(Circulation. 2001;103:1188.)
© 2001 American Heart Association, Inc.
Editorial |
Epidemiological Findings Imply That Goals for Drug Treatment of Hypertension Need to Be Revised
From the Department of Internal Medicine, Broussais Hospital, Paris, France.
Key Words: Editorials • epidemiology • pharmacology • hypertension • arteries • elasticity
In the early
trials exploring the benefit of antihypertensive drug treatment,
diastolic blood pressure (DBP) was chosen as the only criterion for
patient inclusion. This choice had, by definition, influenced the
baseline characteristics of the hypertensive
population.1 The subjects
with both high systolic blood pressure (SBP) and low DBP and, hence,
with a selectively increased pulse pressure (PP) were excluded from the
trials and, therefore, not analyzed in the primary results. This bias
was introduced not only in selecting the subjects at inclusion, but
also at the end of follow-up. Those with an elevated SBP were
considered adequately treated, although only DBP had been normalized
(
90 mm Hg). Perhaps for these reasons, antihypertensive drug therapy
was consistently shown to prevent stroke more than it prevented
ischemic heart disease.1 Such
findings suggested that more attention should be given to
SBP2 and
PP,3 both of which are better
independent predictors of cardiovascular (CV) risk than DBP
alone.
In recent years, numerous therapeutic trials using SBP
as the principal inclusion criterion were performed in elderly
populations. Cardiac events were reduced by 
24% to 27%, which is
somewhat higher than that obtained in DBP-based
trials.4 This diminution of
cardiac events in SBP-based trials could reflect the choice of SBP as
the specific enrolled criterion or the fact that these trials included
only elderly subjects. Nevertheless, in the Hypertension Optimal
Treatment (HOT) study,5 which
was performed in middle-aged hypertensive subjects with
systolic-diastolic hypertension, the failure to prove a benefit in
terms of CV risk with a rigorously controlled DBP may be attributed to
the fact that, although a decrease of SBP was indeed obtained, this
decrease was less than that with DBP, and thus PP remained
elevated.4
The concept that PP plays an independent role in CV risk is difficult to demonstrate, because PP is no more than the arithmetic difference between SBP and DBP. Nevertheless, from the different studies reported in the literature and cited in Reference 66 , it has been clearly demonstrated that, in hypertensive patients >55 years, brachial PP is a stronger CV risk factor than SBP alone, particularly for predicting myocardial infarction. The best predictor function among the possible linear combinations of SBP and DBP was similar to that of PP, suggesting that their association was real and not merely a statistical artifact caused by the correlation between SBP and PP. In particular, age >50 years, CV mortality and, most importantly, myocardial infarction are indeed positively correlated to the SBP level; however, for any given SBP value, CV risk is higher when DBP is lower.4 6 Other confirmations of the predictive value of PP were obtained in subjects with recurrent myocardial infarction, congestive heart failure, and myocardial dysfunction.6
It is within this context that the article by Franklin et al7 should be evaluated. With increasing age, there is a gradual shift from DBP to SBP and PP as predictors of coronary heart disease risk. Below age 50, DBP is the strongest predictor. The decade from 50 to 59 is a transition period3 7 when all 3 BP indices are comparable predictors and, from 60 years onward, DBP is negatively related to coronary risk so that PP surpasses SBP. These findings should now be considered a consensus opinion. In fact, they mean that a DBP reduction in a patient >50 years of age might be due, in the long term, to the drug treatment of hypertension but also potentially to aging alone. The latter generates several problems associated with the definition of hypertension, the meaning of increased PP, and the drug treatment of hypertension that are addressed below.
In fact, PP is a very complex parameter to analyze. After
ventricular ejection, the BP wave propagates at a given speed (6 to
10 m/s), according to a well-established hemodynamic pattern: although
mean BP remains relatively stable along the arterial tree, PP rises
markedly from the central to the peripheral
arteries.8 This PP
amplification results in a significant increase of SBP, together with a
slight decrease of DBP. The radial-aortic pressure differences measured
invasively in normotensive subjects are 12 mm Hg for SBP, -0.8
mm Hg for mean BP, and -1 mm Hg for
DBP.9 These alterations,
which in the case of SBP are higher than those introduced by the simple
variability of BP measurements, result from 2 specific
mechanisms.8 First, the
pressure wave propagates from central to peripheral vessels restrained
by the increasing rigidity of the arterial wall in association with a
progressive reduction of vessel diameter. Second, the BP curve may be
considered the summation of an incident pressure wave, which propagates
from the heart to the peripheral vessels, and a reflected wave, which
returns toward the heart from specific vascular sites, mainly located
at the origin of resistance vessels and/or (in disease states)
arterial bifurcation and calcified plaques.
With increasing age, PP amplification tends to be reduced
due to the rapid elevation of aortic stiffness with age in conjunction
with an earlier return of the backward pressure wave from reflection
sites. Accordingly, by >50 years of age, SBP, DBP, and PP become
identical in all parts of the arterial tree. This finding concords with
the epidemiological result of Franklin et
al7 for individuals >50
years, but it raises the problem of identifying the best predictive
values of aortic versus brachial DBP, SBP, or PP for those 50 years.
SBP and PP are markedly lower in the aorta than in the brachial artery,
suggesting that epidemiological findings could differ depending on
whether aortic SBP and PP were considered rather than brachial SBP and
PP to establish a predictive value. In addition, because PP
amplification is known to rise markedly in the presence of increased
heart rate (at all ages),8 it
remains unknown whether the large number of subjects with tachycardia
and classified as "hypertensive" on the basis of brachial artery
measurements may, in fact, have no BP elevation at the aortic
level.
Physiologically, PP is influenced by 3 hemodynamic factors: ventricular ejection, arterial stiffness, and wave reflections. Theoretically, in those >50 years, each of these factors might play a role in CV risk. However, ventricular ejection, which decreases with age, is not involved in increased PP. In an original approach, London et al10 showed that an increased PP is the hemodynamic hallmark of patients with end-stage renal disease. In these patients, aortic pulse wave velocity, independent of BP (and particularly PP), was a significant predictor of CV and overall mortality.11 A similar finding has been observed in subjects with essential hypertension and preserved renal function.12 Today, it remains to be determined whether an early return of aortic wave reflections might also be an independent predictor of CV risk. Indeed, such an earlier return may alter the heart-vessel coupling and be detrimental to cardiac function. At the same time, as mean DBP tends to decrease as a consequence of increased arterial stiffness, coronary perfusion is reduced, favoring myocardial ischemia.
The recent guidelines on the drug treatment of
hypertension13 emphasized
the need to control adequately DBP and SBP and, consequently, even PP.
However, they did not indicate which regimen might most effectively
obtain this result. Even if the goal of treatment trials is to reduce
both DBP and SBP through multidrug therapy, the normalization of SBP
(140 mm Hg) and, hence, PP is difficult or even impossible to obtain
in 30% of the
patients.1 14 Even
in normotensive subjects, an increased PP remains a powerful
independent predictor of CV
risk.6 Alderman et
al15 demonstrated that
elevated PP is the only mechanical factor predicting CV risk in the
presence of successful antihypertensive drug therapy. Concerning the
dose-response curves for conventional antihypertensive drugs, few data
in the literature indicate that DBP, SBP, and PP decrease in parallel
under drug treatment, and some show that reductions of SBP and PP do
not parallel that in DBP.16
Finally, the present study by Franklin et
al7 leads to wonder whether
the time has come to revise goals of antihypertensive drug
therapy.
The first goal could be to reduce SBP and PP by modifying the timing of wave reflections, thereby delaying the return of the backward pressure wave. This alteration may be obtained easily with nitrates.8 17 This regimen has been shown to be effective in the long-term treatment of elderly subjects with isolated systolic hypertension. Normalization of SBP and PP can be obtained without any significant change in DBP, an aspect of treatment that may avoid the possible deleterious effects of a marked reduction of DBP in elderly populations. However, reductions of CV morbidity and mortality have never been tested using nitric oxide (NO) donors. From a pharmacological viewpoint, the potential use of NO donors and/or stimulators is of major interest, making the NO and cyclic GMP pathways the subject for drug research on the treatment of hypertension in the elderly.
The second goal could be to prevent the age-related increases of SBP and PP and the decrease in DBP that occur in the elderly independent of antihypertensive drug treatment. These aims might be obtained by reducing the increased arterial stiffness associated with aging and, hence, by limiting structural modifications of the arterial wall. Using this approach, drug treatment of hypertension should not only shift the BP toward lower levels but also prevent, in those >50 years, the age-dependent increase of SBP and decrease of DBP. In hypertensive rats, spironolactone, angiotensin-converting enzyme inhibitors, and angiotensin II type 1 receptor blockade prevented the aortic accumulation of collagen fibers18 and, hence, the age-related increase of arterial stiffness, independent of BP. In such trials, reduced sodium intake or diuretics might further improve the arterial mechanical properties.18 In aged rats, aminoguanidine can increase arterial stiffness independent of BP, without modifying collagen and elastin contents. This improvement is obtained through the action on glycosyl end-products, thereby suggesting that arterial mechanical properties can be modified through the use of interstitial molecules acting on cell-cell and cell-matrix attachments and in relationship with integrins and/or proteoglycans.18
Finally, in an earlier study, Franklin et al19 showed that, after age 50, the increase of SBP and PP and decrease of DBP varied widely from one individual to another, suggesting that many environmental (sodium?) and genetic factors may modulate the age-related change of BP.18 In hypertensive humans, specific genetic polymorphisms are significantly associated with increased aortic stiffness, and some (like those involving the angiotensin II type 1 receptor gene), are associated with selective improvement of aortic pulse wave velocity after angiotensin-converting enzyme inhibition,20 thereby demonstrating the importance of selecting populations at risk for drug treatment. Now, research and therapeutic trials should imply a specific impact on conduit arteries. Perhaps the time has come to revise our conceptual approach to the clinical management of hypertension.
Footnotes
Reprint requests to Professeur Michel Safar, Médecine Interne 1, Groupe Hospitalier Broussais–G.-Pompidou, Hôpital Broussais, AP-HP, 96, rue Didot, 75674, Paris Cedex 14, France.
References
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