taking antihypertensive drugs. Yet, in both developed and developing countries, many people with hypertension are not aware of their condition and are not adequately treated. As with other chronic diseases, weaknesses in health care systems probably contribute to the inadequate treatment of hypertension. A health care system comprises all the organizations, institutions, and resources whose primary purpose is to improve health. Weaknesses in health care systems can exist at the national, regional, district, community, and household level. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers investigate how national and regional health care system arrangements influence hypertension awareness, treatment, and control. Actions that might influence hypertension care at this level of health care systems include providing treatment for hypertension at no or reduced cost, the introduction of financial incentives to healthcare practitioners for the diagnosis and treatment of hypertension, and enhanced insurance coverage in countries such as the US where people pay for health care through insurance policies.
What Did the Researchers Do and Find?
The researchers identified 53 studies that analyzed whether regional or national health care systems arrangements were associated with patient awareness of hypertension, treatment of hypertension, adherence to antihypertensive medication treatment, and control of hypertension. The researchers used an established conceptual framework for health care systems and an approach called narrative synthesis to analyze the results of these studies, most of which were conducted in the US (36 studies) and other high-income countries (eight studies). Nearly all the studies evaluated the effects of health system financing on hypertension outcomes, although several looked at the effects of delivery and governance of health systems on these outcomes. The researchers' analysis revealed an association between reduced medication co-payments (drug costs that are not covered by health insurance and that are paid by patients in countries without universal free healthcare) and improved hypertension control and treatment adherence, mainly in US settings. In addition, in US settings, health insurance coverage was associated with improved hypertension outcomes, as was having a routine physician or place of care.
What Do These Findings Mean?
These findings suggest that minimizing co-payments for health care and expansion of health insurance coverage in countries without universal free health care may improve the awareness, treatment, and control of hypertension. Although these findings are based mainly on US studies, they are likely to apply more generally but, importantly, these findings indicate that additional, high-quality studies are needed to unravel the impact of health systems arrangements on the management of hypertension. In particular, they reveal few studies in low- and middle-income countries where most of the global burden of hypertension lies and where weaknesses in health systems often result in deficiencies in the care of chronic diseases. Moreover, they highlight a need for studies that evaluate how aspects of health care systems other than financing (for example, delivery and governance mechanisms) and interactions between health care system arrangements affect hypertension outcomes. Without the results of such studies, governments and national and international organizations will not know the best ways to deal effectively with the global public-health crisis posed by hypertension.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001490.
The US National Heart Lung and Blood Institute has patient information about high blood pressure (in English and Spanish)
The American Heart Association provides information on high blood pressure (in several languages) and personal stories about dealing with high blood pressure
The UK National Health Service (NHS) Choices website provides detailed information for patients about hypertension and a personal story about hypertension
The World Health Organization provides information on controlling blood pressure and on health systems (in several languages); its "A Global Brief on Hypertension" was published on World Health Day 2013
MedlinePlus provides links to further information about high blood pressure (in English and Spanish)
doi:10.1371/journal.pmed.1001490
PMCID: PMC3728036  PMID: 23935461
21.  Is blood pressure reduction a valid surrogate endpoint for stroke prevention? an analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the biomarker-surrogacy (BioSurrogate) evaluation schema (BSES) 
Background
Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit.
Methods
We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3).
Results
In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure.
Conclusions
In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design.
doi:10.1186/1471-2288-12-27
PMCID: PMC3388460  PMID: 22409774
Blood pressure; Stroke; Surrogate Endpoint; Biomarker
22.  Secular Trends in BMI and Blood Pressure Among Children and Adolescents: The Bogalusa Heart Study 
Pediatrics  2012;130(1):e159-e166.
OBJECTIVE:
The prevalence of obesity among children and adolescents increased by almost threefold from the 1970s to 2000. We examined whether these secular changes in BMI were accompanied by increases in blood pressure levels.
METHODS:
A total of 24 092 examinations were conducted among 11 478 children and adolescents (aged 5–17 years) from 1974 to 1993 in the Bogalusa Heart Study (Louisiana).
RESULTS:
The prevalence of obesity increased from 6% to 17% during this period. In contrast, only small changes were observed in levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP), and neither mean nor high (based on the 90th percentile from the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents) levels increased over the 20-year period. Within each race–gender group, mean levels of SBP did not change, whereas mean levels of DBP decreased by 2 mm Hg (P < .001 for trend). Levels of BMI were positively associated with levels of SBP and DBP within each of the 7 examinations, and controlling for BMI (along with other covariates) indicated that only ∼60% as many children as expected had high levels of blood pressure in 1993.
CONCLUSIONS:
Our finding that levels of DBP and SBP among children in this large sample did not increase despite the increases that were seen in obesity indicates that changes in blood pressure levels in a population do not necessarily parallel changes in obesity. Additional study of the potential characteristics that have ameliorated the expected increase in high blood pressure could lead to further reductions in risk.
doi:10.1542/peds.2011-3302
PMCID: PMC3382918  PMID: 22665416
BMI; children; DBP; hypertension; obesity; SBP; secular trends
23.  Blood Pressure Levels in Male Carriers of Arg82Cys in CD300LG 
PLoS ONE  2014;9(10):e109646.
The genetics of hypertension has been scrutinized in large-scale genome-wide association studies (GWAS) with a large number of common genetic variants identified, each exerting subtle effects on disease susceptibility. An amino acid polymorphism, p.Arg82Cys, in CD300LG was recently found to be associated with fasting HDL-cholesterol and triglyceride levels. The polymorphism has not been detected in hypertension GWAS potentially due to its low frequency, but CD300LG has been linked to blood pressure as CD300LG knockout mice have changes in blood pressure. Twenty-four-hour ambulatory blood pressure was obtained in human CD300LG CT-carriers to follow up on these observations.
Methods
Twenty healthy male CD300LG rs72836561 CT-carriers matched for age and BMI with 20 healthy male CC-carriers. Office blood pressure, 24-hour ambulatory blood pressure, carotid intima-media thickness (CIMT), and fasting blood samples were evaluated. The clinical study was combined with a genetic-epidemiological study to replicate the association between blood pressure and CD300LG Arg82Cys in 2,637 men and 3,249 women.
Results
CT-carriers had a higher 24-hour ambulatory systolic blood pressure (122 mmHg versus 115; p = 0.01) and diastolic blood pressure (77 mmHg versus 72; p<0.01) compared with CC-carriers. There were no differences in CIMT between the two groups. Metalloproteinase-9 level was higher in CT-carriers than in CC-carriers (P<0.01). However, no association between office blood pressure and CD300LG genotype was detected in the genetic-epidemiological study.
Conclusions
Although 24-hour blood pressure, measured with a sensitive method, in a small sample of CD300LG rs72836561 CT-carriers was higher than in CC-carriers, this did not translate into significant differences in office blood pressure in a larger cohort. This discrepancy which may reflect differences in methodological approach, underlines the importance of performing replication studies in a larger clinical context, but a formal rejection of a relation between blood pressure and CD300LG requires measurement of 24-hour ambulatory blood pressure in a larger cohort.
doi:10.1371/journal.pone.0109646
PMCID: PMC4196928  PMID: 25314291
24.  Validation of self diagnosis of high blood pressure in a sample of the Spanish EPIC cohort: overall agreement and predictive values 
STUDY OBJECTIVE—High blood pressure is a variable related to several chronic conditions whose repeated measurement in large cohort studies is often not feasible having to rely on the self reporting of the subjects. The aim of the study is to validate such self diagnosis in a sample of members from the Spanish EPIC cohort study.
DESIGN—Comparison of high blood pressure self diagnosis with the information provided by the personal medical record drawn from the primary health centre of reference for such population.
SETTING—A small town near the EPIC-Murcia centre, one of five Spanish EPIC centres located in the south east, where inclusion in the cohort was offered to the general population.
PARTICIPANTS—The agreement between self reported high blood pressure status and data from medical records was measured in a representative sample of men and women (n= 248) aged 30-69 years. Medical records were studied for a diagnosis of high blood pressure, an anti-hypertensive pharmacological treatment or subject's inclusion in a hypertension control programme run in the medical centre only for hypertensive people (definite high blood pressure cases). As well, in the absence of such a diagnosis, medical annotations of systolic or diastolic high blood pressure⩾ 140/90 mm Hg (possible high blood pressure cases) were considered. Sensitivity, specificity, positive and negative predictive values and κ scores were calculated for all, definite and possible high blood pressure cases. Variables associated with the probability of having a true positive or negative self report of high blood pressure were also tested.
MAIN RESULTS—As expected, sensitivity was higher among definite cases (72.7%) than among possible cases (31.6%). Accordingly, the agreement between self report and medical record was higher for definite cases (κ = 0.65) than for possible (κ = 0.29) cases leading to a moderate overall agreement for all cases (κ = 0.58; 95% CI: 0.47, 0.69). Having some level of education (OR: 0.31; 95% CI: 0.09, 1.05) was negatively associated to a true self report of high blood pressure while being female was positively associated (OR: 4.01; 95% CI: 1.04, 16.8). No variable showed any association with having a true self report of being normotensive.
CONCLUSIONS—High blood pressure self report shows a moderate agreement with medical information in this cohort allowing it to be used, with caution, as a surrogate variable of actual blood pressure status. However, because of its moderate sensitivity, it is not possible to rule out some underestimation when using self reported high blood pressure information for high blood pressure frequency measurements such as prevalence or incidence rates. This underestimation will be higher among men and educated people.


Keywords: hypertension; high blood pressure; validation; agreement
doi:10.1136/jech.54.3.221
PMCID: PMC1731632  PMID: 10746117
25.  Twenty-Four-Hour Ambulatory Blood Pressure Monitoring in Hypertension 
Executive Summary
Objective
The objective of this health technology assessment was to determine the clinical effectiveness and cost-effectiveness of 24-hour ambulatory blood pressure monitoring (ABPM) for hypertension.
Clinical Need: Condition and Target Population
Hypertension occurs when either systolic blood pressure, the pressure in the artery when the heart contracts, or diastolic blood pressure, the pressure in the artery when the heart relaxes between beats, are consistently high. Blood pressure (BP) that is consistently more than 140/90 mmHg (systolic/diastolic) is considered high. A lower threshold, greater than 130/80 mmHg (systolic/diastolic), is set for individuals with diabetes or chronic kidney disease.
In 2006 and 2007, the age-standardized incidence rate of diagnosed hypertension in Canada was 25.8 per 1,000 (450,000 individuals were newly diagnosed). During the same time period, 22.7% of adult Canadians were living with diagnosed hypertension.
A smaller proportion of Canadians are unaware they have hypertension; therefore, the estimated number of Canadians affected by this disease may be higher. Diagnosis and management of hypertension are important, since elevated BP levels are related to the risk of cardiovascular disease, including stroke. In Canada in 2003, the costs to the health care system related to the diagnosis, treatment, and management of hypertension were over $2.3 billion (Cdn).
Technology
The 24-hour ABPM device consists of a standard inflatable cuff attached to a small computer weighing about 500 grams, which is worn over the shoulder or on a belt. The technology is noninvasive and fully automated. The device takes BP measurements every 15 to 30 minutes over a 24-to 28-hour time period, thus providing extended, continuous BP recordings even during a patient’s normal daily activities. Information on the multiple BP measurements can be downloaded to a computer.
The main detection methods used by the device are auscultation and oscillometry. The device avoids some of the pitfalls of conventional office or clinic blood pressure monitoring (CBPM) using a cuff and mercury sphygmomanometer such as observer bias (the phenomenon of measurement error when the observer overemphasizes expected results) and white coat hypertension (the phenomenon of elevated BP when measured in the office or clinic but normal BP when measured outside of the medical setting).
Research Questions
Is there a difference in patient outcome and treatment protocol using 24-hour ABPM versus CBPM for uncomplicated hypertension?
Is there a difference between the 2 technologies when white coat hypertension is taken into account?
What is the cost-effectiveness and budget impact of 24-hour ABPM versus CBPM for uncomplicated hypertension?
Research Methods
Literature Search
Search Strategy
A literature search was performed on August 4, 2011 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1997 to August 4, 2011. Abstracts were reviewed by a single reviewer. For those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low, or very low according to GRADE methodology.
Inclusion Criteria
English language articles;
published between January 1, 1997 and August 4, 2011;
adults aged 18 years of age or older;
journal articles reporting on the effectiveness, cost-effectiveness, or safety for the comparison of interest;
clearly described study design and methods;
health technology assessments, systematic reviews, meta-analyses, or randomized controlled trials.
Exclusion Criteria
non-English papers;
animal or in vitro studies;
case reports, case series, or case-case studies;
studies comparing different antihypertensive therapies and evaluating their antihypertensive effects using 24-hour ABPM;
studies on home or self-monitoring of BP, and studies on automated office BP measurement;
studies in high-risk subgroups (e.g. diabetes, pregnancy, kidney disease).
Outcomes of Interest
Patient Outcomes
mortality: all cardiovascular events (e.g., myocardial infarction [MI], stroke);
non-fatal: all cardiovascular events (e.g., MI, stroke);
combined fatal and non-fatal: all cardiovascular events (e.g., MI, stroke);
all non-cardiovascular events;
control of BP (e.g. systolic and/or diastolic target level).
Drug-Related Outcomes
percentage of patients who show a reduction in, or stop, drug treatment;
percentage of patients who begin multi-drug treatment;
drug therapy use (e.g. number, intensity of drug use);
drug-related adverse events.
Quality of Evidence
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria.
As stated by the GRADE Working Group, the following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Short-Term Follow-Up Studies (Length of Follow-Up of ≤ 1 Year)
Based on very low quality of evidence, there is no difference between technologies for non-fatal cardiovascular events.
Based on moderate quality of evidence, ABPM resulted in improved BP control among patients with sustained hypertension compared to CBPM.
Based on low quality of evidence, ABPM resulted in hypertensive patients being more likely to stop antihypertensive therapy and less likely to proceed to multi-drug therapy compared to CBPM.
Based on low quality of evidence, there is a beneficial effect of ABPM on the intensity of antihypertensive drug use compared to CBPM.
Based on moderate quality of evidence, there is no difference between technologies in the number of antihypertensive drugs used.
Based on low to very low quality of evidence, there is no difference between technologies in the risk for a drug-related adverse event or noncardiovascular event.
Long-Term Follow-Up Study (Mean Length of Follow-Up of 5 Years)
Based on moderate quality of evidence, there is a beneficial effect of ABPM on total combined cardiovascular events compared to CBPM.
Based on low quality of evidence, there is a lack of a beneficial effect of ABPM on nonfatal cardiovascular events compared to CBPM; however, the lack of a beneficial effect is based on a borderline result.
Based on low quality of evidence, there is no beneficial effect of ABPM on fatal cardiovascular events compared to CBPM.
Based on low quality of evidence, there is no difference between technologies for the number of patients who began multi-drug therapy.
Based on low quality of evidence, there is a beneficial effect of CBPM on control of BP compared to ABPM. This result is in the opposite direction than expected.
Based on moderate quality of evidence, there is no difference between technologies in the risk for a drug-related adverse event.
PMCID: PMC3377518  PMID: 23074425

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