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1.  Genome-wide linkage scan for genes affecting longitudinal trends in systolic blood pressure 
BMC Genetics  2003;4(Suppl 1):S82.
Only one genome scan to date has attempted to make use of the longitudinal data available in the Framingham Heart Study, and this attempt yielded evidence of linkage to a gene for mean systolic blood pressure. We show how the additional information available in these longitudinal data can be utilized to examine linkages for not only mean systolic blood pressure (SBP), but also for its trend with age and its variability. Prior to linkage analysis, individuals treated for hypertension were adjusted to account for right-censoring of SBP. Regressions on age were fitted to obtain orthogonal measures of slope, curvature, and residual variance of SBP that were then used as dependent variables in the model-free linkage program SIBPAL. We included mean age, gender, and cohort as covariates in the analysis. To improve power, sibling pairs were weighted for informativity using weights derived from both the marker and trait. The most significant results from our analyses were found on chromosomes 12, 15, and 17 for mean SBP, and chromosome 20 for both SBP slope and curvature.
PMCID: PMC1866522  PMID: 14975150
2.  High normal blood pressure and prehypertension: The debate continues 
Subjects with high normal blood pressure are at high risk of developing hypertension. Thus, the criteria of the Canadian Hypertension Education Program for diagnosis of hypertension and recommendations for follow-up now recommend that patients with high normal blood pressure (130 mmHg to 139 mmHg systolic and/or 85 mmHg to 89 mmHg diastolic) be followed up annually for the development of hypertension. Clinical trial data from subjects with high normal blood pressure show that 40% over two years and 63% over four years developed hypertension (140/90 mmHg or higher). These data are consistent with observational data from the Framingham Heart Study, which found a similar risk. Besides annual follow-up, the Canadian Hypertension Education Program recommends lifestyle therapy for individuals with high normal blood pressure. Ongoing research will establish whether any further management is required.
PMCID: PMC2650764  PMID: 17534467
Clinical practice guidelines; High normal blood pressure; Hypertension; Lifestyle therapy; Prehypertension
3.  Isolated diastolic hypotension and incident heart failure in older adults 
Hypertension  2011;58(5):895-901.
Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure <60 mm Hg and a systolic blood pressure ≥100 mm Hg, is associated with incident heart failure. Of the 5795 Medicare-eligible community-dwelling adults age ≥65 years in the Cardiovascular Health Study, 5521 were free of prevalent heart failure at baseline. After excluding 145 individuals with baseline systolic blood pressure <100 mm Hg, the final sample included 5376 participants, of whom 751 (14%) had isolated diastolic hypotension. Propensity scores for isolated diastolic hypotension were calculated for each of the 5376 participants and used to match 545 and 2348 participants with and without isolated diastolic hypotension, respectively who were balanced on 58 baseline characteristics. During over 12 years of median follow-up, centrally-adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension respectively (hazard ratio associated with isolated diastolic hypotension, 1.33; 95% confidence interval, 1.10–1.61; p=0.004). Among the 5376 pre-match individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% confidence interval, 1.09–1.53; p=0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure.
PMCID: PMC3390027  PMID: 21947466
aging; blood pressure; diastolic; heart failure; pulse pressure
4.  Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study. 
BMJ : British Medical Journal  1991;303(6799):385-389.
OBJECTIVE--To examine the hypothesis that a J curve relation between blood pressure and death from coronary heart disease is confined to high risk subjects with myocardial infarction. DESIGN--Cohort longitudinal epidemiological study with biennial examinations since 1950. SETTING--Framingham, Massachusetts, USA. SUBJECTS--5209 subjects in the Framingham study cohort followed up by a person examination approach. MAIN OUTCOME MEASURES--Coronary heart disease deaths and non-cardiovascular disease deaths in men and women with or without myocardial infarction relative to blood pressure. RESULTS--Among subjects without myocardial infarction non-cardiovascular disease deaths were twice to three times as common as coronary heart disease deaths. Furthermore, there was no significant relation between non-cardiovascular disease death and diastolic or systolic blood pressure. Also coronary heart disease deaths were linearly related to diastolic and systolic blood pressures. Among high risk patients (that is, people with myocardial infarction but free of congestive heart failure) death from coronary heart disease was more common than non-cardiovascular disease death. There was a significant U shaped relation between coronary heart disease death and diastolic blood pressure. Although there was an apparent U shaped relation between coronary heart disease death and systolic blood pressure, it did not attain statistical significance when controlling for age and change in systolic blood pressure from the pre-myocardial infarction level. None of the above conclusions changed when adjustments were made for risk factors such as serum cholesterol concentration, antihypertensive treatment, and left ventricular function. The U shaped relation between diastolic blood pressure and high risk subjects existed for both those given antihypertensive treatment and those not. CONCLUSIONS--These data suggest that an age and sex independent U curve relation exists for diastolic blood pressure and coronary heart disease deaths in patients with myocardial infarction but not for low risk subjects without myocardial infarction. The relation seems to be independent of left ventricular function and antihypertensive treatment.
PMCID: PMC1670714  PMID: 1912805
5.  Blood pressure and ageing 
Postgraduate Medical Journal  2007;83(976):109-114.
Isolated systolic hypertension, an elevation in systolic but not diastolic pressure, is the most prevalent type of hypertension in those aged 50 or over, occurring either de novo or as a development after a long period of systolic‐diastolic hypertension with or without treatment. The increase in blood pressure with age is mostly associated with structural changes in the arteries and especially with large artery stiffness. It is known from various studies that rising blood pressure is associated with increased cardiovascular risk. In the elderly, the most powerful predictor of risk is increased pulse pressure due to decreased diastolic and increased systolic blood pressure. All evidence indicates that treating the elderly hypertensive patient will reduce the risk of cardiovascular events. However, there is no evidence yet for the very elderly. This population is particularly susceptible to side effects of treatments and the reduction of blood pressure, although reducing the risk of cardiovascular events such as stroke, may result in increased mortality.
PMCID: PMC2805932  PMID: 17308214
ageing; blood pressure; hypertension
6.  Epidemiology of Stroke: Legacy of the Framingham Heart Study 
Global heart  2013;8(1):67-75.
In the present historical review, we highlight several articles outlining contributions of the Framingham Heart Study over the span of nearly seven decades to our understanding of the epidemiology of blood pressure (BP), atrial fibrillation and genetic factors as they relate to cerebrovascular disease. In 1970, Framingham investigators led by William Kannel, explored the epidemiological relations of BP and its various components to risk of ischemic stroke as well as hemorrhage, and noted the greater impact of hypertension to risk of stroke compared to other cardiovascular outcomes. Framingham investigators changed the prevalent concepts in terms of the contribution of BP components to stroke risk; i.e. they showed systolic pressure to be no less important a component for stroke risk than the diastolic or mean arterial pressures. In addition, they challenged the notion that hypertension was a normal consequence of increasing age, as connoted by the term “essential” hypertension. They also refuted the idea that blood pressure elevation in the elderly is innocuous by demonstrating that increased stroke risk persisted in advanced age in hypertensive persons. Thirty years later, the Framingham Study attained long term follow up of an entire generation of participants with excellent retention to follow-up, thus providing an opportunity to study hypertension and risk of stroke in a general population sample. Framingham investigators examined the impact of various BP components over a 50-year follow-up in normotensive and untreated hypertensive individuals as regards stroke risk, and showed the long term importance of antecedent (midlife) hypertension in future stroke risk . Similarly by calling attention to the importance of chronic non-valvular atrial fibrillation as a contributor to stroke, particularly in the elderly, FHS investigators confirmed the clinical observations of the founder of stroke neurology, C. Miller Fisher, M.D., who had made the clinical and pathological association of AF to stroke. Lastly, in the dawn of the era of individualized preventive medicine, FHS is participating in the effort to further our understanding of the role of genetic factors to stroke incidence.
The contributions of the Framingham Heart Study have been many and have shaped our understanding of the relation of BP, AF and other risk factors to stroke risk, thereby setting the stage for clinical trials which demonstrated how control of these risk contributors could prevent stroke and enable stroke prevention. FHS investigators are collaborating with other geneticists and epidemiologists internationally to elucidate the role of genetic factors and stroke susceptibility, which is likely continue to shape the practice of preventive cardiovascular medicine.
PMCID: PMC3601756  PMID: 23527318
7.  Interindividual Variation in Serum Sodium and Longitudinal Blood Pressure Tracking in the Framingham Heart Study 
Journal of hypertension  2008;26(11):2121-2125.
Recent cross-sectional studies have suggested that higher serum sodium levels may be a marker of elevated blood pressure. It is unclear whether serum sodium levels are related to the risk of developing hypertension in the community.
We investigated the association of serum sodium with longitudinal blood pressure tracking and incidence of hypertension in 2172 non-hypertensive Framingham Offspring Study participants (mean age 42 years, 54% women). We defined an increase in blood pressure as an increment of ≥ 1 category (as defined by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure), and incident hypertension as a systolic pressure of ≥140 or a diastolic pressure ≥90 mm Hg, or use of antihypertensive medications. Serum sodium was analyzed as a continuous variable, and as categories.
Cross-sectionally, serum sodium was not associated with systolic or diastolic blood pressure (p exceeded 0.10). On follow-up (mean 4.4 years), 805 participants (37 %; 418 women) progressed by ≥ 1 blood pressure category, and 318 (15%; 155 women) developed new-onset hypertension. In multivariable logistic regression analyses (adjusting for age, sex, baseline blood pressure, diabetes, body mass index, weight gain and smoking), serum sodium was not associated with blood pressure progression (Odds ratio [OR] per SD increment 0.93, 95% confidence limits [CI] 0.85–1.03), or with hypertension incidence (OR per SD increment 0.94, 95% CI 0.82–1.08).
In our large community-based sample, serum sodium was not associated with blood pressure cross-sectionally, or with blood pressure tracking or hypertension incidence longitudinally.
PMCID: PMC2654385  PMID: 18854750
Hypertension; blood pressure; serum sodium; metabolism; epidemiology; longitudinal studies
8.  Comparison of the Framingham Heart Study Hypertension Model with Blood Pressure Alone in the Prediction of Risk of Hypertension: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Hypertension  2010;55(6):1339-1345.
A prediction model, developed in the Framingham Heart Study (FHS), has been proposed for use in estimating a given individual’s risk of hypertension. We compared this model with systolic blood pressure (SBP) alone and age-specific diastolic blood pressure (DBP) categories for the prediction of hypertension. Participants in the Multi-Ethnic Study of Atherosclerosis, without hypertension or diabetes (n=3013), were followed for the incidence of hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg and/or the initiation of antihypertensive medication). The predicted probability of developing hypertension between four adjacent study examinations, with a median of 1.6 years between examinations, was determined. The mean (standard deviation) age of participants was 58.5 (9.7) years and 53% were women. During follow-up, 849 incident cases of hypertension occurred. The c-statistic for the FHS model was 0.788 (95% CI: 0.773, 0.804) compared with 0.768 (95% CI: 0.751, 0.785; p=0.096 compared to the FHS model) for SBP alone and 0.699 (95% CI: 0.681, 0.717; p<0.001 compared to the FHS model) for age-specific DBP categories. The relative integrated discrimination improvement index for the FHS model versus SBP alone was 10.0% (95% CI: −1.7%, 22.7%) and versus age-specific DBP categories was 146% (95% CI: 116%, 181%). Using the FHS model, there were significant differences between observed and predicted hypertension risk (Hosmer-Lemeshow goodness of fit p<0.001); re-calibrated and best-fit models produced a better model fit (p=0.064 and 0.245, respectively). In this multi-ethnic cohort of U.S. adults, the FHS model was not substantially better than SBP alone for predicting hypertension.
PMCID: PMC3023992  PMID: 20439822
hypertension; epidemiology; systolic blood pressure; diastolic blood pressure; risk prediction
9.  Correlates of Echocardiographic Indices of Cardiac Remodeling Over the Adult Life Course: Longitudinal Observations from the Framingham Heart Study 
Circulation  2010;122(6):570-578.
The heart progressively remodels over the life course, yet longitudinal data characterizing such remodeling in the community are limited.
Methods and Results
Using multilevel modeling, we analyzed up to 4 serial echocardiographic observations obtained over a 16-year period in 4,062 Framingham Study participants (mean age 45 years, 54% women; 11,485 person-observations). We related LV wall thickness (LVWT), LV systolic (LVDS) and diastolic (LVDD) dimensions and fractional shortening (FS) to age, sex, body mass index (BMI), blood pressure (BP, including antihypertensive medication use), smoking, and diabetes (separate analyses for each echocardiographic measure). With advancing age, LV dimensions decreased, whereas FS and LVWT increased concomitantly. Male sex, BMI, and BP indices/hypertension treatment were significantly related to both greater LV dimensions and LVWT. The effect of age on cardiac remodeling was influenced by key covariates (P>0.05 for all interactions): women and individuals with diabetes experienced greater age-associated increases in LVWT; presence of diabetes or a higher BP was associated with a lesser decrease in LV diastolic dimensions with increasing age; antihypertensive medication use was a marker of an attenuated increase in FS with aging.
Cardiac remodeling over the adult life course is characterized by a distinct pattern of increasing LVWT, decreasing LV dimensions and increasing FS with advancing age. Overall, female sex, greater BP load, and presence of diabetes serve to attenuate this remodeling pattern. These observations suggest a mechanism for the preponderance of women with hypertension and individuals with diabetes among patients with diastolic heart failure.
PMCID: PMC2942081  PMID: 20660804
aging; cardiac remodeling; heart failure
10.  Is Peri-Operative Isolated Systolic Hypertension (ISH) a Cardiac Risk Factor? 
Current Cardiology Reviews  2008;4(1):22-33.
We are presenting a review of Isolated Systolic Hypertension (ISH) as a cardiovascular risk factor with emphasis on the perioperative period.
Isolated systolic hypertension is associated with aging and is the most frequent subtype (65%) among patients with uncontrolled hypertension. ISH is strongly associated with increased risks of cardiac and cerebrovascular events exceeding those in comparably aged individuals with diastolic hypertension. Patients with ISH show an increase in left ventricular (LV) mass and an increase in the prevalence of left ventricular hypertrophy (LVH). These LV changes increase cardiovascular events and frequently lead to diastolic dysfunction (DD). Treatment to reduce elevated systolic blood pressure has been shown to reduce the risk of cardiovascular events.
In the perioperative setting, essential hypertension has not been found to be a significant risk factor for cardiac complications. Most of the studies were based on the definition of essential hypertension and underpowered in sample size. The significance of perioperative ISH, however, is not well studied, partly due to its recognition only fairly recently as a cardiovascular risk factor in the non-surgical setting, and partly due to the evolving definition of ISH.
Perioperative cardiac complications remain a significant problem to the healthcare system and to the patient. Although the incidence of perioperative cardiac complications is prominent in high-risk patients as defined by the Revised Cardiac Risk Index (RCRI), the bulk of the cardiac complications actually occur in low-risk group. Currently, little understanding exists on the occurrence of perioperative cardiac complications in low- risk patients. A factor such as ISH, with its known pathophysiological changes, is a potential perioperative risk factor.
We believe ISH is an under-recognized perioperative risk factor and deserves further studying. Our research group has recently been funded by the Heart Stroke Foundation (HSF) to examine ISH as a perioperative risk factor (PROMISE Study).
PMCID: PMC2774582  PMID: 19924274
Isolated systolic hypertension; cardiovascular risk factors; perioperative.
11.  Quantitative trait linkage analysis of longitudinal change in body weight 
BMC Genetics  2003;4(Suppl 1):S7.
One of the great strengths of the Framingham Heart Study data, provided for the Genetic Analysis Workshop 13, is the long-term survey of phenotypic data. We used this unique data to create new phenotypes representing the pattern of longitudinal change of the provided phenotypes, especially systolic blood pressure and body weight. We performed a linear regression of body weight and systolic blood pressure on age and took the slopes as new phenotypes for quantitative trait linkage analysis using the SOLAR package. There was no evidence for heritability of systolic blood pressure change. Heritability was estimated as 0.15 for adult life "body weight change", measured as the regression slope, and "body weight gain" (including only individuals with a positive regression slope), and as 0.22 for body weight "change up to 50" (regression slope of weight on age up to an age of 50). With multipoint analysis, two regions on the long arm of chromosome 8 showed the highest LOD scores of 1.6 at 152 cM for "body weight change" and of >1.9 around location 102 cM for "body weight gain" and "change up to 50". The latter two LOD scores almost reach the threshold for suggestive linkage. We conclude that the chromosome 8 region may harbor a gene acting on long-term body weight regulation, thereby contributing to the development of the metabolic syndrome.
PMCID: PMC1866508  PMID: 14975075
Quantitative trait linkage analysis; longitudinal change; weight change; regression slope; metabolic syndrome
12.  Pleiotropic effects on cardiovascular risk factors within and between the fourth and sixth decades of life: Implications for genotype × age interactions 
BMC Genetics  2003;4(Suppl 1):S54.
We used an approach for detecting genotype × environment interactions to detect and characterize genotype × age interaction in longitudinal measures of three well known cardiovascular risk factors: total plasma cholesterol (TC), systolic blood pressure (SBP), and body weight (Wgt). Our objectives were to determine if the same gene or suite of genes influences quantitative variation in each of these phenotypes in the 4th and 6th decades of life, to assess the impact of additive gene effects in these two decades, and to evaluate the stability of pleiotropic relationships among these phenotypes. Using the Framingham Heart Study data, we constructed two cross-sectional samples comprising individuals on whom these phenotypes were measured at ages 30-39 years (Original Cohort: exam 1, Offspring Cohort: exam 2) and at ages 50-59 years (Original Cohort: exam 11, Offspring Cohort: exam 5). We also constructed a longitudinal sample from the cross-sectional sample members for whom measures on these traits were available at both ages (i.e., 4th and 6th decades of life). Patterns of pleiotropy, inferred from genetic correlations between traits, differ between the two age classes. Further, additive genetic variance in SBP during the 4th decade of life is attributable to a different gene or suite of genes than during the 6th. The magnitude of the effect increases for SBP. Variation in TC and Wgt appear to be influenced by the same gene or genes in both decades. The magnitude of the effect is stable for TC, but increases dramatically with age for Wgt.
PMCID: PMC1866491  PMID: 14975122
13.  Proactive Multifactorial Intervention Strategy Reduces the Risk of Cardiovascular Disease Estimated with Region-Specific Risk Assessment Models in Pacific Asian Patients Participating in the CRUCIAL Trial 
Journal of Korean Medical Science  2013;28(12):1741-1748.
Despite race, ethnic, and regional differences in cardiovascular disease risk, many worldwide hypertension management guidelines recommend the use of the Framingham coronary heart disease (CHD) risk equation to guide treatment decisions. This subanalysis of the recently published CRUCIAL trial compared the treatment-related reductions in calculated CHD and stroke risk among Pacific Asian (PA) patients using a variety of region-specific risk assessment models. As a result, greater reductions in systolic and diastolic blood pressure, low-density lipoprotein cholesterol, and triglycerides were observed in the proactive multifactorial intervention (PMI) arm compared with the usual care arm at Week 52 for PA patients. The relative percentage change in 10-yr CHD risk between baseline and Week 52 in the PMI versus usual care arms was greatest using the NIPPON DATA80 fatal CHD model (LS [least square] mean difference -42.6%), and similar in the SCORE fatal CHD and Framingham total CHD models (LS mean difference -29.4% and -30.8%, respectively). The single-pill based PMI approach is consistently effective in reducing cardiovascular disease risk, evaluated using a variety of risk assessment models. ( registration number: NCT00407537)
PMCID: PMC3857369  PMID: 24339703
Cardiovascular Diseases; Risk Factors; Hypertension; Clinical Trial; Antihypertensive Agents; Anticholesteremic Agents
14.  Heart rate and blood pressure variability in children with chronic kidney disease: a report from the CKiD study 
Autonomic nervous system dysfunction and sympathetic nervous system over-activity play important roles in the development of hypertension associated with chronic kidney disease (CKD). In adults, increased blood pressure variability (BPV) appears to be directly related to sympathetic over-activity with increased risk of end-organ damage and cardiovascular events. Decreased heart rate variability (HRV) has been observed in adults with CKD, and is an independent predictor of mortality.
The purpose of this study was to evaluate BPV and HRV in pediatric patients enrolled in the Chronic Kidney Disease in Children Study. Ambulatory blood pressure monitoring data were available for analysis of 215 person-visits from 144 children that were not receiving antihypertensive medications.
BPV and HRV were determined by standard deviation and coefficient of variation for heart rate and systolic and diastolic blood pressure for each patient averaged for wake/sleep periods during 24-h monitoring. Uniformly lower values were displayed during sleep versus wake periods: BPV was 20 % lower during sleep (p<0.001) and HRV was 30 % lower during sleep (p<0.001). A significant increase in systolic BPV was observed in hypertensive children compared to children with normal blood pressure (6.9 %, p=0.009). Increased diastolic BPV was detected among hypertensive children during sleep period compared to children with normal blood pressure (11.5 %, p=0.008). There was a significant decrease in HRV in hypertensive compared to normotensive children (−8.2 %, p=0.006).
These findings are similar to those in adult patients and may underscore childhood origin and natural progression of adverse cardiovascular outcomes in adults with CKD.
PMCID: PMC4072494  PMID: 24488505
Heart rate variability; Blood pressure variability; Chronic kidney disease; Hypertension; Pediatrics
15.  Relations of Exercise Blood Pressure Response to Cardiovascular Risk Factors and Vascular Function in the Framingham Heart Study 
Circulation  2012;125(23):2836-2843.
Exercise blood pressure (BP) is an important marker of left ventricular hypertrophy, incident hypertension and future cardiovascular events. Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community.
Methods and Results
Framingham Offspring cohort participants (n=2115, 53% women, mean age 59 years) underwent a submaximal exercise test (first 2 stages of the Bruce protocol), applanation tonometry and brachial artery flow-mediated dilation (FMD) testing. We related exercise systolic and diastolic BP at second stage of the Bruce protocol to standard cardiovascular risk factors and to vascular function measures. In multivariable linear regression models, exercise systolic BP was positively related to age, standing BP, standing heart rate, smoking, body mass index, and the total cholesterol-to-high-density cholesterol (HDL) ratio (p≤0.01 for all). Similar associations were observed for exercise diastolic BP. Carotid-femoral pulse wave velocity (p=0.02), central pulse pressure (p<0.0001), mean arterial pressure (p=0.04) and baseline brachial flow (p=0.002) were positively associated with exercise systolic BP, whereas FMD was negatively associated (P<0.001). For exercise diastolic BP, forward pressure wave amplitude was negatively related (p<0.0001) whereas mean arterial pressure was positively related (p<0.0001).
Increased arterial stiffness and impaired endothelial function are significant correlates of a higher exercise systolic BP response. Our findings suggest that impaired vascular function may contribute to exaggerated BP responses during daily living, resulting in repetitive increments in load on the heart and vessels and increased cardiovascular disease risk.
PMCID: PMC3636551  PMID: 22572915
blood pressure; endothelial function; exercise; vascular function; vascular stiffness
16.  Differential control of systolic and diastolic blood pressure in blacks with essential hypertension. 
OBJECTIVE: The risk of cardiovascular and renal diseases has been shown to be higher for systolic blood pressure than diastolic blood pressure. The aim of this study was to assess the differential control of systolic and diastolic blood pressure in Nigerians with primary hypertension. DESIGN AND SETTING: This was a prospective observational study carried out at the Medical Outpatient Department of the State Hospital, Abeokuta, Nigeria. Ethical approval for the study was obtained from the ethical committee of the hospital. METHODOLOGY: The study population consisted of 185 consecutive patients (65 males, 120 females), aged 35-85 years with primary hypertension who had been on drugs one- to 25 years prior to the onset of the study. Clinic blood pressure control was assessed during a year period. Six consecutive clinic blood pressure readings were recorded for each patient and the average calculated (systolic blood pressure and diastolic blood pressure separately). Patients were classified into subgroups based on the pattern of blood pressure control. RESULTS: Clinic systolic blood pressure and diastolic blood pressure was controlled in 58 patients (31.4%). Systolic blood pressure control was less frequent than diastolic blood pressure control (35.7% versus 51.4%, p<0.05). Patients with uncontrolled systolic blood pressure were significantly older than patients with only uncontrolled diastolic blood pressure (66.7+/-7.4 versus 52.9+/-8.7 years, p<0.001). CONCLUSION: Systolic blood pressure is less frequently controlled than diastolic blood pressure in Nigerians treated for primary hypertension. This may increase the patient's risk of developing stroke, and cardiovascular and renal complications.
PMCID: PMC2594866  PMID: 15040512
17.  Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness 
BMC Medical Genetics  2007;8(Suppl 1):S3.
About one quarter of adults are hypertensive and high blood pressure carries increased risk for heart disease, stroke, kidney disease and death. Increased arterial stiffness is a key factor in the pathogenesis of systolic hypertension and cardiovascular disease. Substantial heritability of blood-pressure (BP) and arterial-stiffness suggests important genetic contributions.
In Framingham Heart Study families, we analyzed genome-wide SNP (Affymetrix 100K GeneChip) associations with systolic (SBP) and diastolic (DBP) BP at a single examination in 1971–1975 (n = 1260), at a recent examination in 1998–2001 (n = 1233), and long-term averaged SBP and DBP from 1971–2001 (n = 1327, mean age 52 years, 54% women) and with arterial stiffness measured by arterial tonometry (carotid-femoral and carotid-brachial pulse wave velocity, forward and reflected pressure wave amplitude, and mean arterial pressure; 1998–2001, n = 644). In primary analyses we used generalized estimating equations in models for an additive genetic effect to test associations between SNPs and phenotypes of interest using multivariable-adjusted residuals. A total of 70,987 autosomal SNPs with minor allele frequency ≥ 0.10, genotype call rate ≥ 0.80, and Hardy-Weinberg equilibrium p ≥ 0.001 were analyzed. We also tested for association of 69 SNPs in six renin-angiotensin-aldosterone pathway genes with BP and arterial stiffness phenotypes as part of a candidate gene search.
In the primary analyses, none of the associations attained genome-wide significance. For the six BP phenotypes, seven SNPs yielded p values < 10-5. The lowest p-values for SBP and DBP respectively were rs10493340 (p = 1.7 × 10-6) and rs1963982 (p = 3.3 × 10-6). For the five tonometry phenotypes, five SNPs had p values < 10-5; lowest p-values were for reflected wave (rs6063312, p = 2.1 × 10-6) and carotid-brachial pulse wave velocity (rs770189, p = 2.5 × 10-6) in MEF2C, a regulator of cardiac morphogenesis. We found only weak association of SNPs in the renin-angiotensin-aldosterone pathway with BP or arterial stiffness.
These results of genome-wide association testing for blood pressure and arterial stiffness phenotypes in an unselected community-based sample of adults may aid in the identification of the genetic basis of hypertension and arterial disease, help identify high risk individuals, and guide novel therapies for hypertension. Additional studies are needed to replicate any associations identified in these analyses.
PMCID: PMC1995621  PMID: 17903302
18.  Association of blood lead to blood pressure in men aged 55 to 75 years: effect of selected social and biochemical confounders. NFR Study Group. 
Environmental Health Perspectives  1994;102(Suppl 9):107-111.
The association of blood lead (B-Pb) concentration to blood pressure was investigated in men aged 55 to 75 years living in the Rome area, who had no history of exposure to lead in the workplace and who participated between 1989 and 1990 in an epidemiologic survey for coronary heart disease (New Risk Factor Project). Of the 1856 individuals eligible for the study, 59 were excluded from analyses because not all relevant data were available; and 478 were excluded because they were treated for hypertension. In the remaining subjects (n = 1319) the median B-Pb concentration was 113 micrograms/l (range: 40-442 micrograms/l). Systolic blood pressure (SBP) averaged 140 +/- 18 (standard deviation) mm Hg (range 98-220) and diastolic blood pressure (DBP) 84 +/- 9 mm Hg (range 56-118). Median B-Pb values increased significantly from 111 micrograms/l in subjects with normal blood pressure (n = 668) to 113.5 micrograms/l in subjects with borderline high blood pressure (n = 373) and to 120 micrograms/l in subjects with increased blood pressure (n = 278). After log-normal conversion of B-Pb, the linear correlation coefficient between In[B-Pb(ug/l)] and both SBP and DBP was statistically significant (r = 0.1332, p < 0.001 and r = 0.0737, p = 0.007, respectively). The linear regression coefficient was 6.8 mm Hg/In(micrograms/l) for SBP and 1.8 mm Hg/In(microgram/l) for DBP. Multiple regression analyses revealed that, after correction for body mass index (BMI), age, heart rate, skinfold thickness, serum lipids, and glucose levels; blood lead was still a significant predictor of increased SBP and DBP.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1566780  PMID: 7698070
19.  NADH Dehydrogenase Subunit-2 237 Leu/Met Polymorphism Modulates the Effects of Coffee Consumption on the Risk of Hypertension in Middle-Aged Japanese Men 
Journal of Epidemiology  2009;19(5):231-236.
Habitual coffee consumption has been reported to lower blood pressure in the Japanese population. The NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity and modifies the effects of alcohol consumption on blood pressure in the Japanese population. The objective of this study was to determine whether this polymorphism also modifies the effects of coffee consumption on blood pressure or the risk of hypertension in middle-aged Japanese men.
A total of 398 men (mean age ± standard deviation, 53.8 ± 7.8 years) were selected from among individuals visiting the hospital for regular medical check-ups. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or antihypertensive drug treatment. Polymerase chain reaction-restriction fragment length polymorphism using the restriction enzyme AluI was performed to determine ND2-237 Leu/Met genotype.
In subjects with ND2-237Leu, coffee consumption was significantly and negatively associated with diastolic blood pressure (P = 0.007). The odds ratio (OR) for hypertension was significantly lower in subjects with ND2-237Leu who consumed 2 or 3 cups of coffee per day than in those who consumed less than 1 cup of coffee per day (OR, 0.517; 95% confidence interval [CI], 0.276 to 0.968; P = 0.039). After adjustment, the OR remained significant (OR = 0.399; 95% CI, 0.184 to 0.869; P = 0.020). Moreover, after adjustment, the OR was significantly lower in subjects with ND2-237Leu who consumed more than 4 cups of coffee per day than in those who consumed less than 1 cup of coffee per day (OR, 0.246; 95% CI, 0.062 to 0.975; P = 0.046). However, the association between ND2-237Met genotype and hypertension did not depend on coffee consumption.
The present results suggest that the ND2-237 Leu/Met polymorphism modulates the effects of coffee consumption on hypertension risk in middle-aged Japanese men.
PMCID: PMC3924125  PMID: 19667492
coffee consumption; hypertension; NADH dehydrogenase; polymorphism; personalized preventive medicine
20.  Blood Pressure and Cardiovascular Disease Risk in the Veterans Affairs Diabetes Trial 
Diabetes Care  2010;34(1):34-38.
Blood pressure ranges associated with cardiovascular disease (CVD) events in advanced type 2 diabetes are not clear. Our objective was to determine whether baseline and follow-up (On-Study) systolic blood pressure (SBP), diastolic blood pressure (DBP), and SBP combined with DBP predict CVD events in the Veterans Affairs Diabetes Trial (VADT).
Participants in the VADT (n = 1,791) with hypertension received stepped treatment to maintain blood pressure below the target of 130/80 mmHg in standard and intensive glycemic treatment groups. Blood pressure levels of all subjects at baseline and On-Study were analyzed to detect associations with CVD risk. The primary outcome was the time from randomization to the first occurrence of myocardial infarction, stroke, congestive heart failure, surgery for vascular disease, inoperable coronary disease, amputation for ischemic gangrene, or CVD death.
Separated SBP ≥140 mmHg had significant risk at baseline (hazards ratio [HR] 1.508, P < 0.001) and On-Study (HR 1.469, P = 0.002). DBP <70 mmHg increased CVD events at baseline (HR 1.482, P < 0.001) and On-Study (HR 1.491, P < 0.001). Combined blood pressure categories indicated high risk for CVD events for SBP ≥140 with DBP <70 mmHg at baseline (HR 1.785, P = 0.03) and On-Study (HR 2.042, P = 0.003) and nearly all SBP with DBP <70 mmHg.
Increased risk of CVD events with SBP ≥140 mmHg emphasizes the urgency for treatment of systolic hypertension. Increased risk with DBP <70 mmHg, even when combined with SBP in guideline-recommended target ranges, supports a new finding in patients with type 2 diabetes. The results emphasize that DBP <70 mmHg in these patients was associated with elevated CVD risk and may best be avoided.
PMCID: PMC3005453  PMID: 21059830
21.  Effect of eprosartan-based antihypertensive therapy on coronary heart disease risk assessed by Framingham methodology in Canadian patients: results of the POWER survey 
The Canadian Hypertension Education Program (CHEP) has identified blood pressure (BP) control as a key target for an overall reduction in cardiovascular disease risk. The POWER survey (Physicians’ Observational Work on Patient Education According to their Vascular Risk) used Framingham methodology to investigate the impact of an angiotensin-receptor-blocker-based regimen on arterial BP and total coronary heart disease (CHD) risk in a subset of patients recruited in Canada.
309 Canadian practices screened for patients with either newly diagnosed or uncontrolled mild/moderate hypertension (sitting systolic blood pressure [SBP] >140 mmHg with diastolic blood pressure [DBP] <110 mmHg). Treatment comprised eprosartan 600 mg/day with add-on antihypertensive therapy after 1 month if required. The primary efficacy variable was change in SBP at 6 months; the secondary variable was the absolute change in the Framingham 10-year CHD risk score.
1,385 patients were identified, of whom 1,114 were included in the intention-to-treat (ITT) cohort. Thirty-eight point four percent of ITT patients were managed with monotherapy at 6 months, versus 35.2% and 13.7% with two-drug or multiple-drug therapy, respectively. SBP in the ITT cohort declined 22.4 (standard deviation [SD] 14.8) mmHg and DBP declined 10.5 (SD 10.3) mmHg during that time. The absolute mean Framingham score declined 2.1 (SD 3.1) points with significant age and sex variation (P<0.001) and differences between the various Framingham methods used.
Primary care physicians were able to use a strategy of BP lowering and CHD risk assessment to achieve significant reductions in BP and Framingham-assessed CHD risk. The effect size estimate of the different Framingham methods varied noticeably; reasons for those differences warrant further investigation.
PMCID: PMC3908905  PMID: 24493928
blood pressure; hypertension; angiotensin-receptor blocker; observational study
22.  Impact of treating hyperlipidemia or hypertension to reduce the risk of death from coronary artery disease 
OBJECTIVE: To compare the prevalence of modifiable risk factors for cardiovascular disease among hypertensive and nonhypertensive adults and to estimate the effect of treating hyperlipidemia or hypertension to reduce the risk of death from coronary artery disease. METHODS: The authors evaluated a sample of 7814 subjects aged 35-74 years free of clinical cardiovascular disease from the Canadian Heart Health Surveys to estimate the prevalence of cardiovascular risk factors. They identified hyperlipidemic subjects (ratio of total cholesterol to high-density lipoprotein cholesterol [total-C/HDL-C] 6.0 [corrected] or more for men and 5.0 [corrected] or more for women) and hypertensive subjects (systolic or diastolic blood pressure 160/90 mm Hg or greater, or receiving pharmacologic or nonpharmacologic treatment). A life expectancy model was used to estimate the rate of death from coronary artery disease following specific treatments. RESULTS: An elevated total-C/HDL-C ratio was significantly more common among hypertensive than nonhypertensive men aged 35-64 (rate ratio [RR] 1.56 for age 35-54, 1.28 for age 55-64) and among hypertensive than nonhypertensive women of all ages (RR 2.73 for age 35-54, 1.58 for age 55-64, 1.31 for age 65-74). Obesity and a sedentary lifestyle were also more common among hypertensive than among nonhypertensive subjects. According to the model, more deaths from coronary artery disease could be prevented among subjects with treated but uncontrolled hypertension by modifying lipids rather than by further reducing blood pressure for men aged 35-54 (reduction of 50 v. 29 deaths per 100,000) and 55-64 (reduction of 171 v. 104 deaths per 100,000) and for women aged 35-54 (reduction of 44 v. 39 deaths per 100,000). Starting antihypertensive therapy in subjects aged 35-74 with untreated hypertension would achieve a greater net reduction in deaths from coronary artery disease than would lipid lowering. Nonetheless, the benefits of lipid therapy were substantial: lipid intervention among hypertensive subjects aged 35-74 represented 36% of the total benefits of treating hyperlipidemia in the total hyperlipidemic population. INTERPRETATION: The clustering of hyperlipidemia and the potential benefits of treatment among hypertensive adults demonstrate the need for screening and treating other cardiovascular risk factors beyond simply controlling blood pressure.
PMCID: PMC1232605  PMID: 10352634
23.  Study of Sustained Blood Pressure-Lowering Effect of Azelnidipine Guided by Self-Measured Morning and Evening Home Blood Pressure: Subgroup Analysis of the At-HOME Study 
Drugs in R&d  2013;13(1):75-85.
Morning hypertension is a risk factor for cardiovascular and cerebrovascular events, and consequently diagnosis and control of morning hypertension are considered very important. We previously reported the results of the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study, which indicated that azelnidipine effectively controlled morning hypertension.
The objective of this At-HOME subgroup analysis was to evaluate the sustained blood pressure (BP)-lowering effect of azelnidipine, using mean morning and evening systolic BP [ME average] and morning systolic BP minus evening systolic BP (ME difference).
We analyzed the self-measured home BP data (measured in the morning and at bedtime) from this 16-week prospective observational study to clarify the effect of morning dosing of azelnidipine (mean [± standard deviation] maximum dose 14.3 ± 3.6 mg/day). A subgroup of patients from the At-HOME Study who had an evening home BP measurement within 28 days prior to the baseline date were used for efficacy analysis (n = 2,546; mean age, 65.1 years; female, 53.6 %).
Home systolic BP/diastolic BP levels in the morning and evening were significantly lowered (p < 0.0001) by −19.4 ± 17.1/−10.3 ± 10.6 and −16.9 ± 17.0/−9.4 ± 10.6 mmHg, respectively. Home pulse rates in the morning and evening were also significantly lowered (p < 0.0001) by −3.5 ± 7.8 and −3.5 ± 7.3 beats/min, respectively. At baseline, patients whose ME average was ≥135 mmHg and whose ME difference was ≥15 mmHg (defined as morning-predominant hypertension) accounted for 20.4 % of the study population. However, at the end of the study, the number of such patients was significantly reduced to 7.9 % (p < 0.0001). Patients whose ME average was ≥135 mmHg and whose ME difference was <15 mmHg (defined as sustained hypertension) accounted for 71.1 % of the study population at baseline. This was reduced significantly to 42.8 % at the end of the study (p < 0.0001). ME average decreased significantly from 153.8 ± 15.5 mmHg to 135.6 ± 11.9 mmHg, and ME difference also decreased significantly from 6.7 ± 13.1 mmHg to 4.7 ± 10.8 mmHg (both p < 0.0001).
These results suggest that azelnidipine improved morning hypertension with its sustained BP-lowering effect.
Electronic supplementary material
The online version of this article (doi:10.1007/s40268-013-0007-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3627021  PMID: 23519655
24.  Body mass index and change in blood pressure over a 7-year period in older Mexican Americans 
Clinical Interventions in Aging  2006;1(3):275-282.
Obesity and hypertension are major public health concerns in the US. We examined the relationship between body mass index (BMI) and blood pressure in older Mexican Americans using data from the Hispanic Established Population for the Epidemiological Study of the Elderly (EPESE), a longitudinal study of Mexican Americans aged 65 and over residing in the southwestern US. The study sample was 2404 older Mexican American adults with a mean age of 72.6 years of age at baseline (1993–4). Both systolic and diastolic blood pressures were higher in subjects with high BMI categories. The rate of change in systolic blood pressure and diastolic blood pressure were −0.11 mm Hg and −0.32 mm Hg per year over a 7-year period, respectively. The rate of decline in systolic and diastolic blood pressure over a 7-year period was greater in subjects with BMI categories of 25–<30 kg/m2 and 30–<35 kg/m2 as compared with those subjects with in the lowest and in the highest BMI categories. Hypertension is one of the most prevalent medical conditions affecting older adults. Understanding possible modifiable risk factors that may play a role in the management of hypertension will be beneficial.
PMCID: PMC2695178  PMID: 18046881
aging; hypertension; BMI; Mexican Americans
25.  Blood Pressure Tracking Over the Adult Life Course: Patterns and Correlates in the Framingham Heart Study 
Hypertension  2012;60(6):1393-1399.
The extent to which select vascular risk factors differentially influence blood pressure (BP) is incompletely understood. Thus, we used multilevel modeling to analyze serial BP measurements using 21,732 person-observations obtained on Framingham Heart Study participants (mean age 38 years, 52% women; 4,993 unique individuals) over a 28-year period. We related longitudinal tracking of each BP measure (systolic BP [SBP], diastolic BP [DBP], mean arterial pressure [MAP], and pulse pressure [PP]) to age, sex, body mass index (BMI), smoking, diabetes, total/high-density lipoprotein (HDL) cholesterol ratio, and heart rate. In multivariable-adjusted analyses, we observed that older age, male sex, greater BMI, and higher heart rate were positively associated with increase in all BP measures (p<0.0001). Notably, higher total/HDL cholesterol ratio was associated with greater MAP (p<0.01). Conversely, diabetes and smoking were associated with higher PP (p<0.01). We also observed effect modification by sex: the increase in PP with age and BMI was more pronounced in women compared to men (p<0.0001). All BP measures tracked at higher levels in both men and women with multiple vascular risk factors. Taken together, our longitudinal observations of a large community-based sample demonstrate a greater pulsatile load in women than men with increasing age. We also observed a differential impact of select vascular risk factors on the individual components of BP, underscoring distinct regulation of these measures over the life course.
PMCID: PMC3499677  PMID: 23108660
aging; blood pressure; epidemiology; hypertension; risk factors

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