Published online before print January 27, 2003, doi: 10.1161/01.HYP.0000049882.23078.EB
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(Hypertension. 2003;41:193.)
© 2003 American Heart Association, Inc.
Editorial Commentary |
False Claims of Blood Pressure–Independent Protection by Blockade of the Renin Angiotensin Aldosterone System?
From the Department of Laboratory Medicine, University of California, San Francisco, Calif.
Correspondence to Theodore W. Kurtz, MD, Professor of Laboratory Medicine, 505 Parnassus Avenue, Room L518, UCSF Medical Center, Box 0134, San Francisco, CA 94143-0134. E-mail KurtzT{at}Labmed2.ucsf.edu
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Introduction |
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 Top Introduction Relevance to Human Studies,...Further Implications for...What the Studies of...ConclusionReferences |
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In the wake of a number of recent clinical trials, claims that blockade of the renin-angiotensin-aldosterone system (RAAS) provides vascular protective effects that are not simply secondary to reductions in blood pressure (so-called BP-independent effects) have become increasingly popular. How accurate are these kinds of claims? The report by Griffin, Bidani, and coworkers in this issue of Hypertension1 is one of a series of studies from this group in animal models of hypertension that, together with recent clinical studies by other investigators, have begun to raise serious questions about such claims regarding RAAS blockade.
In the current study of RAAS blockade in the stroke-prone spontaneously hypertensive rat (SHRsp) and in previous studies in the remnant kidney model of hypertension, Griffin et al have done something that should be axiomatic for those involved in blood pressure research yet is ironically neglected in many, if not most, clinical and experimental studies of hypertension: they have paid careful attention to obtaining an accurate and thorough assessment of the blood pressure profile. By using radiotelemetry to obtain continuous, 24-hour measurements of blood pressure throughout the course of their studies, Griffin et al have demonstrated that the renoprotection afforded by enalapril or spironolactone in salt-supplemented SHRsp is tightly related to the effects of these agents on blood pressure. These results are similar to their earlier radiotelemetry studies of ACE inhibition or angiotensin receptor blockade in the remnant kidney model of hypertension showing a highly robust relationship between blood pressure and renoprotection that is remarkable when one considers the inherent variability of these complex, biologic phenotypes.2 In their previous studies in which blood pressure profiles were also carefully assessed, Griffin et al demonstrated that other antihypertensive drugs that do not compromise renal autoregulation can provide renoprotective effects that are equivalent to those afforded by agents that block the renin-angiotensin system.3 Thus, the work of Griffin, Bidani, and colleagues suggests that the BP effects of RAAS blockade may be largely, if not entirely, responsible for the renal protection afforded by RAAS blockade.1–3
In contrast to the studies of Griffin, Bidani, and colleagues, a large number of experimental reports have claimed to demonstrate that agents that block the RAAS have a special ability to protect target organs in a manner that goes well beyond their effects on blood pressure (reviewed in Taal and Brenner,4 Hostetter et al,5 and Epstein6). But these contrary studies have been based on inferior BP measurement techniques (eg, intermittent measurements obtained with direct or indirect methods) that are fundamentally incapable of evaluating the true blood pressure load on the vasculature. In fact, there are no studies in any experimental model that have clearly shown unique BP-independent protection by these agents when continuous 24-hour measurements have been used to assess BP burden over the entire course of drug administration. Indeed, other investigators using continuous radiotelemetry measurements in SHRsp have found that the superior ability of losartan or perindopril to attenuate cardiac and vascular hypertrophy, in comparison with a hydralazine/hydrochlorothiazide combination, may also be related to their superior ability to reduce blood pressure.7 Thus, the findings of Griffin et al may be relevant to the protective effects of RAAS blockade on a variety of forms of target organ damage. These kinds of radiotelemetry studies not only raise questions about claims regarding BP-independent mechanisms that mediate the protective effects of RAAS blockade, but they also remind us of what should be obvious but is so often ignored in hypertension research: that to draw valid conclusions about the relationship between blood pressure and any other variable, it is important to obtain a thorough and accurate assessment of all phenotypes—including blood pressure!
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Relevance to Human Studies, Including RENAAL, IDNT, HOPE, LIFE, and ALLHAT |
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TopIntroductionRelevance to Human Studies,...Further Implications for...What the Studies of...ConclusionReferences |
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Given the clinical trial data in both diabetic and non-diabetic nephropathy showing the superiority of renin-angiotensin system blockade compared with other antihypertensive regimens in slowing renal disease progression,8–12 one might ask whether insights gained from the radiotelemetry studies of Griffin et al in rodent models are applicable to humans. In fact, as discussed further below, the limited data that are available using 24-hour ambulatory blood pressure monitoring (ABPM) in humans, like the radiotelemetry studies of Griffin et al in rodents, suggest the need for caution in evaluating claims about BP-independent protection of RAAS blockade that are based on intermittent measurements of clinic BP.13,14
It has long been recognized that BP is fundamentally labile and exhibits considerable variability related to the time of the day, activity and stress levels, food intake, and other known and unknown factors.15 In addition, it is unclear which aspects of blood pressure (eg, peak systolic pressure, average systolic pressure, pulse pressure, nocturnal pressures, etc.) are most important with respect to the pathogenesis of target organ damage. Thus, it is unrealistic to expect intermittent measurements of BP in the clinic to precisely reflect the "true" BP load on the vasculature. Nevertheless, despite its widely recognized limitations as a surrogate measure of the "true" average BP, the office BP has remained the primary index of BP burden in clinical trials because of considerations of cost, convenience, and practicality. And indeed, there is little doubt that office BP provides a reasonably accurate measure of large changes in the BP burden, thus accounting for its success in demonstrating the broadly linear relationship between BP and target organ damage in large populations.16,17
Yet, although measurements of office BP may be capable of detecting large changes in BP load on the vasculature, there is increasing evidence that isolated clinic measurements may not provide an adequate tool for detecting more modest, yet clinically important, effects on BP. This issue becomes particularly relevant in drug trials attempting to uncover more modest, yet clinically important, differences among the effects of various antihypertensive agents on target organ damage.
The recently reported Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy (IDNT) trials illustrate the limitations of office BP measurements when it comes to studying mechanisms that may mediate differences among various antihypertensive regimens on progression of renal damage.11,12 In these trials in patients with diabetic nephropathy, the subjects treated with angiotensin receptor blockers (ARBs) had a decline in estimated glomerular filtration rate (GFR) of approximately 5 mL/min per year, whereas subjects treated with different regimens, including calcium channel blockers, had a decline in GFR of approximately 6 mL/min per year. Compared with the generally accepted rates of decline in GFR of 12 mL/min per year in diabetic nephropathy patients with untreated hypertension,17,18 it is evident that all of the BP treatment regimens, not just those including ARBs, afforded substantial renoprotection. The further GFR protection of 1 mL/min per year afforded by ARBs over other treatment regimens is modest in comparison with the overall renal protection afforded by antihypertensive treatment per se. This difference in GFR protection of 1 mL/min per year between the ARB treatments and the other regimens was felt to be not explainable by the small but statistically significant differences in clinic BP of 3 to 4 mm Hg favoring the ARB-treated groups. However, as recently demonstrated in the Heart Outcomes Prevention Evaluation (HOPE) substudy with ramipril,19 such small differences in office BP as noted in these and other similar clinical trials, may be accompanied by much larger differences in nocturnal and 24-hour BP (17 mm Hg and 10 mm Hg, respectively, in systolic BP in the HOPE substudy). Similarly, a recently published study in type 1 diabetics has demonstrated that increases in nocturnal BP, but not daytime blood pressures, predict which patients go on to develop microalbuminuria,20 consistent with other studies that have shown similar correlations between proteinuria and 24-hour and/or nocturnal BP.21–23 Indeed, several other studies have also shown that substantial effects on 24-hour BP or on nocturnal BP may exist even in the absence of substantial effects on clinic blood pressures and that ABPM, but not clinic BP, correlates with markers of target organ damage.24–28 These studies underscore the distinct possibility that in some clinical trials we are failing to detect important effects on BP because of reliance on conventional methods of BP measurement. In the recent Losartan Intervention for Endpoint Reduction (LIFE) trial, it was found that losartan affords superior cardiovascular protection compared with atenolol independently of any differences in sitting blood pressures obtained at trough levels of the drugs.29 It would be interesting to know whether this greater cardiovascular protection afforded by losartan versus atenolol is independent of thorough measurements of the blood pressure profile. Finally, it should be noted that in the landmark Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, antihypertensive treatment with the diuretic chlorthalidone, a drug that activates the RAAS, was more effective in preventing aggregate cardiovascular events than treatment with the ACE inhibitor lisinopril, a drug that blocks the RAAS.30 The superior cardiovascular protection afforded by the diuretic was associated with only modestly lower clinic blood pressures, and it is unknown whether such clinic measurements were reflecting greater effects on blood pressure during other times of the day or night.
Fortunately, the limitations of clinic blood pressure measurements, downplayed by many investigators, are being increasingly recognized by others. In fact, it is conceivable that more widespread use of ABPM in the future may someday confirm claims that the vascular protective effects of RAAS blockade or other antihypertensive strategies are not solely related to changes in BP. For example, Schiffrin et al31 have reported that losartan, but not atenolol, improves structure and endothelial function of resistance arteries from patients with essential hypertension despite equivalent reductions in blood pressure as judged by frequent clinic measurements and by two 24-hour BP measurements taken 1 year apart. However, more frequent measurements of 24-hour blood pressures throughout such studies, along with separate analyses of daytime and nighttime pressures, will be required to definitively establish that the differential effects of these drugs on the vasculature are not simply secondary to any differential effects on the blood pressure profile.
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Further Implications for Clinical Therapy of Hypertension |
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TopIntroductionRelevance to Human Studies,...Further Implications for...What the Studies of...ConclusionReferences |
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The study of Griffin et al illustrates some additional concepts that are important for understanding the pathophysiology and prevention of hypertension-induced target organ damage. Their work demonstrates how, in some cases, even very small changes in blood pressure are capable of affording a very impressive degree of protection against vascular injury. In the salt-loaded SHRsp, substantial renal damage ensued when the 24-hour average systolic BP exceeded approximately 200 mm Hg, whereas minimal renal damage was observed when the 24-hour average blood pressure remained below 200 mm Hg. These observations provide elegant evidence of the previously suspected, but undemonstrated, threshold relationship between BP and renal damage in a model of malignant nephrosclerosis. Given the rather high BP threshold for renal damage in the SHRsp, it is evident how even very modest reductions in BP that do not achieve complete BP normalization might afford significant renoprotection in this model. In contrast to the SHRsp, the threshold for renal damage may be much lower in models of reduced renal mass hypertension or diabetic hypertension.32,33
In their earlier studies using BP radiotelemetry in the remnant kidney model, Griffin et al34,35 also provided evidence that the slope of the relationship between renal damage and BP (increase in percentage glomerulosclerosis/mm Hg increase in average BP) can be increased by therapeutic agents such as the dihydropyridine calcium channel blockers. Indeed, Griffin, Bidani, and coworkers have been pioneers in demonstrating that, in contrast to other agents, dihydropyridine calcium channel blockers impair renal autoregulation, which may enhance susceptibility to blood pressure–induced renal damage in some circumstances (ie, when systemic blood pressure is not well controlled). In this regard, the inferior renoprotection afforded by calcium antagonists compared with agents that block the renin angiotensin system should not necessarily be interpreted as reflecting special protective effects of ACE inhibition or angiotensin receptor blockade; rather, the inferior outcomes obtained with calcium antagonists may simply reflect the adverse effects of these agents on mechanisms that govern transmission of systemic blood pressure to the renal microvasculature. Presumably, variation in the slope relationship between damage and pressure as well as in the BP threshold for damage can also arise because of differences in disease etiology, environmental factors, and perhaps underlying genetic factors. An important implication of the work of Griffin et al in various models of renal disease is that similar degrees of BP reduction may have different degrees of impact on renal damage in different individuals or disease states. The current emphasis on the need for particularly aggressive blood pressure control in patients with renal disease or diabetes compared with other groups16,17 is in accord with the pathophysiologic insights provided by the radiotelemetry studies of Griffin et al in their rodent models of hypertension.
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What the Studies of Griffin et al Do Not Show |
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TopIntroductionRelevance to Human Studies,...Further Implications for...What the Studies of...ConclusionReferences |
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The studies of Griffin et al do not question whether the vascular protective effects of RAAS blockade involve something more than the effects of RAAS blockade on office blood pressures. Their work simply questions whether the vascular protective effects of these agents involve something more than their effects on the true blood pressure profile.
It should also be emphasized that the work of Griffin et al does not question whether some agents that block the RAAS may provide superior vascular protection in clinical practice where office measurements of BP are the rule. Similarly, their work does not question whether agents that block the RAAS should sometimes be preferred over other antihypertensive agents with potentially harmful features (eg, on renal autoregulation) that can countervail their ability to protect against target organ damage. It should also be recognized that the work of Griffin et al does not question the fact that RAAS blockade can give rise to all sorts of interesting phenomena in vitro that are not simply secondary to effects on blood pressure. However, it is very difficult to establish that these phenomena provide vascular benefits that go beyond the beneficial BP effects of RAAS blockade in vivo. Finally, it should be recognized that Griffin et al have tested only a limited number of compounds in a limited number of disease models. Thus, their work does not preclude the possibility that some agents which block the RAAS may have additional features unrelated to the RAAS or blood pressure that are beneficial to the vasculature. Even within a single class of drugs (eg, angiotensin receptor blockers), there are major structural differences among the available molecules, and it would be naïve to assume that all of the drugs within a class are functionally equivalent under all circumstances.
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Conclusion |
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TopIntroductionRelevance to Human Studies,...Further Implications for...What the Studies of...ConclusionReferences |
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In conclusion, the studies of Griffin et al simply and pointedly suggest that the vascular protective effects of some agents that block the RAAS may be largely, if not almost entirely, secondary to their effects on the true blood pressure profile, a profile that is not faithfully represented by intermittent measurements of blood pressure. Of course, the studies of Griffin et al cannot exclude the possibility that some limited component of the vascular protection afforded by RAAS blockade may be unrelated to the blood pressure effects of RAAS blockade. However, in the absence of accurate assessments of the true blood pressure profile, ie, at least in the absence of continuous measurements of BP over extended periods of both the day and night, claims about BP-independent protection by any intervention should be regarded with skepticism. These days, we tend to be enthralled by large clinical trials, fascinating new ideas about disease mechanisms, and anything labeled with the "omics" suffix. The work of Griffin et al should serve as a wake-up call to remember the fundamentals when it comes to performing and interpreting measurements of blood pressure.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionRelevance to Human Studies,...Further Implications for...What the Studies of...ConclusionReferences |
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30. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288: 2981–2997.
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