Stanley S. Franklin

Is Pulse Pressure Useful in Predicting Risk for Coronary Heart Disease? The Framingham Heart Study

BACKGROUND Current definitions of hypertension are based on levels of systolic blood pressure (SBP) and diastolic blood pressure (DBP), but not on pulse pressure (PP). We examined whether PP adds useful information for predicting coronary heart disease (CHD) in the population-based Framingham Heart Study. METHODS AND RESULTS We studied 1924 men and women between 50 and 79 years of age at baseline with no clinical evidence of CHD and not taking antihypertensive drug therapy. Cox regression, adjusted for age, sex, and other risk factors, was used to assess the relations between blood pressure components and CHD risk over a 20-year follow-up. The association with CHD risk was positive for SBP, DBP, and PP, considering each pressure individually; of the 3, PP yielded the largest chi(2) statistic. When SBP and DBP were jointly entered into the multivariable model, the association with CHD risk was positive for SBP (HR, 1.22; 95% CI, 1.15 to 1.30) and negative for DBP (HR, 0. 86; 95% CI, 0.75 to 0.98). Four subgroups were defined according to SBP levels (<120, 120 to 139, 140 to 159, and >/=160 mm Hg). Within each subgroup, the association with CHD risk was negative for DBP and positive for PP. A cross-classification of SBP-DBP levels confirmed these results. CONCLUSIONS In the middle-aged and elderly, CHD risk increased with lower DBP at any level of SBP>/=120 mm Hg, suggesting that higher PP was an important component of risk. Neither SBP nor DBP was superior to PP in predicting CHD risk.

Impact of the Metabolic Syndrome on Mortality From Coronary Heart Disease, Cardiovascular Disease, and All Causes in United States Adults

Background—Mortality resulting from coronary heart disease (CHD), cardiovascular disease (CVD), and all causes in persons with diabetes and pre-existing CVD is high; however, these risks compared with those with metabolic syndrome (MetS) are unclear. We examined the impact of MetS on CHD, CVD, and overall mortality among US adults. Methods and Results—In a prospective cohort study, 6255 subjects 30 to 75 years of age (54% female) (representative of 64 million adults in the United States) from the Second National Health and Nutrition Examination Survey were followed for a mean±sd of 13.3±3.8 years. MetS was defined by modified National Cholesterol Education Program criteria. From sample-weighted multivariable Cox proportional-hazards regression, compared with those with neither MetS nor prior CVD, age-, gender-, and risk factor–adjusted hazard ratios (HRs) for CHD mortality were 2.02 (95% CI, 1.42 to 2.89) for those with MetS and 4.19 (95% CI, 3.04 to 5.79) for those with pre-existing CVD. For CVD mortality, HRs were 1.82 (95% CI, 1.40 to 2.37) and 3.14 (95% CI, 2.49 to 3.96), respectively; for overall mortality, HRs were 1.40 (95% CI, 1.19 to 1.66) and 1.87 (95% CI, 1.60 to 2.17), respectively. In persons with MetS but without diabetes, risks of CHD and CVD mortality remained elevated. Diabetes predicted all mortality end points. Those with even 1 to 2 MetS risk factors were at increased risk for mortality from CHD and CVD. Moreover, MetS more strongly predicts CHD, CVD, and total mortality than its individual components. Conclusions—CHD, CVD, and total mortality are significantly higher in US adults with than in those without MetS.

Does the Relation of Blood Pressure to Coronary Heart Disease Risk Change With Aging? The Framingham Heart Study

Background — We examined the relative importance of diastolic (DBP), systolic (SBP) and pulse pressure (PP) as predictors of coronary heart disease (CHD) risk in different age groups of Framingham Heart Study participants. Methods and Results — We studied 3060 men and 3479 women between 20 and 79 years of age who were free of CHD and were not on antihypertensive drug therapy at baseline. Cox regression adjusted for age, sex, and other risk factors was used to assess the relations of BP indexes to CHD risk over a 20-year follow-up. In the group <50 years of age, DBP was the strongest predictor of CHD risk (hazard ratio [HR] per 10 mm Hg increment, 1.34; 95% CI, 1.18 to 1.51) rather than SBP (HR, 1.14; 95% CI, 1.06 to 1.24) or PP (HR, 1.02; 95% CI, 0.89 to 1.17). In the group 50 to 59 years of age, risks were comparable for all 3 BP indexes. In the older age group, the strongest predictor of CHD risk was PP (HR, 1.24; 95% CI, 1.16 to 1.33). When both SBP and DBP were considered jointly, the former was directly and the latter was inversely related to CHD risk in the oldest age group Conclusions — With increasing age, there was a gradual shift from DBP to SBP and then to PP as predictors of CHD risk. In patients <50 years of age, DBP was the strongest predictor. Age 50 to 59 years was a transition period when all 3 BP indexes were comparable predictors, and from 60 years of age on, DBP was negatively related to CHD risk so that PP became superior to SBP.

Predominance of Isolated Systolic Hypertension Among Middle-Aged and Elderly US Hypertensives: Analysis Based on National Health and Nutrition Examination Survey (NHANES) III

The purpose of the present study was to examine patterns of systolic and diastolic hypertension by age in the nationally representative National Health and Nutrition Examination Survey (NHANES) III and to determine when treatment and control efforts should be recommended. Percentage distribution of 3 blood pressure subtypes (isolated systolic hypertension, combined systolic/diastolic hypertension, and isolated diastolic hypertension) was categorized for uncontrolled hypertension (untreated and inadequately treated) in 2 age groups (ages <50 and ≥50 years). Overall, isolated systolic hypertension was the most frequent subtype of uncontrolled hypertension (65%). Most subjects with hypertension (74%) were ≥50 years of age, and of this untreated older group, nearly all (94%) were accurately staged by systolic blood pressure alone, in contrast to subjects in the untreated younger group, who were best staged by diastolic blood pressure. Furthermore, most subjects (80%) in the older untreated and the inadequately treated groups had isolated systolic hypertension and required a greater reduction in systolic blood pressure than in the younger groups (-13.3 and -16.5 mm Hg versus -6.8 and -6.1 mm Hg, respectively;P =0.0001) to attain a systolic blood pressure treatment goal of <140 mm Hg. Contrary to previous perceptions, isolated systolic hypertension was the majority subtype of uncontrolled hypertension in subjects of ages 50 to 59 years, comprised 87% frequency for subjects in the sixth decade of life, and required greater reduction in systolic blood pressure in these subjects to reach treatment goal compared with subjects in the younger group. Better awareness of this middle-aged and older high-risk group and more aggressive antihypertensive therapy are necessary to address this treatment gap.

Systolic Blood Pressure, Diastolic Blood Pressure, and Pulse Pressure as Predictors of Risk for Congestive Heart Failure in the Framingham Heart Study

Context Hypertension is a recognized risk factor for the development of congestive heart failure (CHF). By measuring blood pressure, however, we have not yet been able to understand the significance of pulse pressure as a contributor to CHF in middle-aged men and women. Contribution Using data from the Framingham Heart Study, the authors found that although elevations of systolic, diastolic, and pulse pressure were all related to the risk for CHF, the relation was strongest for systolic and pulse pressure. Cautions Understanding the relationships between systolic, diastolic, and pulse pressure and risk for CHF is helpful; however, they do not help determine the increased risk faced by a person with systolic hypertension who also has increased pulse pressure. The Editors Hypertension is the most common risk factor for congestive heart failure (CHF). It confers a twofold risk for the occurrence of CHF and also carries the highest population attributable risk among all risk factors for CHF (1, 2). Placebo-controlled clinical trials in patients with hypertension have demonstrated a consistent reduction in risk for CHF attributable to the lowering of elevated blood pressure (3-6). The causal role of hypertension in the pathogenesis of CHF underscores the need to identify high-risk patients because early treatment may prevent or delay the occurrence of CHF (2, 7). The prognostic significance of systolic and diastolic blood pressure in CHF has been reported. However, blood pressure may also be divided into two other components: steady (mean arterial pressure) and pulsatile (pulse arterial pressure) (8-10). Pulse pressure, a simple correlate of conduit vessel stiffness, is associated with left ventricular hypertrophy (11). Increased pulse pressure has also been implicated in the development and progression of large-vessel atherosclerosis and small-vessel disease (12-14). Accumulating evidence indicates that pulse pressure (defined as the difference between systolic and diastolic blood pressure) may be an important predictor of cardiovascular events (15-18). Pulse pressure predicts the risk for CHF in elderly persons (19, 20); however, the association of pulse pressure with CHF in middle-aged men and women has not been examined. The Framingham Heart Study provides an opportunity to examine the long-term associations of systolic, diastolic, and pulse pressure with the new onset of CHF in middle-aged and elderly men and women. Blood pressure and traditional risk factors have been measured repeatedly at serial examinations in this community-based cohort with long-term follow-up. We examined systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for CHF in the Framingham Heart Study. Methods The Framingham Heart Study, which began in 1948, has followed 5209 participants (28 to 62 years of age at entry to the study) as part of a prospective epidemiologic study of cardiovascular disease. Enrollment criteria and study design have been published previously (21). Biennial follow-up visits included a medical history, physical examination, blood pressure measurements, 12-lead electrocardiography, and laboratory tests. Eligibility requirements for inclusion in our study were as follows: Participants had to be free of coronary heart disease and CHF and not be receiving antihypertensive therapy at Framingham Heart Study clinic baseline examinations 10, 11, or 12 (1968 to 1973). Participants were followed for onset of CHF through mid-1994. We obtained data for selected risk factors from the baseline examination. Methods for assessing risk factors have been published previously (21, 22). Risk factors, including age, sex, cigarette smoking, heart rate, antihypertensive medication use, and total and high-density lipoprotein cholesterol levels, were assessed. Sitting systolic and diastolic blood pressure were measured twice by the examining physician (using a mercury column sphygmomanometer) and averaged. We used body mass index (kg/m2) as a measure of obesity. Participants were categorized as smokers if they smoked cigarettes regularly within the 1-year period before the baseline examination. Electrocardiography revealed left ventricular hypertrophy when increased voltage was associated with major ST-T repolarization changes (strain pattern) (22). Diabetes mellitus was defined on the basis of a fasting blood glucose level greater than 7.77 mmol/L (>140 mg/dL), two random nonfasting blood glucose levels greater than 11.10 mmol/L (>200 mg/dL), or the use of insulin or an oral hypoglycemic agent. Diagnostic criteria for CHF have been described previously (21, 22). At each clinic examination, a history of interim hospitalizations and symptoms of CHF were obtained. Outside medical records of participants who did not attend an examination were evaluated for incident CHF. All suspected interim events were reviewed by a panel of three physicians who evaluated relevant Framingham Heart Study clinic notes, outside physician reports, and hospitalization records. Congestive heart failure was diagnosed when at least two major or one major and two minor criteria were present. Minor criteria were considered only if their presence could not be attributed to another disease process. Major criteria were paroxysmal nocturnal dyspnea, pulmonary rales, distended jugular veins, enlarging heart size on chest radiography, acute pulmonary edema, hepatojugular reflux, third heart sound, jugular venous pressure of 16 cm or greater, and weight loss of 4.5 kg or greater in response to diuresis. Major criteria also included pulmonary edema, visceral congestion, or cardiomegaly on autopsy. Minor criteria were bilateral ankle edema, nocturnal cough, shortness of breath on ordinary exertion, hepatomegaly, pleural effusion, decrease in vital capacity by one third from the previous maximum recorded value, and heart rate of 120 beats/min or more. Statistical Analysis We used multivariable Cox proportional-hazards regression models to examine the relations of systolic, diastolic, and pulse pressure with CHF. After accounting for age and sex and using a P value less than 0.15 as the selection criterion, we determined covariates by stepwise selection from the following list: body mass index, diabetes, smoking status, total cholesterol level, high-density lipoprotein (HDL) cholesterol level, totalHDL cholesterol ratio, left ventricular hypertrophy, and heart rate. Only total cholesterol level and totalHDL cholesterol ratio did not enter the model. After accounting for relevant covariates, we used Cox proportional-hazards models to obtain hazard ratio estimates with 95% CIs for standardized values of systolic, diastolic, and pulse pressure. These estimates were obtained individually and pairwise by using SAS software (SAS Institute, Inc., Cary, North Carolina) (23). We repeated analyses for participants stratified according to hypertension status and sex. Because blood pressure and age are correlated, we conducted separate analyses for participants younger than 60 years of age and 60 years of age and older. To examine constancy of effects over time, follow-up was divided into early and late periods (<10 years, 10 years), and hazard ratios were calculated separately for early and late follow-up. In addition, we analyzed blood pressure as a time-varying covariate and assessed the effect of antihypertensive treatment after the baseline blood pressure measurements. We used the KaplanMeier method to plot age- and sex-standardized cumulative incidence rates for CHF as a function of pulse pressure tertile at baseline. Descriptive data are presented as percentages or means (SD). A P value less than 0.05 was considered statistically significant. Role of the Funding Sources The funding sources had no role in the design, conduct, analyses, and reporting of the study or in the decision to submit the manuscript for publication. Results A total of 894 men and 1146 women, age 50 to 79 years, fulfilled criteria for inclusion in our study. Table 1 presents baseline clinical characteristics for these persons. During 35 497 person-years of follow-up (mean, 17.4 years [range, 0.06 to 24 years]), CHF developed in 234 (11.8%) persons. Myocardial infarction preceded CHF in 59 (25%) persons. Table 1. Baseline Clinical Characteristics of the Study Participants Increments of 1 SD in systolic pressure, pulse pressure, and diastolic pressure were associated with hazard ratios for congestive failure of 1.56, 1.55, and 1.24, respectively, after adjustment for age, sex, smoking, left ventricular hypertrophy, body mass index, diabetes mellitus, HDL cholesterol level, and heart rate (Table 2). When blood pressure tertiles were used, similar associations were observed among various components of blood pressure and CHF. No threshold effect or J-shaped association was documented (Table 2). The cumulative incidence of CHF according to tertiles of baseline pulse pressure is plotted in the Figure. Table 2. Risk FactorAdjusted Association of Blood Pressure with Congestive Heart Failure Figure. Cumulative incidence of congestive heart failure according to pulse pressure tertiles at the baseline examination. The joint influences of different blood pressure components were also examined, with adjustment for the covariates mentioned previously. Of note, correlations among the blood pressure variables ranged from modest to very high (r = 0.20 for diastolic and pulse pressure, r = 0.65 for diastolic and systolic pressure, and r = 0.88 for systolic and pulse pressure). Diastolic pressure was not significant (hazard ratio, 1.12 [CI, 0.98 to 1.29]) in conjunction with pulse pressure (hazard ratio, 1.51 [CI, 1.33 to 1.72]). Likewise, diastolic pressure was not significant (hazard ratio, 0.86 [CI, 0.72 to 1.03]) in conjunction with systolic pressure (hazard ratio, 1.71 [CI, 1.45 to 2.01]), but joint estimates were less stable than those obtained for individual pressure variables. Finally,

Single Versus Combined Blood Pressure Components and Risk for Cardiovascular Disease: The Framingham Heart Study

Background— The utility of single versus combined blood pressure (BP) components in predicting cardiovascular disease (CVD) events is not established. We compared systolic BP (SBP) and diastolic BP (DBP) versus pulse pressure (PP) and mean arterial pressure (MAP) combined and each of these 4 BP components alone in predicting CVD events. Methods and Results— In participants in the original (n=4760) and offspring (n=4897) Framingham Heart Study who were free of CVD events and BP-lowering therapy, 1439 CVD events occurred over serial 4-year intervals from 1952 to 2001. In pooled logistic regression with the use of BP categories, combining SBP with DBP and PP with MAP improved model fit compared with individual BP components (P<0.05 to P<0.0001). Significant interactions were noted between SBP and DBP (P=0.02) and between PP and MAP (P=0.01) in their respective multivariable models. Models with continuous variables for SBP+DBP and PP+MAP proved identical in predicting CVD events (Akaike Information Criteria=10 625 for both). Addition of a quadratic DBP2 term to DBP and SBP further improved fit (P=0.0016). Conclusions— Combining PP with MAP and SBP with DBP produced models that were superior to single BP components for predicting CVD, and the extent of CVD risk varied with the level of each BP component. The combination of PP+MAP (unlike SBP+DBP) has a monotonic relation with risk and may provide greater insight into hemodynamics of altered arterial stiffness versus impaired peripheral resistance but is not superior to SBP+DBP in predicting CVD events.

Systolic and Diastolic Blood Pressure Lowering as Determinants of Cardiovascular Outcome

Based on individual patient data, we performed a quantitative overview of trials in hypertension to investigate to what extent lowering of systolic blood pressure (SBP) and diastolic blood pressure (DBP) contributed to cardiovascular prevention. We selected trials that tested active antihypertensive drugs against placebo or no treatment. Our analyses included 12 903 young (30 to 49 years of age) patients randomized in 3 trials and 14 324 old (60 to 79 years of age) and 1209 very old (≥80 years of age) patients enrolled in 8 trials. Antihypertensive treatment reduced SBP/DBP by 8.3/4.6 mm Hg in young patients, by 10.7/4.2 mm Hg in old patients, and by 9.4/3.2 mm Hg in very old patients, respectively, resulting in ratios of DBP to SBP lowering of 0.55, 0.39, and 0.32, respectively (P=0.004 for trend with age). In spite of the differential lowering of SBP and DBP, antihypertensive treatment reduced the risk of all cardiovascular events, stroke and myocardial infarction in the 3 age strata to a similar extent. Absolute benefit increased with age and with lower ratio of DBP to SBP lowering. Furthermore, in patients with a larger-than-median reduction in SBP, active treatment consistently reduced the risk of all outcomes irrespective of the decrease in DBP or the achieved DBP. These findings remained consistent if the achieved DBP averaged <70 mm Hg. In conclusion, our overview suggests that antihypertensive drug treatment improves outcome mainly through lowering of SBP.

Nitric Oxide and the Regulation of Large Artery Stiffness: From Physiology to Pharmacology

The association between arterial stiffening and aging is well described and can be observed in almost all populations worldwide. A number of other cardiovascular risk factors including diabetes and cigarette smoking are also associated with increased large artery stiffness, often referred to as “premature arterial stiffening.” It is now apparent that the aortic pulse wave velocity (PWV), a measure of arterial distensibility, predicts outcome in a variety of different populations, including hypertensives,1 diabetics,2 individuals with end-stage renal disease (ESRD),3 and even in older adults.4 Indeed, in some populations, aortic PWV is a better predictor of future events than peripheral blood pressure.4 Moreover, arterial stiffening may be more than just a marker of cardiovascular risk; stiffening may also play a more direct role in the development of atherosclerotic plaques. Thus, arterial stiffness would appear to be a novel therapeutic target for the prevention of excess cardiovascular morbidity and mortality. To exploit such an exciting prospect fully, it is necessary to understand the factors regulating arterial stiffness. Traditionally, the stiffness of a vessel was viewed as simply a function of the structural elements of the vessel wall and distending (mean arterial) pressure. However, the large arteries also have a generous coat of smooth muscle, which can alter the distribution of stresses between the elastic and collagenous fibers of the vessel wall and thus alter arterial stiffness. Because smooth muscle tone is influenced by a number of circulating and local vasoactive mediators, arterial stiffness may be actively regulated, and indeed modifiable, at least in the short-term. The muscular arteries have a rich sympathetic innervation, and catecholamines are known to alter smooth muscle tone. Moreover, removal of the vascular endothelium in animals alters large artery stiffness,5,6 suggesting that endothelial-derived substances regulate arterial stiffness in vivo. However, the endothelium …

Predictors of New-Onset Diastolic and Systolic Hypertension: The Framingham Heart Study

Background—Factors leading differentially to the development of isolated diastolic (IDH), systolic-diastolic (SDH), and isolated systolic (ISH) hypertension are poorly understood. We examined the relations of blood pressure (BP) and clinical risk factors to the new onset of the 3 forms of hypertension. Methods and Results—Participants in the Framingham Heart Study were included if they had undergone 2 biennial examinations between 1953 and 1957 and were free of antihypertensive therapy and cardiovascular disease. Compared with optimal BP (SBP <120 and DBP <80 mm Hg), the adjusted hazard ratios (HRs) for developing new-onset IDH over the ensuing 10 years were 2.75 for normal BP, 3.29 for high-normal BP (both P<0.0001), 1.31 (P=0.40) for SDH, and 0.61 (P=0.36) for ISH. The HRs of developing new-onset SDH were 3.32, 7.96, 7.10, and 23.12 for the normal BP, high-normal BP, ISH, and IDH groups, respectively (all P<0.0001). The HRs of developing ISH were 3.26 for normal and 4.82 for high-normal BP (both P<0.0001), 1.39 (P=0.24) for IDH, and 1.69 (P<0.01) for SDH. Increased body mass index (BMI) during follow-up predicted new-onset IDH and SDH. Other predictors of IDH were younger age, male sex, and BMI at baseline. Predictors of ISH included older age, female sex, and increased BMI during follow-up. Conclusion—Given the propensity for increased baseline BMI and weight gain to predict new-onset IDH and the high probability of IDH to transition to SDH, it is likely that IDH is not a benign condition. ISH arises more commonly from normal and high-normal BP than from “burned-out” diastolic hypertension.

Different Prognostic Impact of 24-Hour Mean Blood Pressure and Pulse Pressure on Stroke and Coronary Artery Disease in Essential Hypertension

Background—We tested the hypothesis that the steady and pulsatile components of blood pressure (BP) exert a different influence on coronary artery disease and stroke in subjects with hypertension. Methods and Results—We analyzed data on 2311 subjects with essential hypertension. All subjects (mean age 51 years, 47% women) underwent off-therapy 24-hour ambulatory BP monitoring. Over a follow-up period of up to 14 years (mean 4.7 years), there were 132 major cardiac events (1.20 per 100 person-years) and 105 cerebrovascular events (0.90 per 100 person-years). After adjustment for age, sex, diabetes, serum cholesterol, and cigarette smoking (all P <0.01), for each 10 mm Hg increase in 24-hour pulse pressure (PP), there was an independent 35% increase in the risk of cardiac events (95% CI 17% to 55%). Twenty-four-hour mean BP was not a significant predictor of cardiac events after controlling for PP. After adjustment for age, sex, and diabetes (all P <0.05), for every 10 mm Hg increase in 24-hour mean BP, the risk of cerebrovascular events increased by 42% (95% CI 19% to 69%), and 24-hour PP did not yield significance after controlling for 24-hour mean BP. Twenty-four-hour PP was also an independent predictor of fatal cardiac events, and 24-hour mean BP was an independent predictor of fatal cerebrovascular events. Conclusions—In subjects with predominantly systolic and diastolic hypertension, ambulatory mean BP and PP exert a different predictive effect on the cardiac and cerebrovascular complications. Although PP is the dominant predictor of cardiac events, mean BP is the major independent predictor of cerebrovascular events.