Borderline Hypertension: An Overview

Symposium on Hypertension

Borderline Hypertension An Overview

Stevo Julius, M.D.*

It is estimated that 18 million adult Americans have marginal elevations in blood pressure (Fig. 1). The management of this large group of subjects constitutes a perplexing problem. Some of these patients later become normotensive, while in others severe hypertension develops. A review of the medical literature is not helpful. For example, a recent national recommendation was made that treatment be individualized in borderline hypertension,61 but no criteria for such individualization was provided. The purpose of this paper is to review the pathophysiology and epidemiology of borderline hypertension in order to assess the clinical importance of this entity and to provide a basis for a rational approach to the patient.

TERMINOLOGY AND CLASSIFICATION Various terms have been used to describe the "gray zone" between normotension and hypertension. "Prehypertension" is not applicable since it implies the inevitability of subsequent hypertension, which is not always the case. Severe hypertension does not necessarily develop in all individuals with borderline hypertension; though it develops more often than in subjects with normal blood pressure. The terms "labile," "occasional," and "transient" hypertension also have drawbacks. They intend to differentiate between the constantly elevated ("stable") and occasionally elevated ("labile") levels in relation to a narrow and arbitrary range of blood pressure. Thus if a diastolic pressure of 90 mm Hg is considered the upper limit of normal, a patient with three determinations of 92 mm Hg diastolic will have "stable" hypertension whereas the individual with levels of 88, 92, and 94 mm Hg will have the presumably more benign "labile" hypertension. The average readings in these two patients are the same. Sokolow and co-workers 51 have clearly shown that *Professor of Internal Medicine, and Director of Hypertension Division, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

Medical Clinics of North America-Vol. 61, No. 3, May 1977

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severity of hypertension depends on the average blood pressure levels and not on the range of the blood pressure. The term "borderline" hypertension, on the other hand, is sufficiently descriptive and does not carry unwarranted connotations. Blood pressure can be classified by setting the limits of normotension and indisputable hypertension and designating the range between these two limits as borderline hypertension, making allowances for the age of the individual. Utilizing the known distribution of blood pressure in a large sample of the adult population 1 and morbidity data, 26 the classification given in Table 1 appears reasonable. It should be pointed out that hypertension is considered borderline if (1) levels are always between the hypertensive and normotensive range, or (2) some levels in the borderline or hypertensive range with occasional normal values, and (3) there Table 1. Blood Pressure Classification AGE

Normotension Hypertension Borderline hypertension

A

or

B

17-40

AGE

41-60

AGE

>60

<160/90 <140/90 <150/90 >175/100 >1601100 >160/100 >150/90 >160/90 > 140190 <175/100 <160/100 <160/100 Some levels hypertensive, some normotensive

BORDERLINE HYPERTENSION

497

is no target organ damage. If a subject has borderline blood pressure readings but also has Grade I or II hypertensive retinopathy, or electrocardiographic signs of ventricular hypertrophy, or impaired renal function, he is considered to have established arterial hypertension.

PATHOPHYSIOLOGY OF BORDERLINE HYPERTENSION If an individual's elevated blood pressure returns to the normal range after rest, it is generally assumed that all the underlying circulatory abnormalities have been corrected and that the individual is healthy. We investigated in our laboratory 145 men with borderline hypertension. 32 The average intra-arterial blood pressures were 135 ± 2 mm Hg systolic, 74 ± 2 diastolic (± = standard error). These levels are obviously normotensive, yet the patients exhibited a wide array of physiologic abnormalities. Table 2 lists the abnormalities described in borderline hypertension by various investigators. These observations suggest that borderline hypertension represents a profound and complex abnormality of the blood pressure regulating systems. Since it is known that borderline hypertension may be a precursor of established hypertension, physiologic abnormalities in borderline hypertension assume particular significance. The minimal increase in blood pressure in borderline hypertension precludes the possibility of altered cardiac function, resetting of arterial baroreceptors, changes in the arteriolar structure and other possible secondary adjustments to the high levels of blood pressure which occur in established hypertension. Thus borderline hypertension offers an opportunity to assess mechanisms which play a role in the initiation rather than the maintenance of essential hypertension. Abnormalities listed in Table 2 are not present in all subjects with

Table 2. Physiologic Abnormalities Observed in Subjects with Borderline Hypertension * Biochemical indices of increased sympathetic activity'3 Cardiac index increased" Tachycardia17 Stroke volume Increased 7 Decreased39 Peripheral resistance abnormal Increased47 Inappropriate in relation to flow 27 Peripheral to central distribution of the blood in the capacitance vessels" Plasma volume decreased'· Plasma renin activity High17

Low·

*References are to representative papers. Extensive references can be found in a recent review."'

498

STEVO ]ULIUS

borderline hypertension. Certain patterns of pathophysiologic abnormalities can be discerned, and will be analyzed from three points of reference: hemodynamics, involvement of the autonomic nervous system, and blood pressure variability. The relationship of the abnormal patterns to various concepts of the initiation and development of established hypertension will be discussed. Hemodynamic Patterns In established hypertension, peripheral resistance is elevated and cardiac output is normal. 13 A substantial proportion of patients with borderline hypertension have elevated cardiac output, the hallmark of the hyperkinetic circulation of borderline hypertension (Fig. 2). The cardiac output is increased because of a fast heart rate and a larger stroke volume. This increase is maintained by a neurogenic mechanism; when autonomic nervous influence on the heart is abolished, cardiac output returns to the normal range. 29 Both sympathetic and parasympathetic cardiac efferents are involved. Thus removal of the sympathetic cardiac

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Figure 2. Distribution of cardiac indices in patients with borderline hypertension (triangles) and normotensive central subjects (circles). Measurements are taken after 10 minutes by dye dilution with indocyanine green. Reprinted from Julius, S., and Conway, J.: Circulation, 38 :282-288, 1968. By courtesy of The American Heart ASSOciation, Inc.

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drive by high doses of intravenous propranolol does not suffice; only after the vagal inhibition is abolished with atropine does the cardiac output fall to normal. 29 In this regard the hyperkinetic circulation in borderline hypertension differs from the hyperkinetic heart syndrome 19 and the hyperdynamic beta adrenergic state 16 where an apparent isolated sympathetic overresponsiveness prevails. As can be seen from Figure 2, the majority of patients with borderline hypertension have normal cardiac output. The hemodynamics of these patients are similar to those of established essential hypertension, where the predominant abnormality is an elevated peripheral resistance. In established hypertension the peripheral resistance is elevated predominantly through a non-neurogenic mechanism. 35 Presumably, the contractile properties of the smooth muscle in the arteriolar wall are altered, 55 or secondary structural changes have developed in response to the increased pressure. 50 In the high resistance type of borderline hypertension, such changes in the vascular wall are already present, in spite of a minimal increase in blood pressure. In our studies, sympathetic blockade lowered peripheral resistance to normal in only 30 per cent of patients. s High resistance borderline hypertension resembles established hypertension in other ways: the plasma volume is decreased,2s,47 the heart rate is elevated but, as in established hypertension,35 the tachycardia is due to decreased para sympathetic inhibition,29 not increased sympathetic stimulation. The occurrence of high output and high resistance patterns in borderline hypertension raises a fundamental question about the development of hypertension. Is hypertension initiated by a cardiac output which is elevated above the metabolic needs of the tissues and does this then trigger an "autoregulatory" increase of the peripheral resistance? According to Guyton 20 this autoregulatory increase in resistance results in limitation of the flow and a new state of normal cardiac output and a high resistance hypertension develops. Hit were indeed proven that patients with high output borderline hypertension subsequently develop normal cardiac output-high resistance hypertension, the investigations into the causes of essential hypertension would have to be radically changed. The emphasis would shift from studying factors which change the arteriolar resistance to factors which alter the cardiac output. Hypertension would become a primary cardiogenic or at least heart-mediated disease. Among such individuals with elevated cardiac output who were studied serially, some subsequently developed high resistance fixed hypertension, while others did not. 2,6 The role of autoregulation in the development of human hypertension must be assessed in individuals with high cardiac output studied serially over time. The Cleveland group23 recently described patients with severe established hypertension who had increased cardiac output but who apparently never developed increased resistance by autoregulation. Furthermore Onesti and coworkers 45 have shown that volume expansion in some anephric patients causes an increase in cardiac output without a subsequent increase in

500

STEVO ]ULIUS

the peripheral resistance. Finally, in hyperkinetic borderline hypertension the stimulus for autoregulation seems to be absent. Autoregulation occurs when blood flow exceeds oxygen demands. Provided there is normal oxygen transport and oxygen utilization, the resting oxygen consumption should reflect the total tissue needs for oxygen. Autoregulation would occur in hyperkinetic borderline hypertension if the total blood flow (cardiac output) exceeded total oxygen consumption. However, in hyperkinetic borderline hypertension, oxygen consumption is increased 25 ,39,48 and the high output is appropriately related to this increase. 25 The role of cardiac output in the development of human hypertension should be investigated further. The development of hypertension through autoregulation remains an attractive but unproven hypothesis. Autonomic Nervous System Patterns

Abnormal regulation of the autonomic nervous system has been reported in borderline hypertension,31 but the abnormality is not present in all patients. If complete autonomic blockade results in normalization of a patient's blood pressure, it is reasonable to assume that the hypertension was mediated by a neurogenic mechanism. U sing this approach, one can define a group of patients with borderline hypertension who have a large neurogenic component, and others who exhibit little neurogenic abnormality. The plasma renin activity in the standing position related to the 24 hour urinary sodium excretion offers a means for discriminating between the "neurogenic" and "non-neurogenic" subsets of borderline hypertension. Signs of autonomic nervous activity are most prominent in patients with high plasma renin activitY,17 and in these patients total autonomic blockade causes normalization of the blood pressure. 8 The sympathetic activity in high renin borderline hypertension results in increased cardiac sympathetic drive,31 increased arteriolar alphaadrenergic tone 8 and increased beta-adrenergic tone. 54 Indirect evidence strongly suggests that the elevation in renin activity itself is another manifestation of the general increase in sympathetic tone. 8 In contrast, patients with low plasma renin activity appear to have decreased sympathetic tone. Their heart rate is not increased, signs of excessive cardiac sympathetic drive are absent, and there is no evidence for increased alpha-adrenergic drive. 8 Catecholamine levels have been reported to be low in low renin mild hypertension,9 and the blood pressure responds subnormally to tyramine, reflecting a low-level release of catecholamines from sympathetic nerve endings. The presence of a neurogenic factor in borderline hypertension suggests that in some cases established hypertension may have been initiated by a neurogenic mechanism. Reports of elevated plasma norepinephrine levels in a proportion of patients with borderline and with established hypertension 31 lend credence to the concept of sympathetic overactivity as a cause of established hypertension. The overall impression is that neurogenic factors play an important

BORDERLINE HYPERTENSION

501

role in the development of hypertension. The proof, however, must await serial studies of patients with borderline hypertension and various degrees of sympathetic involvement.

Patterns of Blood Pressure Variability Largely because of the connotations of the term "labile" hypertension (to differentiate "occasional" from "permanent" hypertension), it is frequently assumed that large fluctuations in blood pressure are the rule in borderline hypertension. There is no good evidence that this is the case. 26 There appears to be no relationship between the blood pressure elevation and blood pressure variability in borderline hypertension. 18 Excessive variability in blood pressure is thought to reflect a tendency to overrespond to various pressure-elevating physiologic stimuli. The original notion that patients with borderline hypertension are "cold pressor" hyperresponders has not been substantiated,26 and their blood pressure responses to dynamic 25,39,48 and static exercise 49 are normal. The majority of patients also have normal blood pressure response to tilt, but a subgroup are hyperresponsive. 15 Hyperresponsiveness to the stress of mental arithmetic in borderline hypertension has also been described. 44 The overall picture in borderline hypertension, therefore, is of one of normal variability in blood pressure. Nevertheless certain subgroups may well be hyperresponsive to specific stimuli. The question of blood pressure variability is of interest since it is postulated that repeated pressor episodes may lead to permanent hypertension. In Folkow's view, as the initial pressor stimuli causes medial hypertrophy in the arterioles, the wall to lumen ratio changes. 12 Arterioles with a thicker wall respond to normal physiologic stimuli with a substantially larger increase of the peripheral resistance than arterioles with normal wall thickness; consequently, the hypertension escalates and becomes self-perpetuating. It must be noted, however, that experimentally induced excessive variability in blood pressure does not invariably lead to sustained hypertension. Folkow and Rubinstein l l produced only mild hypertension by eliciting repeated pressor episodes through electrical stimulation of the central nervous system. Similarly, repeated pressor episodes from mental stress in squirrel monkeys produces only mild hypertension. 21 Finally, in dogs whose arterial baroreceptors have been removed, extreme variability in pressure occurs, but sustained hypertension fails to develop.4 In summary it is not likely that excessive blood pressure variability in borderline hypertension plays a major role in the development of fixed human hypertension.

EPIDEMIOLOGY OF BORDERLINE HYPERTENSION Prevalence The magnitude of the problem of borderline hypertension is illustrated in Figure 1. Many subjects with borderline hypertension remain undetected. In view of recent major efforts at educating the population

502

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J ULIUS

about hypertension and the increase in detection programs in the United States, practicing physicians may expect referral of ever increasing numbers of patients with borderline hypertension. A practical approach to these patients must be developed. The key lies in the natural history of borderline hypertension. Natural History Borderline hypertension is not an innocuous condition. The overall mortality exceeds the age-adjusted mortality for the general population. In the majority of studies, this excess is at least 100 per cent,43-47 but a 300 per cent excess has also been reported. 44 In order to draw appropriate therapeutic conclusions it must first be shown that the large mortality is directly related to the elevated blood pressure, and not to other characteristics of these patients. Psychosomatic abnormalities have been reported in borderline hypertension 26 and these could be independently related to the excessive mortality. In fact, one of the studies 36 reported an excess of accidental deaths and suicides in patients with borderline hypertension. If all excess deaths were proven to be related to the patients' mental status, the blood pressure elevation could be considered as a relatively unimportant incidental finding. Established hypertension, however, causes a clear pattern of morbidity, and if the blood pressure increase in borderline hypertension is harmful, the causes of death should resemble those observed in established hypertension. In Table 3, several studies are listed which indicate that borderline hypertension causes excessive cardiovascular morbidity and that the pattern of this morbidity resembles the well known cardiac sequelae of established hypertension. Of particular interest are observations in younger subjects in whom the initial marginal blood pressure elevation could not have been an expression of underlying atherosclerosis. These presumably healthy individuals with borderline hypertension, even when observed over a relatively short period of time, developed an excessive number of cardiovascular complications. The case becomes even stronger when one assesses the development of true established hypertension in patients who previously had borderline levels. In several studies,51-54 patients with borderline hypertension developed substantially more established hypertension than their normotensive counterparts. In conclusion, there are many patients with borderline hypertension and these patients suffer from excessive mortality which appears to be related to the later development of sustained hypertension and its sequelae. CLINICAL ASPECTS OF BORDERLINE HYPERTENSION The Clinical Dilemma Since development of late sustained hypertension appears to be the major cause of morbidity in patients with borderline hypertension, antihypertensive treatment should prove useful in borderline hypertension.

140/90 to 159/94 Diastolic>90 (20% readings >100) Frequently, but not always, diastolic>90

Mathewson41 Males Stamler et al 52 Males Thompson59 Both sexes

Levy et ala6 Males

BP>140/90 Av. 145/90 First casual 140/90-160/95 First casual 140/90-160/95 BP> 150 or 90 followed by normal readings

BLOOD PRESSURE IN MMHG

Heyden et al 22 Both sexes Kannel et alaa Males Females

AUTHOR

Cardiovascular complications (congestive heart failure, angina, myocardial infarction, ECG changes) strokes

Hypertension heart disease

Coronary heart disease

15 yr

Av. 10 yr exposure 20 yr 30 yr 15 yr

30-39 below 30 below 55 above 55 below 55 above 55

14 yr

Coronary heart disease 5 yr periods

below 50 above 50 below 50 above 50 30-34 35-39 40-44 45-49 50-54 55-59 15-44

14 yr

Disability and retirement for cardiovascular causes

21

AGE FIRST OBSERVED

Sustained hypertension with cardiovascular complications Coronary heart disease

LENGTH OF FOLLOW-UP 7 yr

TYPE OF MORBIDITY

Table 3. Cardiovascular Morbidity in Borderline Hypertension

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However, while it is true that established hypertension develops at least twice as frequently in patients with borderline hypertension as in normotensive subjects, the incidence of future hypertension is not overwhelming. The average prevalence reported in several series is 20 per cent;51'54 consequently in 10 to 20 years 80 per cent of young subjects with borderline hypertension will not develop significant hypertension. Since benefits from antihypertensive treatment can be expected only in the 20 per cent who are destined to become hypertensive, the question arises: should all subjects with borderline hypertension receive antihypertensive treatment in order to prevent complications in a minority of the whole group? The answer lies in determining whether the salutory effects ofthe treatment outweigh the possible harmful side-effects of the medication in the whole group. Presently this dilemma can not be adequately solved. The problem has been identified, and a number of prospective studies have been initiated to answer these specific questions. The results will be available within a few years. Until then, however, useful projections can be developed from reports in the literature. For example, experience of the Veterans Administration Cooperative Study 60 on the effect of treatment in mild hypertension can be combined with available data on the incidence (per cent development of new cases in a year) of future sustained hypertension in patients with borderline hypertension. 26 Assuming that (a) a certain percentage of patients with borderline hypertension will develop hypertension of similar severity to that seen in the Veterans Administration Study, (b) only in those subjects will the treatment be useful, and (c) benefits of the treatment in those subjects will be similar to those observed in the Veterans Administration Study, if one treats 100 patients with borderline hypertension, 4 would be "saved" from a potential hypertensive complication. 14 However, it is also assumed that (1) patient compliance will be as good as in the highly preselected Veteran Administration patients followed in special clinics supported by a large logistical apparatus, and that (2) all patients with borderline hypertension will develop hypertension in the first year of the observation and thus benefit from 5 full years of antihypertensive treatment. In reality, therefore, the effect of treating an unselected group of patients with borderline hypertension probably is poorer than would be anticipated. Consequently it is not reasonable to commit all patients with borderline hypertension to antihypertensive therapy. Guidelines for Management and Treatment Since indiscriminate treatment of all patients is not warranted, a rational system of management and of selection for treatment in patients with borderline hypertension must be developed. In our clinic, we use a system based on the following principles: Since the risk is increased, all patients must be continuously observed, and nonpharmacologic measures to reduce cardiovascular risk must be instituted. An effort must be made to identify the subgroup which is at highest risk of developing hypertension.

BORDERLINE HYPERTENSION

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In the high risk group, treatment with mild agents in doses which do not produce subjective or chemical side-effects should be attempted and, if successful, continued. Escalation to higher doses to achieve blood pressure control "at any cost" is not warranted. ASSESSMENT OF A PATIENT WITH BORDERLINE HYPERTENSION. Initial assessment of the patient aims at determining whether there are signs of hypertensive target organ damage (left ventricular hypertrophy, decreased renal function, abnormal fundoscopic findings) and assessing risk factors for atherosclerosis and hypertension. The diagnosis of borderline hypertension presumes an absence of target organ damage; if such target organ involvement is found in patients with borderline blood pressure readings, for purposes of classification the patients should be considered to have mild hypertension. The risk factors can be grouped according to risk for atherosclerosis and risk for hypertension. Risk factors for atherosclerosis are hyperlipidemia, abnormal glucose metabolism, elevated uric acid, sedentary life habits, and smoking. These well-known risk factors will not be discussed further. Risk factors for later development of hypertension (listed in order of importance) are average blood pressure level, family history,58 race, tachycardia, and obesity. 52 Three of these are of special interest. The blood pressure level is by far the strongest factor predisposing to future hypertension. Even in the very narrow range of borderline blood pressure readings, higher initial blood pressure values lead to more future hypertension. 53 It is, therefore, very important to obtain multiple and representative blood pressure readings in an individual with borderline hypertension. The tachycardia in itself is a weak indicator of future hypertension. 46• 53 Far more important than its own strength for predicting hypertension is the realization that tachycardia is not a benign condition. It is frequently and erroneously assumed that tachycardia in the physician's office is a sign of temporary anxiety and as such is innocent. Tachycardia carries higher risk for future hypertension even if the subject had normal blood pressure readings !37 Significant hypertension is more prevalent in blacks in the United States than in the white population, but the prevalence of borderline hypertension is similar.1 Therefore, a black patient with borderline hypertension has probably three times the chance of a white individual of developing significant hypertension. ASSESSMENT OF THE BLOOD PRESSURE. The therapeutic decision, estimation ofthe effect ofthe antihypertensive treatment, and long-term observation of blood pressure trends can be based only on reliable blood pressure readings. Any standardized method of obtaining a large number of repeated blood pressurE) readings is acceptable, but we prefer to use blood pressure self-determination by the patient. In a study, 49 normotensive subjects and 112 patients who exhibited borderline hypertension in the physician's office measured their blood pressure twice daily during 7 consecutive days. 30 In a comparison with self-determined values in normotensive

506

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subjects, the self-determination in patients with borderline hypertension offered a new insight. Outside the physician's office, and presumably under conditions of normal daily routine, fully 30 per cent of patients remained hypertensive (2 standard deviations above the normotensive mean) 42 per cent remained borderline (between 1 and 2 standard deviations above the mean), and 28 per cent became normotensive. It can be seen from Figure 3 that repeated determinations (three times) in the physician's office were not useful in predicting the home blood pressure trends. Only by the use of the self-determination could a sufficient number of readings be obtained to reveal an accurate picture of blood pressure swings. Particularly noteworthy is the observation that all patients with borderline hypertension had tachycardia in the clinic. The assumption that patients with tachycardia have temporary anxiety-related blood pressure elevation and that the pressure is likely to be normal "under usual circumstances" is erroneous. The use of the blood pressure self-determination is not impractical, a good instruction program can be developed, and almost all patients learn

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Normotensive CLASSIFICATION

Borderline

Hypertensive

ACCORDING TO

AVERAGE HOME BLOOD PRESSURE Figure 3. Average of three clinic readings (on different days) of blood pressure and heart rate in patients with borderline hypertension. Patients are subdivided into three groups, based on the value of 14 blood pressure readings obtained at home. ao Note the similarity of clinic values, regardless of whether the blood pressure at home became normal, remained borderline, or became hypertensive. For details see text.

507

BORDERLINE HYPERTENSION

to take accurate readings. A limited number of cuffs can be purchased and lent to a larger group of patients if they are not able to purchase their own. MANAGEMENT

AND

TREATMENT

OF

BORDERLINE

HYPERTEN-

The fact that pharmacologic treatment may not be immediately indicated does not absolve the physician from a continuous obligation to manage all patients with borderline hypertension. The patient should be educated about the importance of increased blood pressure and the need for repeated measurements of blood pressure. Blood pressure trends should be observed by repeated yearly blood pressure self-determination. An increase of the baseline of 10 mm Hg in a year or an increase of 5 mm Hg in two consecutive years, calls for consideration of the treatment. Correction of risk factors is another goal of management. Obesity, elevated plasma lipids, and blood sugar abnormalities lend themselves to dietary modification. Smoking should be discouraged. Patients should be urged to exercise. Exercising is of no proven value in preventing complications, but may be useful in weight control and may contribute to the patient's feeling of well-being. We recommend limitation of salt intake. Again, this is not of proven value, but an association between sodium intake and prevalence of hypertension is frequently found. 14 Since there are no known harmful side-effects of prolonged severe sodium restriction (many populations live on practically no sodium intake), and restriction may be useful, from an ethical viewpoint low sodium diet can be suggested without reservations. The aim is to change the patient's eating habits rather than to enforce a long-term rigid diet. The main sources of excess sodium should be identified and modified, and the use of commercially prepared food as well as the addition of salt to already prepared foods should be discouraged. A scheme for the treatment of borderline hypertension is proposed in Figure 4. Self-determination of blood pressure is the pivotal test in this scheme. In young subjects (18 to 35 years) the upper limit of normal for an average of 14 readings taken over seven consecutive days is 140 mm Hg systolic, 90 diastolic, or less. On this basis, three groups of "severity" of borderline hypertension are recognized. Inherent in the scheme is the assumption that risk factors are important and that complications and the rate of development of hypertension depend on the severity of the initial blood pressure elevation. It is also recognized that complications of borderline hypertension are a function of time and that there is no evidence that patients with late onset hypertension are more prone to morbidity. The scheme outlined in Figure 4 takes all this into consideration. The choice of treatment remains at the physician's discretion. This author prefers propranolol, up to 160 mg, in patients who have tachycardia and somatic signs of anxiety. In others, small doses of diuretics are often useful. Reserpine is not favored since it increases appetite. Agents interfering with central and peripheral sympathetic function (guanethidine, methyldopa, clonidine hydrochloride) frequently cause side effects, and require addition of a diuretic. As indicated earlier, even few SION.

508

STEVO JULIUS Family History Physical Ex.am Laboratory ExamFundoscopy ECG Signs of LVH Chest x-ray Body Weight Urine, Creatinine Lipids, FBS

All Patients)

·Correct Overweight -Low No Diet ·Correct Lipid Abnormality by Diet ·Patient Education 'Periodic Revisits: Check Weight Blood Pressure

Check Diet

Figure 4.

Proposed scheme for management and treatment of borderline hypertension.

side effects are not acceptable since they may well outweigh the positive effect of the treatment. The scheme proposed in Figure 4 favors trial of treatment and allows for discontinuation either at the initiation or after two years of treatment. If treatment is discontinued it is extremely important not to convey to the patient the impression that he is "cured." The patient must understand the need for continuous following of blood pressure trends in the future. Too frequently, one meets a patient who received a short period of treatment, was told that his blood pressure had improved, and consequently did not consult a physician until severe hypertensive complications forced him to seek help. The proposed program of treatment represents this author's personal view. The National Task Force on Hypertension took the position that treatment of patients with diastolic readings (casual) below 95 mm Hg is not warranted. 61 This was done in order to concentrate national resources on a large number of patients who clearly need treatment and are at present untreated. From the viewpoint of national policy and directives to health care delivery systems, such a position is fully justified. However, an individual physician with a commitment to intlividual patients can and should do better. We believe that our approach is

509

BORDERLINE HYPERfENSION

based on sound assumptions. One should not, simply because the scientific proof of usefulness in the literature is not yet available, deny the treatment to carefully selected patients, in whom one can anticipate success with reasonable certainty.

SUMMARY Borderline hypertension is widespread. Though the increased blood pressure appears to be innocent, and upon rest frequently returns to the normal range, signs of complex and profound alteration of the physiologic control of the circulation can already be found. The pathophysiology of borderline hypertension is of particular interest since it may reveal clues about the processes which initiate the hypertension rather than the consequences of the primary blood pressure elevation. Patients with borderline hypertension are at a higher risk of developing future sustained hypertension and its consequences. The risk, however, is not sufficient to justify treatment in all cases. Patients must be followed to observe blood pressure trends and treatment attempted in the selected minority which has the highest risk. The determination of risk is based on repeated measurements of blood pressure and on the assessment of risk factors for atherosclerosis and for future hypertension.

REFERENCES 1. Alameda County Blood Pressure Study, State of California Department of Public Health, Berkeley, 1968. 2. Birkenhiiger, W. H., Schalekamp, M. A. D., Krauss, X. H., et a!.: Consecutive haemodynamic patterns in essential hypertension. Lancet, 1 :560--567, 1972. 3. Case, D. B., Wallace, J. M., Keim, H. J., et al.: Usefulness and limitations ofsaralasin, a partial competitive agonist of angiotensin n, for evaluating the renin and sodium factors in hypertensive patients. Amer. J. Med., 60:825-836, 1976. 4. Cowley, A. W., Jr., Liard, J. F., and Guy ton, A. C.: Role of the baroreceptor reflex in daily control of arterial blood pressure and other variables in dogs. Circ. Res., 32 :564-576, 1973. 5. Eich, R. H., Peters, R. J., Cuddy, R. P., et al.: The hemodynamics in labile hypertension. Amer. Heart J., 63 :188-195, 1962. 6. Eich, R. H., Cuddy, R. P., Smulyan, H., et al.: Hemodynamics in labile hypertension: A follow-up study. Circulation, 34 :299-307, 1966. 7. Ellis, C. N., and Julius, S.: Role of central blood volume in hyperkinetic borderline hypertension. Brit. Heart J., 35 :450-455, 1973.1 8. Esler, M. D., Julius, S., Randall, O. S., et al.: Relation of renin status to neurogenic vascular resistance in borderline hypertension. Amer. J. Cardiol., 36:708-715, 1975. 9. Esler, M., Zweifler, A., and Randall, 0.: Suppression of sympathetic nervous function in low-renin essential hypertension. Lancet, 2: 115-119, 1976. 10. Evans, W.: Hypertonia or uneventful high blood pressure. Lancet, 2 :53-59, 1957. 11. Folkow, B., and Rubinstein, E. H.: Cardiovascular effects of acute and chronic stimulation of the hypothalamic defense area in the rat. Acta Physiol. Scand., 64 :48, 1966. 12. Folkow, B.: The neurogenic component in spontaneously hypertensive rats; a survey. In Julius, S., and Esler, M., eds.: The Nervous System in Arterial Hypertension. Springfield, Illinois, Charles C Thomas, 1976, pp. 3-43. 13. Freis, E. D.: Hemodynamics of hypertension. Physiol. Rev., 40:27-54, 1960. 14. Freis, E. D.: Salt, volume and the prevention of hypertension. Circulation, 53 :589-595, 1976. 15. Frohlich, E. D., Tarazi, R. C., Ulrych, M., et al.: Tilt test for investigating a neural component in hypertension. Circulation, 36 :387-393, 1967. 16. Frohlich, E. D., Tarazi, R. C., and Dustan, H. P.: Hyperdynamic beta-adrenergic cir-

510 17. 18. . 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41.

42. 43.

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culatory state: Increased beta-receptor responsiveness. Arch. Intern. Med., 123 :1-7, 1969. Frohlich, E. D., Kozul, V. J., Tarazi, R. C., et al.: Physiological comparison oflabile and essential hypertension. Circ. Res., 46(Suppl. 1):55--B9, 1970. Glock, C. Y., Vought, R. L., Clark, E. G., et al.: Studies in hypertension-I1. Variability of daily blood pressure measurements in the same individuals over a 3-week period. J. Chron. Dis., 4 :469-476, 1956 . Guazzi, M., Polese, A., Magrini, F., et al.: Long-term treatment of the hyperkinetic heart syndrome with propranolol. Amer. J. Med. Sci.,270(3):465-474, 1975. Guyton, A. C., and Coleman, T. G.: Quantitative analysis of the pathophysiology ofhypertension. Circ. Res., 24, 25(Supp!. 1):I1-I19, 1969. Herd, J. A., Kelleher, R. T., Morse, W. H., et al.: Behavioral modification of blood pressure in monkeys. In Julius, S., and Esler, M., eds.: The Nervous System in Arterial Hypertension. Springfield, Illinois, Charles C Thomas, 1976, pp. 162-181. Heyden, S., Bartel, A. G., Hames, C. G., et al.: Elevated blood pressure levels in adoles· cents, Evans County, Georgia: 7-year follow-up of30 patients and 30 controls. J.A.M.A., 209: 1683-1689, 1969. Ibrahim, M. M., Tarazi, R. C., Dustan, H. P., et a!.: Hyperkinetic heart in severe hypertension: A separate clinical hemodynamic entity. Amer. J. Cardio!., 35 :667-674, 1975. Julius, S., Harburg, E., McGinn, N. F., et al.: Relation between casual blood pressure readings in youth and at age 40: A retrospective study. J. Chronic. Dis., 17:397-404, 1964. Julius, S., and Conway, J.: Hemodynamic studies in patients with borderline blood pressure elevation. Circulation, 38 :282-288, 1968. Julius, S., and Schork, M. A.: Borderline hypertension-A critical review. J. Chron. Dis., 23(10 & 11):723-754, 1971. Julius, S., Pascual, A. V., Sannerstedt, R., et al.: Relationship between cardiac output and peripheral resistance in borderline hypertension. Circulation, 43 :382-390, 1971. Julius, S., Pascual, A. V., Reilly, K., et al.: Abnormalities of plasma volume in borderline hypertension. Arch. Intern. Med., 127 :116-119, 1971. Julius, S., Pascual, A. V., and London, R.: Role of parasympathetic inhibition in the hyperkinetic type of borderline hypertension. Circulation, 44 :413-418, 1971. Julius, S., Ellis, C. N., Pascual, A. V., et al.: Home blood pressure determination: Value in borderline ("labile") hypertension. J.A.M.A., 229:663--B66, 1974. Julius, S., and Esler, M.: Autonomic nervous cardiovascular regulation in borderline hypertension. Amer. J. Cardio!', 36:685--B96, 1975. Julius, S., Esler, M. D., and Randall, O. S.: Role of the autonomic nervous system in mild human hypertension. Clin. Sci. Molec. Med., 48 :243s-252s, 1975. Kannel, W. B., Schwartz, M. J., and McNamara, P. M.: Blood pressure and risk of coronary heart disease: The Framingham study. Dis. Chest, 56:43-52, 1969. Kooperstein, S. 1., Schifrin, A., and Leahy, T. J.: Level of initial blood pressure and subsequent development of essential hypertension: A 10 and 15 year follow-up study. Amer. J. Cardio!., 10:416-423, 1962. Korner, P. 1., Shaw, J., Uther, J. B., et al.: Autonomic and nonautonomic circulatory components in essential hypertension in man. Circulation, 48 :107-117, 1973. Levy, R. L., Hillman, C. C., Stroud, W. D., et al.: Transient hypertension: Its significance in terms of later development of sustained hypertension and cardiovascular-renal diseases. J.A.M.A., 126:829-833, 1944. Levy, R. L., White, P. D., Stroud, W. D., et a!.: Transient tachycardia: Prognostic significance alone and in association with transient hypertension. J.A.M.A., 129 :585-588, 1945. Lew, E. A.: Blood pressure and mortality-Life insurance experience. In Stamler, J., Stamler, R., and Pullman, T. N., eds.: The Epidemiology of Hypertension: Proceedings of an International Symposium. New York, Grune and Stratton, 1967, pp. 392-397. Lund-Johansen, P.: Hemodynamics in early essential hypertension. Acta Med. Scand., 4B2(Suppl.):1-105, 1967. MacKenzie, L. F., and Shepherd, P.: The significance of past hypertension in applicants later presenting normal average blood pressures. Proc. Ass. Life Insur. Med. Dir. Amer., 24 :157-178, 1937. Mathewson, F. A., Brereton, C. C., Keltie, W. A., et a!.: The University of Manitoba follow-up study: A prospective investigation of cardiovascular disease-II. Build, blood pressure and electrocardiographic factors possibly associated with the development of coronary heart disease. Can. Med. Assoc. J., 92 :1002-1006, 1965. Mathisen, H. S., Loken, H., Brox, D., et a!.: The prognosis in essential hypertension. Scand. J. Clin. Lab. Invest., 17(Supp!. 84):257-261, 1965. Nestel, P. J., and Doyle, A. E.: The excretion of free noradrenaline and adrenaline by

BORDERLINE HYPERTENSION

44. 45. 46. 47. 48. 49.

50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60.

61.

511

healthy young subjects and by patients with essential hypertension. Aust. Ann. Med., 17:295-299,1968. Nestel, P. J.: Blood pressure and catecholamine excretion after mental stress in labile hypertension. Lancet, 1 :692-694, 1969. Onesti, G., Kim, K. E., Greco, J. A., et al.: Blood pressure regulation in end-stage renal disease and anephric man. Circ. Res., 36, 37(Suppl. 1):1145-1152, 1975. Paffenbarger, R S., Jr., Thome, M. C., and Wing, A. L.: Chronic disease informer college students-VIII. Characteristics in youth predisposing to hypertension in later years. Amer. J. Epidemiol., 88:25-32, 1968. Safar, M. E., Weiss, Y. A., Levenson, J. A., et al.: Hemodynamic study of85 patients with borderline hypertension. Amer. J. Cardiol., 31 :315-319, 1973. Sannerstedt, R: Hemodynamic response to exercise in patients with arterial hypertension. Acta Med. Scand. Suppl., 458 :1-83, 1966. Sannerstedt, R, and Julius, S.: Systemic haemodynamics in borderline arterial hypertension: Responses to static exercise before and under the influence of propranolol. Short title: Static exercise in borderline hypertension. Cardiovasc. Res., 6 :398-403, 1972. Sivertsson, R.: The hemodynamic importance of structural vascular changes in essential hypertension. Acta Physiol. Scand. Suppl. 343,79:3-56, 1970. Sokolow, M., Wedegar, D., Kain, H. K., et al.: Relationship between level of blood pressure measured casually and by portable recorder, and severity of complications in essential hypertension. Circulation, 34 :279-298, 1966. Stamler, J., Lindberg, H. A., Berkson, D. M., et al.: Epidemiological analysis ofhypertension and hypertensive disease in the labor force of a Chicago utility company. Proc. Coun. High Blood Press. Res., 7:23-52, 1958. Stamler, J., Berkson, D. M., Dyer, A., et al.: Relationship of multiple variables to blood pressure. In Paul, 0., ed.: Epidemiology and Control of HypertenSion, Symposia Specialists. Miami, 1975, p. 307. Stumpe, K. 0., Kolloch, R, Vetter, H., et al.: Acute and long-term studies of the mechanisms of action of beta-blocking drugs in lowering blood pressure. Amer. J. Med., 60:853-865, 1976. Suck, A. F., Mendiowitz, M., Wolf, R L., et al.: Identification of essential hypertension in patients with labile blood pressure. Chest, 59:402-406, 1971. Tarazi, R. C., Frohlich, E. D., and Dustan, H. P.: Plasma volume in men with essential hypertension. New Eng. J. Med., 278 (14):762-765, 1968. Tarazi, R. C., Ibrahim, M. M., Dustan, H. P., et al.: Cardiac factors in hypertension. Circ. Res., 34, 35(Suppl. 1):1-213-1-243, 1974. Thomas, C. B., Ross, D. C., and Higgenbottom, C. Q.: Precursors of hypertension and coronary disease among healthy medical students. Discriminant function analysis II using parental history as the criterion. Bull. Johns Hopkins Hosp., 115 :245, 1964. Thomson, K. J.: Some observations on the development and course of hypertensive vascular disease. Proc. Ann. Meet. Med. Sect. Amer. Life Convention, 38 :85-112, 1950. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90-114 mm Hg. J.A.M.A., 213 :1143-1152, 1970. U.S. Department of Health, Education and Welfare, National Institute of Health, The National High Blood Pressure Education Program, DHEW Publication No. (NIH) 74593, U.S. Government Printing Office, 1973.

Hypertension Division Department of Internal Medicine University of Michigan Medical Center Ann Arbor, Michigan 48109