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Journal of Hypertension:
doi: 10.1097/HJH.0b013e328122d9af
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Predicting hypertension complications from small artery structure

Heagerty, Anthony M

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Cardiovascular Research Group, Division of Cardiovascular and Endocrine Sciences, Core Technology Facility, University of Manchester, Manchester, UK

Corespondence and requests for reprints to Professor Anthony M. Heagerty, Cardiovascular Research Group, Division of Cardiovascular and Endocrine Sciences, Core Technology Facility, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK Tel: +44 (0)161 2751199; fax: +44 (0)161 2751183; e-mail: tony.heagerty@manchester.ac.uk

Since it was established that hypertension is a disease of increased peripheral vascular resistance, the spotlight has been directed at understanding the way the vasculature reacts to bring this about. Aalkjaer et al. [1] showed that small arteries contracted normally but that the wall was thickened and the lumen diameter decreased. Detailed measurements by Korsgaard et al. [2] and others [3] then demonstrated that these arteries underwent eutrophic inward remodelling, where the pre-existing cells re-aligned in the vascular wall thereby increasing the number of cell layers and reducing the internal lumen diameter [4].

Although it has been debated, the evidence seems to point to this change in vascular wall structure being a consequence of hypertension rather than a contributing factor. The cause has yet to be clarified fully but is probably because eutrophic inward remodelling is a relatively fast functional adaptation to prolonged vasoconstriction and as such is an energetically advantageous mechanism that preserves a reduced lumen for prolonged periods [5]. Furthermore, it is the preferred physiological mechanism by which wall stress can be normalized whilst maintaining vaso-motor tone.

Hypertrophy of the vascular wall is usually not a feature of pressure-induced changes: indeed, it is observed when blood pressure is fulminant, accelerated or rapidly increased, and the normal physiological responses are overwhelmed and break down. It is entirely possible that genomically determined abnormalities of the vasculature might also contribute to such failure and explain why hypertrophy replaces eutrophic inward remodelling. Such a response to pressure is not so energetically efficient and its presence may be the harbinger of target organ damage and events downstream, such as stroke, heart failure and renal damage.

Because eutrophic inward remodelling may represent the earliest type of organ damage associated with hypertension and precede other prognostically important features, such as left ventricular hypertrophy, studies have been carried out to examine whether it is reversed with treatment. To date, the evidence suggests that this is possible with a variety of drugs. Previously, however, only one study has attempted to investigate the possible prognostic significance of remodelling of small arteries. Using a heterogeneous high-risk group of patients drawn from cohorts with secondary forms of hypertension and diabetes as well as essential hypertension, Rizzoni et al. [6] showed that the media: lumen ratio, was a strong and an independent predictor of cardiovascular risk. A subsequent re-analysis of the data also showed that it was more likely that patients who sustained events during the follow-up period actually had increased hypertrophy in the vascular wall, that is, they had replaced eutrophic inward remodelling with the less efficient compensatory mechanism of smooth muscle cell growth [7].

Rizzoni et al. [6] conceded that the heterogeneity of their patient population meant that the extrapolation of the findings to essential hypertension was uncertain; hence, the interest in the report by Mathiassen et al. [8] in this issue of the journal. These workers examined the possible prognostic relevance of resistant artery structure in a homogeneous and moderate risk group of patients with essential hypertension but without diabetes or other concomitant diseases. They were testing the hypothesis that patients with increased media thickness: lumen diameter ratio of their small arteries would demonstrate a higher rate of cardiovascular complications during a mean follow-up period of 10 years.

The cohort comprised 168 patients with essential hypertension who had undergone a biopsy of skin and subcutaneous fat in advance of taking part in clinical trials. After losing some patients to follow-up, a final cohort was assembled which consisted of 159 subjects who were then followed up.

Thirty patients sustained a cardiovascular event during the period of follow-up. These individuals were slightly older, had slightly higher blood pressures and contained an increased number of smokers. Predictably, their heart risk score was also higher but what was not in doubt was that these patients also had an increase in media thickness: lumen diameter ratio compared to patients who did not sustain an event.

As such, we now have a study which demonstrates that structural alterations in small arteries may predict cardiovascular events in uncomplicated essential hypertension. The authors concede that the heart risk score which integrates five important risk factors (gender, age, smoking habits, systolic blood pressure and cholesterol) provided a similar prediction of the outcome but, when media thickness: lumen diameter ratio and the heart risk score were analysed together in a Cox regression model, the result remained significant for both parameters; therefore, an abnormal media thickness: diameter ratio was as least as strong a predictor as the heart score. It is of interest that these patients were entered into clinical trials and so for some time were receiving treatment programmes for antihypertensive medication, although for how long this was maintained and whether good blood pressure control was a consistent finding, is uncertain. Nevertheless, this makes the report even more intriguing because, despite these patients having been identified as having hypertension and structural changes in their small arteries, the initial arterial dimensions still pointed to the prognostic importance of an increased medial thickness: diameter ratio. The medial cross-sectional area is not different in groups of patients with events compared to those without, suggesting that there is no gross evidence for hypertrophy in the arterial wall of patients who have sustained events but this could be the subject of subsequent analyses.

What is not in doubt is that there are two large reports associating changes in structural parameters in small arteries with the subsequent development of cardiovascular events. Of course, to obtain such data, patients have to undergo a small but undoubtedly invasive procedure and if this were to be potentially important in terms of therapeutic decision-making then a non-invasive assessment of small artery structure will have to be developed.

The second issue is to focus more sharply on whether antihypertensive medication can reverse the structural changes and protect such patients from the development of their events. The analogy between identifying patients with left ventricular hypertrophy and exposing them to rigorous treatment programmes and demonstrating that those that regress their hypertrophy do better than those that do not and becomes obvious. A meta-analysis of drug therapy on small artery structural change indicates that newer classes of drugs such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium channel antagonists may be superior to more established drug classes such as atenolol but the numbers of patients in these studies are relatively small and we await larger-sized investigations in the future [9]. The final point is that the early development of structural changes in the evolution of hypertensive circulatory disease has opened the possibility of introducing treatment programmes at an earlier timepoint in an attempt to prevent the transition from pre-hypertension to blood pressure at a level when treatment is undoubtedly warranted. The TROPHY trial suggested that this was possible [10] but other studies have failed to confirm this. The circulation is an integrated unit but the small blood vessels clearly have important haemodynamic functions. When exposed to high levels of pressure, their shape changes and we now know for certain that this is associated with an adverse prognostic when the wall thickens and the lumen narrows.

Mathiassen et al. [8] are to be congratulated on a long-term series of follow-up studies that have provided such interesting data and revealed yet again that our hypertensive patients must be identified and treated aggressively if circulatory events are to be reduced to an absolute minimum.

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References

1 Aalkjaer C, Heagerty AM, Petersen KK, Swales JD, Mulvany MJ. Evidence for increased media thickness, increased neuronal amine uptake, and depressed excitation-contraction coupling in isolated resistance vessels from essential hypertensives. Circ Res 1987; 61:181–186.

2 Korsgaard N, Aalkjaer C, Heagerty AM, Izzard AS, Mulvany MJ. Histology of subcutaneous small arteries from patients with essential hypertension. Hypertension 1993; 22:523–526.

3 Heagerty AM, Aalkjaer C, Bund SJ, Korsgaard N, Mulvany MJ. Small artery structure in hypertension. Dual processes of remodelling and growth. Hypertension 1993; 21:391–397.

4 Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodelling. Hypertension 1996; 28:505–506.

5 Bund SJ, West KP, Heagerty AM. Effects of protection from pressure on resistance artery morphology and reactivity in spontaneously hypertensive and Wistar-Kyoto rats. Circ Res 1991; 68:1230–1240.

6 Rizzoni D, Porteri E, Guelfi D, Muiesan ML, Valentini U, Cimino A, et al. Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus. Circulation 2001; 103:1238–1244.

7 Izzard AS, Rizzoni D, Agabiti-Rosei E, Heagerty AM. Small artery structure and hypertension: adaptive changes and target organ damage. J Hypertens 2005; 23:247–250.

8 Mathiassen ON, Buus NH, Sihm I, Thybo NK, Moern B, Schroeder AP, et al. Small artery structure is an independent predictor of cardiovascular events in essential hypertension. J Hypertens 2007; 25:1021–1026.

9 Schiffrin EL. Small artery remodelling in hypertension: can it be corrected? Am J Med Sci 2001; 322:7–11.

10 Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al. Trial of preventing hypertension (TROPHY) study investigators. N Engl J Med 2006; 354:1685–1697.

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© 2007 Lippincott Williams & Wilkins, Inc.

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