Early Treatment to Prevent Hypertension: A Laudable Goal

See the Original Article on page 1381. The article from Sasamura et al.1 (this issue) describing the STAR CAST study deals with a simple concept—that early short-term pharmacological treatment might prevent permanently the development of hypertension. STAR CAST is the third study of its kind in humans, preceded by the Trial of Prevention of Hypertension (TROPHY) Study2 and the Danish Hypertension Prevention Project (DHyPP).3Table 1 compares some key features of these studies. All of these studies used an angiotensin receptor blocker to attempt to impede the anticipated progression to high blood pressure.4 The expectation of such progression was based on either high-normal personal blood pressures (prehypertension) or family history of clinical hypertension. The period of treatment in DHyPP and STAR CAST was half that of the 2 years in TROPHY (Table 1). The effects of the angiotensin receptor blockers were compared with placebo in DHyPP and TROPHY and with a calcium channel blocker in STAR CAST (Table 1). Human and experimental studies of prevention of hypertension. aExpressed as an approximate period of equivalent human years. Human and experimental studies of prevention of hypertension. aExpressed as an approximate period of equivalent human years. None of these studies was entirely successful, but they offered glimpses to the possibilities. STAR CAST and TROPHY suggested apparent delays in the progression of blood pressure to hypertensive levels. STAR CAST also suggested that the class of treatment was important, with a slower return of blood pressure after the angiotensin blocker treatment than after the calcium antagonist. These studies were brave attempts and any disappointment in no way undermines the importance of the fundamental question they address. Indeed, for a story that began more than 30 years ago,5,6 it is just reaching its prime. It’s a story that emphasizes the importance and utility of animal models for human conditions and has increasing relevance to the remarkable advances in the understanding of the genome structure and function. The real star of the prevention paradigm is the spontaneously hypertensive rat (SHR) in which the plot line is most thoroughly developed. Well known as a model of human essential hypertension, there is debate over the pathophysiology of hypertension in SHR but agreement that it is genetically determined. It is here that prevention of hypertension with short-term treatment in the young SHRs has provided insights into when, where, and how some of the genes that contribute to hypertension operate. Numerous independent studies have shown that inhibitors of the renin-angiotensin system (RAS) (typically angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers) administered in the prehypertensive period (typically from 6 to 10 weeks of age7) to SHRs result in a permanent reduction in blood pressure and prolongation of life8 (Table 1). These persistent effects of RAS inhibition are not simply a nonspecific effect of blood pressure reduction during the prehypertensive phase because as they are not observed in SHRs after treatment with vasodilators (e.g., hydralazine) or calcium antagonists.9,10 The underlying hypothesis is one of a genetically programmed transition from prehypertension to hypertension that depends on the RAS. The relative advantage of RAS inhibition is hinted in the results of STAR CAST by the slower rate of return of blood pressure between the angiotensin receptor blocker and the calcium channel blocker. The failure to replicate the SHR story in the human studies after 1 or 2 years of treatment in adulthood is not surprising when one considers that treatment from 6 to 10 weeks of age in the rat is roughly equivalent to 4 years of treatment around puberty in humans. However, timing and length of treatment in humans are not the only challenges. Here again the rats can help. Not all inbred hypertensive rat strains mimic SHRs. For example, RAS inhibition in the Milan hypertensive strain does not elicit a persistent reduction in blood pressure.11 This implies that distinct genetic mechanisms exist in the SHRs that program the long-term response to RAS inhibition and such genetic factors are not present in the Milan strain. Given the outbred and heterogeneous nature of human populations, it will be necessary to identify human subjects carrying mechanisms contributing to high blood pressure that are susceptible to short-term RAS inhibition in early life. In other words identify human SHRs. Such selection needs to be based on more sophisticated measures than family history (Table 1) and will need pathophysiological phenotypes and/or genotypic markers. The kidney might be important here. The prehypertensive SHR has abnormally increased renal vascular resistance sufficient to compromise renal blood flow and glomerular filtration rate. These renal hemodynamic abnormalities in SHRs respond acutely to RAS inhibition.6 A similar reduction in renal vascular resistance was observed in the DHyPP Study.3 Whether these changes persisted after treatment in DHyPP subjects (whose blood pressure was not reduced after treatment) is unknown, but in SHRs long-term blood pressure reduction is a associated with improvements in renal hemodynamics after short-term treatment.7 The importance of the kidney in SHRs is further emphasized by the results of renal transplantation studies. The blood pressure “follows the kidney” in cross-transplantation experiments between previously RAS-inhibited and untreated SHRs.12 Despite the apparent importance of the kidneys and evidence of renal abnormalities that might exist in young subjects predisposed to hypertension,13 renal phenotypes are not simple or precise measures in individuals. If they can be discovered, less variable molecular markers might be useful. The molecular potential is illustrated by findings that renal expression of nerve growth factor is increased in prehypertensive SHRs and is persistently reduced after brief ACE inhibitor treatment.14 When the genetic codes that underlie hypertension, such as the ones that determine renal nerve growth factor expression in SHR, are discovered15 and detected in humans, they might be used to select those in whom short-term RAS inhibition might have long-term effects. It is certain that the simple and tantalizing story of preventing hypertension for the duration of life with brief early treatment is riddled with subtexts and intrigues that have yet to be fully revealed. However, hats off to investigators in the complementary worlds of both experimental and human hypertension who have the stamina and faith that are needed to see this one through. The authors declared no conflict of interest.