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Background Patients with isolated systolic hypertension are at increased risk for cardiovascular disorders. We attempted to determine whether those with borderline isolated systolic hypertension (defined as a systolic blood pressure of 140 to 159 mm Hg and a diastolic blood pressure below 90 mm Hg) have a greater risk of progression to definite (more severe) hypertension and of major morbid or fatal events than people with normal blood pressure (<140/90 mm Hg).
Methods A total of 2767 of the original participants in the Framingham Heart Study were monitored with biennial examinations for up to 34 years for the development of definite hypertension (defined as a systolic blood pressure of
Results Borderline isolated systolic hypertension was the most common type of untreated hypertension among adults over the age of 60. After 20 years of follow-up, 80 percent of those with borderline isolated systolic hypertension had progression to definite hypertension, as compared with 45 percent of the normotensive participants (P<0.001). After adjustment for age, sex, and risk factors for cardiovascular disease, participants with borderline isolated systolic hypertension had an excess long-term risk of cardiovascular disease (hazard ratio, 1.47; 95 percent confidence interval, 1.24 to 1.74) and death from cardiovascular disease (hazard ratio, 1.57; 95 percent confidence interval, 1.24 to 2.00), as compared with normotensive participants. In an analysis of pooled data from biennial examinations to study short-term sequelae, subjects with borderline isolated systolic hypertension had an increased risk of progression to definite hypertension (odds ratio, 3.84; 95 percent confidence interval, 3.35 to 4.41) and of cardiovascular disease (odds ratio, 1.39; 95 percent confidence interval, 1.06 to 1.82).
Conclusions In both the short term and the long term, subjects with borderline isolated systolic hypertension are at increased risk of progression to definite hypertension and the development of cardiovascular disease.
160 mm Hg, a diastolic blood pressure of 90 mm Hg, or the initiation of antihypertensive therapy) and for major cardiovascular events.
Borderline isolated systolic hypertension, defined as a systolic blood pressure between 140 and 159 mm Hg and a diastolic blood pressure below 90 mm Hg, was introduced as a category of hypertension by the Joint National Committee10 in 1984 and was further emphasized in the 198811 and 199312 reports on the detection, evaluation, and treatment of high blood pressure. In their 1993 guidelines for the management of mild hypertension, the World Health Organization and the International Society of Hypertension also identified borderline isolated systolic hypertension as a distinct subgroup13. Although borderline isolated systolic hypertension is now classified separately, little is known about its prevalence, its natural history, and the risks of major cardiovascular disease associated with it.
The goals of this investigation were to determine the prevalence of borderline isolated systolic hypertension, to examine its progression to definite hypertension, and to evaluate whether it is associated with an increased risk of cardiovascular disease and death.
Methods
The Framingham Heart Study began in 1948 with the enrollment of 5209 men and women 28 to 62 years of age. These participants have been examined every two years since. Each examination includes an extensive cardiovascular history taking and physical examination, blood-pressure determinations, 12-lead electrocardiography, and measurement of other physiologic variables. Morbidity and mortality are continuously monitored by hospital surveillance and by communication with personal physicians and relatives. All new cardiovascular events are reviewed by a panel of three experienced investigators. Detailed descriptions of sampling methods, examination techniques and procedures, and the criteria for various end points related to cardiovascular disease have been published14,15,16.
Readings of systolic and diastolic blood pressure are taken from the left arm of each subject with a mercury-column sphygmomanometer while the subject is sitting. Readings are recorded to the nearest even number. A larger cuff is used when required. The fifth Korotkoff sound (disappearance) is used to determine diastolic pressure unless the sound persists to zero, in which case the fourth sound is recorded. Data on the use of antihypertensive agents are obtained at each examination.
Definition and Categorization of Normal and High Blood Pressure
Determinations of systolic and diastolic blood pressure were based on the average of two separate measurements recorded by the examining physician at each examination. Normal blood pressure was defined as a systolic blood pressure below 140 mm Hg and a diastolic blood pressure below 90 mm Hg. Borderline isolated systolic hypertension was defined as a systolic blood pressure between 140 and 159 mm Hg and a diastolic blood pressure below 90 mm Hg11. Definite isolated systolic hypertension was defined as a systolic blood pressure of at least 160 mm Hg and a diastolic blood pressure below 90 mm Hg. Isolated diastolic hypertension was defined as a diastolic blood pressure of at least 90 and a systolic blood pressure below 160. Definite hypertension was defined as a systolic blood pressure of at least 160 mm Hg or a diastolic blood pressure of at least 90 mm Hg. Subjects taking antihypertensive medications were considered to have definite hypertension regardless of their measured blood pressure. Measurements from the first biennial examination were not used because blood-pressure values at that examination (both systolic and diastolic) were higher than those of subsequent examination cycles. This finding is consistent with the presence of a first-visit, "white coat" hypertensive effect.
End Points
The end points used in this study included progression to definite hypertension; fatal or nonfatal coronary heart disease; total cardiovascular events, including coronary heart disease, cerebrovascular events, and congestive heart failure; mortality from cardiovascular disease; and mortality from all causes. All cardiovascular events were assessed by a panel of three physicians. The subjects were considered to have coronary heart disease if they fulfilled previously published criteria16 for angina pectoris, coronary insufficiency (angina pectoris lasting 20 minutes or more and accompanied by ischemic electrocardiographic changes), myocardial infarction, or death from coronary heart disease. Stroke was defined as the abrupt onset of a localized neurologic deficit, such as hemiparesis, aphasia, or homonymous hemianopia, lasting 24 hours or more. A transient ischemic attack was defined as a focal neurologic deficit lasting less than 24 hours.
Statistical Analysis
Progression to definite hypertension, the incidence of cardiovascular events, and mortality from all causes were analyzed on a long-term and a short-term basis, with adjustment for the subjects' sex, age (according to decade), and other indicator variables. Key risk factors for cardiovascular disease were included. All P values were two-tailed, with a P value of less than 0.05 considered to indicate statistical significance, and 95 percent confidence intervals were computed for hazard ratios and odds ratios.
Long-Term Follow-up
At each examination, the participants were classified as having normal blood pressure, borderline isolated systolic hypertension, or definite hypertension. Subjects were excluded if they did not attend examination 2, 3, or 4 (n = 281); if they had definite hypertension (n = 1900) or cardiovascular disease (n = 96) at any of those examinations; or if they had no further follow-up (n = 165). The remaining participants (n = 2767) were classified according to blood-pressure status at examinations 2, 3, and 4. They were considered normotensive if they were normotensive at each examination attended (n = 2416), but were classified as having borderline isolated systolic hypertension (n = 351) if they had borderline isolated systolic hypertension at examination 2, 3, or 4.
Follow-up for hypertension extended to the most recent examination attended, whereas follow-up for cardiovascular events and for mortality extended to the date of death or last contact. In both cases, the upper limit of follow-up was the 19th examination date.
Age-stratified (according to decade) and sex-stratified analyses were used for incident events. Life-table analysis and the log-rank test17 were used to analyze progression to definite hypertension with the SAS Lifetest procedure18. Proportional-hazards regression models17 were used to analyze the length of time to cardiovascular events and survival with the SAS Phreg procedure19. These models adjusted for the following cardiovascular risk factors: total cholesterol level (in milligrams per deciliter), body-mass index (the weight in kilograms divided by the square of the height in meters), glucose intolerance (no vs. yes), and cigarette smoking (fewer than 10 cigarettes per day vs. 10 or more per day).
Short-Term Follow-up
The pooled-examination approach20,21 was used to analyze events occurring between successive biennial examinations. Starting with the 2nd and ending with the 18th examination, each examination attended by a subject was considered an index visit. A visit was used for analysis if the subject was free of cardiovascular disease and had no history of it. Blood-pressure classification was made at each index visit. Attendance at the subsequent biennial examination was necessary to determine whether definite hypertension had occurred in the interim. Subjects who died before the next scheduled examination, or who did not attend it, did not provide data about definite hypertension for the interim period. Since data on mortality and nonfatal cardiovascular events were obtained from multiple sources, not just the clinic visits, attendance at the subsequent examination was not required to assess these events. If a subject failed to attend the next scheduled visit, the follow-up ended at the date of last contact or two years after the index visit, whichever was earlier.
Logistic models22 were used to analyze interim events with the SAS Logistic procedure18. All models included indicator variables for sex and age (according to decade) as well as the cardiovascular risk factors mentioned above.
Results
Prevalence of Borderline Isolated Systolic Hypertension
The prevalence of borderline isolated systolic hypertension among untreated participants increased with age in both sexes and rose continuously from 30 to 70 years of age. By the age of 70, almost 20 percent of the men and women had borderline isolated systolic hypertension (Figure 1). The frequencies of the various forms of untreated hypertension are shown in Figure 2 for men and Figure 3 for women. In men 30 to 59 years of age, isolated diastolic hypertension was the most frequent type of untreated hypertension, but beyond the age of 60, borderline isolated systolic hypertension was the most common category. The distribution of the various types of untreated hypertension was similar among the women.
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Long-Term Follow-up
Among 2767 subjects eligible for long-term analyses, 41 percent were men and 59 percent were women (mean age, 47.4 years; range, 31 to 68). A total of 351 participants (130 men and 221 women) free of cardiovascular disease who attended examination 2, 3, or 4 met the criteria for borderline isolated systolic hypertension; another 2416 were normotensive. The subjects with borderline isolated systolic hypertension were more likely to have progression to definite hypertension than those with a normal blood pressure at base line (Table 1). These differences were already apparent after 10 years of follow-up. After 20 years of follow-up, 80 percent of the men and 81 percent of the women with borderline isolated systolic hypertension had progression to definite hypertension, as compared with 45 percent of the men and 45 percent of the women with normal blood pressure at base line. Age-stratified log-rank tests showed that the increased risk of progression to definite hypertension was statistically significant for each sex (P<0.001).
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A total of 22,419 person-examinations were analyzed; 39 percent were for men and 61 percent were for women (mean age, 54.0 years; range, 31 to 91). Odds ratios adjusted for age, sex, and risk factors revealed a substantially increased risk of short-term progression to definite hypertension among subjects with borderline isolated systolic hypertension as compared with those with normal blood pressure (odds ratio, 3.84; 95 percent confidence interval, 3.35 to 4.41) (Table 3).
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Additional Analyses
As compared with subjects with optimal blood pressure (systolic pressure below 120 mm Hg and diastolic pressure below 80 mm Hg), those with borderline isolated systolic hypertension had a significantly increased long-term risk of cardiovascular disease (hazard ratio, 1.80), coronary heart disease (hazard ratio, 1.65), and death from cardiovascular disease (hazard ratio, 2.29). They also had an increased risk of cardiovascular disease (odds ratio, 1.71), coronary heart disease (odds ratio, 1.74), and progression to definite hypertension (odds ratio, 11.68) in the short term.
Secondary analyses of our long-term data showed that subjects classified as having borderline hypertension more than once during examination 2, 3, or 4 had an increased risk of cardiovascular sequelae as compared with subjects who had just one elevated reading. Because of the small numbers of events in each subgroup, there was not enough power to detect statistically significant differences between subgroups.
Discussion
Systolic blood pressure is a continuous variable, and its associated risks increase from the lowest to the highest values. This has been shown by the Build and Blood Pressure studies in 1959 and 197923,24 and by the recent analyses of data from subjects screened in the Multiple Risk Factor Intervention Trial8,25. Consequently, any cutoff points used to define the existence of hypertension are arbitrary. Nevertheless, categorical definitions of hypertension are useful when they differentiate levels of risk and when they lead to blood-pressure treatment that reduces risk. When the risk associated with a blood-pressure category approaches two times, or even one and a half times, the risk associated with the most favorable "normal" blood pressure in the population, the blood-pressure level associated with that risk warrants recognition26.
In the present study, borderline isolated systolic hypertension was the most common form of untreated hypertension, with a prevalence of 18 percent among participants 65 years of age and older. Subjects with this type of hypertension were at substantially increased risk of progression to definite hypertension in both short-term and long-term analyses. Subjects with borderline isolated systolic hypertension also had a greater risk of morbidity (long-term and short-term) and mortality (long-term) from cardiovascular disease than normotensive subjects. The increased risk of cardiovascular disease was even more striking when we compared subjects with borderline isolated systolic hypertension with those with optimal blood pressure.
In 1984, the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure introduced the concept of borderline isolated systolic hypertension10. In that report, the prevalence of borderline isolated systolic hypertension was said to be 8.4 percent in subjects 18 to 73 years of age; it was the second most common type of hypertensive condition (26 percent). Recently, this category of blood pressure was further emphasized in the fifth report of the Joint National Committee12. In that report, borderline isolated systolic hypertension was included in the category of stage 1 (mild) hypertension and recognized as a form associated with increased morbidity from cardiovascular disease warranting effective long-term therapy. Despite the fact that borderline isolated systolic hypertension is common, it is the least thoroughly studied type of hypertension.
Contrary to earlier beliefs that the diastolic component of blood pressure is the chief determinant of cardiovascular risk, there is a growing body of evidence that systolic hypertension may be a more important contributor to risk than its diastolic counterpart2,3,4,5,6,7,8,9,25. These observations are particularly important and timely in terms of therapy for elderly persons. For example, the Systolic Hypertension in the Elderly Program recently documented that the treatment of definite isolated systolic hypertension in elderly persons substantially decreases the incidence of stroke and major cardiovascular events9.
Progression to Definite Hypertension
Subjects with borderline isolated systolic hypertension had progression to definite hypertension more often than those with normal blood pressure. These findings are in accord with previous studies that found that the level of blood pressure (systolic and diastolic) at base line was predictive of the development of hypertension27,28. Leitschuh et al.27 showed that subjects in the Framingham Heart Study who had high-normal diastolic blood pressure had progression to hypertension two to three times as often as those with normal blood pressure. They recommended that such subjects be monitored more frequently and counseled on methods of modifying other risk factors for cardiovascular disease.
Two recent clinical trials on the primary prevention of hypertension29,30 showed that nonpharmacologic measures could prevent progression to more advanced hypertension in subjects with high-normal blood pressure. Our findings indicate that further research is needed to determine whether progression from borderline isolated systolic hypertension to definite hypertension is preventable by nonpharmacologic means.
Borderline Isolated Systolic Hypertension and Cardiovascular Disease Sequelae
A recent report7 from the Cardiovascular Health Study showed that borderline isolated systolic hypertension is strongly related to some measures of subclinical cardiovascular disease, such as myocardial infarction and increased left ventricular mass. Yet the authors conceded that the cross-sectional nature of their analysis limited the ability to infer a causal association. Our study was based on repeated measurements of blood pressure from as many as 18 biennial examinations over a 34-year period of follow-up, permitting the exclusion of subjects with definite hypertension at any previous examination. A prospective study design allows a better assessment of the risks associated with this form of hypertension. The current study supports the view that borderline isolated systolic hypertension and the risk of cardiovascular disease are causally related.
Mechanisms of Risk
Hypertension has been shown to accelerate atherogenesis in animals, and reducing blood pressure has been shown to retard this process31,32. The increased risk of cardiovascular disease sequelae in our subjects with borderline isolated systolic hypertension was partly mediated by the high rate of progression to definite hypertension. In the long-term analyses of subjects with borderline isolated systolic hypertension in whom a cardiovascular disease end point occurred, 60 percent had gone on to have definite hypertension before the cardiovascular event occurred, whereas the remaining 40 percent of subjects had no evidence of progression to definite hypertension before the cardiovascular event. These findings suggest that borderline isolated systolic hypertension may increase the risk of cardiovascular disease directly, without progression, or indirectly by progression to definite hypertension. Either way, borderline isolated systolic hypertension is a risk factor for cardiovascular disease.
Limitations
The study sample consisted mostly of white, middle-class subjects, so the results and recommendations of this study should be interpreted with caution when applied to other populations.
Questions have been raised about the use of base-line blood-pressure measurements on a single occasion as a predictor of the risk of cardiovascular disease26. Yet data from several prospective epidemiologic studies have shown that the risks of morbidity and mortality over stated intervals of follow-up are predicted by such measurements16,23,24,33. Previous data from the Framingham Heart Study indicated that the measurements obtained at the first visit predict the incidence of cardiovascular disease at least as well as do measurements obtained on subsequent occasions2. According to the final report of the Working Group on Risk and High Blood Pressure,26 the risks can be predicted from single measurements of blood pressure, whereas the effects of treatment can be shown only in terms of the change in blood pressure in relation to levels recorded on two or more occasions before treatment.
Another potential limitation of the study is the lability of blood pressure, which can lead to misclassification of the hypertension status of subjects. Kannel et al., using multivariable analyses, demonstrated that there is no evidence that lability of pressure independently influences cardiovascular risk in subjects with isolated systolic hypertension2. Finally, since blood pressure was measured only once every two years, it is possible that during this interval some patients with borderline isolated systolic hypertension had progression to more advanced hypertension without detection.
Clinical Implications
In our study, participants with borderline isolated systolic hypertension were at increased risk of progression to definite hypertension, cardiovascular disease morbidity, and death from cardiovascular disease. In the light of these findings, earlier interventions to prevent the progression of borderline isolated systolic hypertension to more severe hypertension would appear justified. Accordingly, people with borderline isolated systolic hypertension should be informed of their blood pressure and observed more frequently. Nonpharmacologic measures of blood-pressure reduction and the modification of cardiovascular disease risk factors should be considered for those with borderline isolated systolic hypertension. It is not known whether nonpharmacologic or pharmacologic treatment of borderline isolated systolic hypertension can reduce the substantial cardiovascular burden associated with it.
Source Information
From the Framingham Heart Study, Framingham, Mass. (A.S., M.G.L., D.L.); the National Heart, Lung, and Blood Institute, Bethesda, Md. (M.G.L., D.L.); the Divisions of Epidemiology and Preventive Medicine, Boston University School of Medicine, Boston (D.L.); and the Divisions of Cardiology and Clinical Epidemiology, Beth Israel Hospital, Boston (D.L.). Dr. Sagie was a visiting Research Fellow from Beilinson Medical Center, Petah Tikva, Israel, and the Tel Aviv University Sackler School of Medicine, Tel Aviv, Israel.Presented at the 66th Scientific Sessions of the American Heart Association, November 8-11, 1993.
Address reprint requests to Dr. Levy at the Framingham Heart Study, 5 Thurber St., Framingham, MA 01701.
References
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Related Letters:
Borderline Systolic Hypertension
Selverstone N. J., Sagie A., Larson M. G., Levy D.
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Full Text
N Engl J Med 1994;
330:1392, May 12, 1994.
Correspondence
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