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Combination Therapy: The Comprehensive Management Of Vulnerable Hypertensive Patients

The Heterogeneity of Hypertension: Why Doesn't Every Patient Respond to Every Antihypertensive Drug?

Sever, P.

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Journal of Cardiovascular Pharmacology: Volume 31 - Issue - p S1-S4
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There are still some researchers who believe that a unifying hypothesis will ultimately identify a single causative agent for essential hypertension. The over-whelming weight of evidence is, however, at variance with this. Studies in experimental models of hypertension and observations in man strongly indicate that high BP arises as a result of a complex interplay between various environmental factors and an underlying genetic predisposition. There is thus a wide heterogeneity underlying hypertension.

Epidemiological studies have provided good evidence that, in at least some patients, obesity, stress, sodium intake and alcohol are aetiologically related to high BP in adult life (1). The importance of genetic factors is, however, less widely appreciated. Hypertension is frequently observed to cluster in families, and twin studies indicate that a substantial component of BP is genetically determined. Also, recent studies show an association between certain genetic polymorphisms and BP.

The failure to demonstrate a strong relationship between any single environmental factor and elevated BP in some populations has been used as an argument against the importance of such factors. This view ignores the fact that, when there are multiple environmental factors and individual susceptibility, a simple correlation may be hard to find.


Epidemiological studies have shown that, in a number of traditional, unacculturated communities. BP levels are low and fail to rise with advancing age, and that hypertension-however defined-and its cardiovascular complications do not occur (2).

In an early cross-sectional study, the BP levels of individuals who migrated from such communities to a more westernised environment contrasted strikingly with the BP levels in non-migrants: BP was higher and rose with age, and a proportion of subjects had become hypertensive (Fig. 1)(3). Such studies clearly demonstrate the all-important role of the environment in the pathogenesis of higher BP levels. A reasonable premise is that the factor(s) responsible for the change in BP associated with migration would be similar to, if not identical with, those factors responsible for the pathogenesis of hypertension.

FIG. 1
FIG. 1:
The distribution of BP and changes in BP with age, showing how BP is low and fails to advance with age in unacculturated communities, but rises on migration to a westernised environment.

In this unique study, conducted with colleagues some years ago, we observed the migration of a cohort of unacculturated Africans from a rural subsistence farming community in Western Kenya to an urban environment in Nairobi (3). This migration was associated with dramatic changes in BP in a relatively short period (four to six weeks) and we attributed this finding to increases in dietary sodium intake, together with exposure to the stress of an new environment.

This was the first study in which individual changes in BP have been observed, and it demonstrated that there was a marked heterogeneity with a wide range of individual BP responses (Fig. 2)(4). While this observation could be explained by differential exposure to dietary change and/or environmental stress, a more likely explanation is that BP increased only in individuals who were genetically predisposed. As indicated above, whatever the underlying mechanisms, it would be a reasonable hypothesis that they are relevant to the aetiology and pathogenesis of hypertension.

FIG. 2
FIG. 2:
Individual BP responses to migration to an urban environment in traditional African rural dwellers. Reproduced, by permission of Springer-Verlag, from Sever et al., 1989 (4).


In modelling the possible underlying genetic basis for heterogeneity in hypertension, it can be envisaged that four different genes predetermine whether or not an individual develops high BP in later life. In Fig. 3, these genes have been arbitrarily labelled G1 to G4. Each is hypothesised to determine a specific outcome in response to a specific stimulus (phenotypes P1 to P4).

FIG. 3
FIG. 3:
Genes coding for four different phenotypes [G = gene; P = phenotype].

In the model, G1 causes "salt sensitivity," perhaps by coding for a membrane abnormality in the kidney that prevents sodium from being excreted in response to increases in dietary sodium. G2 causes insulin resistance. G3 predisposes patients to neurogenic hyper-responsiveness and individuals with this gene over-respond to certain environmental stresses. G4 is hypothesised to cause primary abnormalities in vascular structure which increase vascular resistance, and hence BP.

The important principle is that BP only increases when an individual with a specific gene is exposed to the appropriate environmental stimulus, for example, a high-salt diet (Fig. 4). This means that, in any population of hypertensive patients, different individuals will have developed the condition through different pathogenetic mechanisms. The theory explains why a low-salt diet or correction of obesity is unlikely to lower BP in a patient whose BP is neurogenically determined, and why not all patients respond to any one of the five classes of anti-hypertensive drugs that act on different physiological mechanisms.

FIG. 4
FIG. 4:
Interaction between phenotypes and environmental stressors [G = gene; P = phenotype; E = environmental stimulus].

Clearly, the model is necessarily simplistic. It is likely that many candidate genes will be found in the future that will add to our understanding of the pathogenetic mechanisms linking genetic predisposition, environmental factors and elevated BP.


Given the apparently high level of heterogeneity in the pathogenesis of hypertension, it is not surprising that there is heterogeneity in responsiveness to treatment. It is widely known that when any therapeutic intervention is applied to a group of hypertensive patients, whether pharmacological or non-pharmacological, some patients show excellent responses while in others, little or no fall in BP occurs. With any single drug treatment, no more than 25-50% of a patient population will achieve good BP control.

This is supported by the results of the Veterans' Study, which showed that 64% of black patients responded to calcium antagonists, whereas only about 30% responded to ACE-inhibitors (5). In the Caucasian population, the opposite was true: ACE-inhibitors were more successful (55% response) than calcium antagonists or diuretics.

In support of the concept of heterogeneity, cross-over studies show that patients who respond to one class of drug do not necessarily respond to a different class. The data in Fig. 5 show the lack of association between responsiveness to ACE-inhibitors and calcium antagonists (6). However, drugs that act on the same physiological system-for example beta-blockers and ACE-inhibitors, both of which affect the RAA system-may be more likely to exert similar effects on BP in the same individual.

FIG. 5
FIG. 5:
Scatter plot showing the lack of correlation between changes in SBP produced by two antihypertensive agents in individual patients [P = NS; r = 0.17]. Reproduced, by permission of Current Science Ltd, from Attwood et al., 1994 (6).


From these findings, it is possible to predict that combination therapy in hypertension would be likely to control BP in a greater number of patients than any single drug used alone. In addition to the heterogeneity argument, there is an additional basis for favouring combination therapy over monotherapy. This is based upon the observation that whenever a single physiological system is perturbed by an antihypertensive drug, there is commonly a reflex reaction of another BP-regulating mechanism that attempts to counteract the antihypertensive effect. BP control is therefore more likely to be achieved if the compensatory response could be blocked by the use of a second drug.

It is therefore possible that good BP control could be achieved in a larger proportion of patients by using combination therapy regimens that comprise low doses of two drugs which act on different physiological systems. Low-dose combination therapy is recommended because the aim of anti-hypertensive treatment is to provide BP control while minimising dose-related side-effects.

Today, we have no simple way of predicting which patients will respond to which class of anti-hypertensive drug, although there are some clues (e.g., age and race). Bearing in mind that in current clinical practice. BP is inadequately controlled in more than 50% of hypertensive patients, the case for low-dose combination therapy is attractive.


1. Whincup PH, Perry IJ, Shaper AG. Blood pressure in other populations. B: Regional differences in blood pressure in developed countries: fetal influences. In: Swales JD, ed. Textbook of hypertension. Blackwell, Oxford, 1994:36-45.
2. Perry IJ, Whincup PH, Shaper AG. Environmental factors in the development of essential hypertension. In: Reid J, Swales JD, eds. Hypertension in theory and practice. Br Med Bull 1994;50:246-259.
3. Poulter NR, Khaw KT, Hopwood BEC, et al. The Kenyan Luo Migration Study: observations on the initiation of a rise in blood pressure. BMJ 1990;300:967-972.
4. Sever PS, Poulter NR, Khaw KT. Migration studies and blood pressure: a model for essential hypertension. In: Mathias CJ, Sever PS, eds. Concepts in hypertension. Springer-Verlag, New York, 1989:55-66.
5. Materson BJ, Reda DJ, Cushman WC, et al. Single drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med 1993;328:914-921.
6. Attwood S, Bird R, Burch K, et al. Within-patient correlation between the antihypertensive effects of atenolol, lisinopril and nifedipine. J Hypertens 1994;12:1053-1060.

Section Description

Proceedings of satellite symposium of the 8th European Meeting on Hypertension June 13, 1997; Milan, Italy


Hypertension; Pathogenesis; Environmental factors; Genetics; Antihypertensive therapy; Combination therapy

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