Resetting Genetic Predisposition to Hypertension

Conditions such as high blood pressure generally become obvious in middle age. But what explains the transition from normal blood pressures to high blood pressure? One might expect to find clues to the processes around early adulthood, when genes that predispose to high blood pressure might be activated by some developmental-stage specific signal. Although we know little about the precise molecular basis for genetic predisposition, it is possible to study the physiological changes that might be activated in predisposed young adults.

One might expect to find the physiological characteristics of the predisposition to high blood pressure in young adult offspring from families in which both parents have documented high blood pressure. Our studies in such subjects have revealed abnormalities in the function of the kidneys, taking the form of a significant increase in the rate at which the kidneys filter blood – the glomerular filtration rate (GFR) [1]. Such an increase might in itself damage the kidneys long-term, but it might also be indicative of an underlying abnormality of blood vessel (in this case glomerular) control. Indeed, the pattern of blood flow and filtration would be consistent with increased actions of the hormone angiotensin II [2], which is a key component of the renin-angiotensin system (RAS) and a major cardiovascular control system. We have also found evidence to support activation of the RAS in young adults from families in which both parents have high blood pressure. These changes seem to be transient, because in high blood pressure in later life, the GFR and activation of the RAS falls.

We have observed similar activation of the RAS in young animals without hypertension from a widely used rat model of high blood pressure – the Spontaneously Hypertensive Rat (SHR). However, RAS activation in SHR is associated with a different pattern of renal function, being characterised by a reduction in GFR [3]. Breeding experiments showed that these abnormalities appear to be linked to the genes that determine blood pressure [4]. Just as in humans, these abnormalities disappear as high blood pressure develops in later adulthood.

These apparently transient expressions of genetic programming for high blood pressure raise the possibility that if one could block these effects at a critical time it might be possible to reset the inherent predisposition.

In young SHR, it is possible to normalise the abnormalities in renal function and lower blood pressure by treatment with agents that interfere with the RAS. More importantly, a brief period of treatment is followed by a sustained reduction in blood pressure in adulthood [5] and depends on the kidneys [6]. In fact, it is possible to define that 4-weeks treatment from 6 to 10 weeks of age in SHR can reduce blood pressure long-term [7] and extend life [8].

This remarkable ability to reduce blood pressure long after treatment has stopped offers interesting potential for redefining treatment paradigms. Could we treat young people in their adolescence and early adulthood and avoid long-term drug use in later life?

This possibility is the focus of the TROPHY Study [9] and the forth coming STAR-CAST Study [10]. The TROPHY selected subjects simply on the basis of blood pressure and there was no account taken of family history of high blood pressure or measures of renal function or activity of the RAS. Two years after stopping 2-years of treatment with an angiotensin receptor blocking drug, the blood pressure was slightly lower than control subjects and still rising towards control levels.

The results of the TROPHY Trial are far from conclusive and it has created a deal of controversy on methodological grounds. However, it could also be criticised for not following subjects long enough after treatment to determine whether a real “persistent” effect exists.

However, perhaps the most important issue for studies such as TROPHY is the ability to select those who might actually harbour a genetic predisposition that is actually dependent on the RAS and sensitive to its blockade. Among inbred strains of rats, very few other than SHR show prevention after short-term treatment. In man the hypothesis needs to be tested on those who share the genetic mechanisms of the SHR. Eventually this might be direct genetic testing, but at least family history and RAS/renal phenotypes could help those most likely to achieve a benefit.

The possibility of resetting genetic predisposition to hypertension is tantalising indeed. The potential to reduce blood pressure-related morbidity and mortality while at the same reducing drug side-effects and costs is certainly a goal worthy of further effort.

Références

[1] Harrap S.B., Cumming A.D., Davies D.L., Foy C.J.W., Fraser R., Lever A.F., Watt G.C.M., “Glomerular hyperfiltration, high renin and low-extracellular volume in high blood pressure”, Hypertension, 35, 2000, 952-957.

[2] Watt G.C.M., Harrap S.B., Foy C.J.W., Holton D.W., Edwards H.E., Davidson H.R., Connor J.M., Lever A.F., Fraser R., “Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four corners approach to the identification of genetic determinants of blood pressure”, J. Hypertension, 10, 1992, 473-482.

[3] Harrap S.B., Doyle A.E., “Renal hemodynamics and total body sodium in immature spontaneously hypertensive and wistar kyoto rats”, J. Hypertension, 4(suppl 3), 1986, S249‑S252.

[4] Harrap S.B., Doyle A.E., “Genetic co-segregation of blood pressure and renal hemodynamics in the spontaneously hypertensive rat”, Clin. Sci., 74, 1987, 63-69.

[5] Harrap S.B., Nicolaci J., Doyle A.E., “Persistent effects on blood pressure and renal hemodynamics following chronic converting enzyme inhibition with perindopril”, Clin. Exp. Pharm. Physiol., 13, 1986, 753-765.

[6] Harrap S.B., Wang B.-Z., MacLellan D.G., “Transplantation studies of the role of the kidney in long-term blood pressure reduction following brief ACE inhibitor treatment in young spontaneously hypertensive rats”, Clin. Exp. Pharmacol. Physiol., 21, 1994, 129-13.

[7] Harrap S.B., Van der Merwe W.M., Griffin S.A., Macpherson F., Lever A.F., “Brief ACE inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term”, Hypertension, 16, 1990, 603-614.

[8] Harrap S.B., Mirakian C., Datodi S.R., Lever A.F., “Blood pressure and lifespan following brief ACE inhibitor treatment in young spontaneously hypertensive rats”, Clin. Exp. Pharmacol. Physiol., 21, 1994, 125-128.

[9] Julius S., Nesbitt S.D., Egan B.M., Weber M.A., Michelson E.L., Kaciroti N., Black H.R., Grimm R.H.Jr, Messerli F.H., Oparil S. & Schork M.A., “Trial of Preventing Hypertension (TROPHY) Study Investigators (2006). Feasibility of treating prehypertension with an angiotensin-receptor blocker.”, N. Engl. J. Med., 354, 1685-1697.

[10] Sasamura H., Nakaya H., Julius S., Takebayashi T., Sato Y., Uno H., Takeuchi M., Ishiguro K., Murakami M., Ryuzaki M., Itoh H., “The Short Treatment with the Angiotensin Receptor Blocker Candesartan Surveyed by Telemedicine (STAR CAST) Study : Rationale and Study Design”, Hypertension Research, 31, 2008, 1843-184.