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Journal of Hypertension:
doi: 10.1097/HJH.0b013e328353f85a
Editorial Commentaries

Wall-to-lumen ratio of retinal arterioles: a reproducible, valid and noninvasive approach for evaluation of early arteriolar changes in arterial hypertension in vivo

Schmieder, Roland E.; Ritt, Martin

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Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Germany

Correspondence to Professor Dr medicine Roland E. Schmieder, Department of Nephrology and Hypertension, Clinical Research Center, University of Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany. Tel: +49 9131 853 6245; fax: +49 9131 853 6215; e-mail: roland.schmieder@uk-erlangen.de

Small resistance arteries (small arteries and arterioles with a diameter <350 μm) are major regulators of peripheral vascular resistance, which represents the hemodynamic hallmark of arterial hypertension. According to Hagen-Poiseuille‘s law, flow resistance is inversely related to the fourth power of the vessel. Thus, even mild narrowing (either structural or functional or both) increases total peripheral vascular resistance, and thereby blood pressure. To determine changes in small arteries and arterioles, either within a participant or between participants, media-to-lumen ratio or wall-to-lumen ratio of small resistance arteries and arterioles has been measured [1–3] and found to represent an early phenomenon in the pathophysiology of arterial hypertension [4]. Moreover, in a cohort of 45 never-treated individuals with primary hypertension and 40 normotensive individuals, SBP and DBP were significantly related to media-to-lumen ratio of isolated subcutaneous small arteries and arterioles indicating that the degree of blood pressure elevation is related to the severity of small artery and arteriolar changes [5].

Of most interest and clinical importance, increased media-to-lumen ratio of isolated and in-vitro examined subcutaneous small arteries and arterioles (using a myograph) were found to predict cardiovascular outcome in individuals with arterial hypertension [6–8]. In an Italian study, 128 participants (including 59 individuals with primary hypertension, 17 with pheochromocytoma, 20 with primary aldosteronism, 12 with renovascular hypertension and 20 normotensive individuals with diabetes mellitus) were followed-up for an average period of 5.4 years, and increased media-to-lumen ratio of isolated subcutaneous small arteries and arterioles was predictive of reduced event-free survival [6]. In a Danish study comprising 159 participants with primary hypertension and moderate cardiovascular risk, media-to-lumen ratio of isolated subcutaneous small arteries and arterioles indicated the incidence of adverse cardiovascular outcome during the follow-up of 1661 days even after adjustment for the Heart Score level (10-year mortality risk-estimate, integrating age, sex, SBP, cholesterol and smoking) [7]. In a subsequent analysis of 303 participants [including 111 individuals with primary hypertension (33% of them with diabetes mellitus), 109 patients with secondary forms of hypertension and 83 normotensive individuals], increased media-to-lumen ratio of isolated subcutaneous small arteries and arterioles was of prognostic significance with respect to adverse cardiovascular and cerebrovascular outcome over the follow-up period of 6.9 years [8].

However, the evaluation of small artery and arteriolar structure of isolated subcutaneous small vessels require an invasive procedure, namely the performance of a biopsy of subcutaneous tissue. Hence, this methodology is not suitable for routine patient management and its use might, therefore, be limited for scientific purposes. Eventually, an innovative approach allowing the assessment of retinal arteriolar structure, that is wall-to-lumen ratio of retinal arterioles, safely, noninvasively and in vivo, was introduced by our group 8 years ago, offering the potential to become a future tool for evaluation of small artery and arteriolar changes in patients with arterial hypertension in a routine clinical setting [9]. We found that first, wall-to-lumen ratio of retinal arterioles assessed by scanning laser Doppler flowmetry (SLDF), without the need of applying mydriatic drugs, is increased in hypertensive patients with cerebrovascular disease compared to treated hypertensive and normotensive individuals; second, treated hypertensive patients with uncontrolled blood pressure revealed greater wall-to-lumen ratio of retinal arterioles than those with controlled blood pressure [9]; third, never-treated male patients with primary hypertension revealed greater wall-to-lumen ratio of retinal arterioles than normotensive controls [10]; and finally, patients with subclinical organ damage such as increased urinary albumine excretion [11] and intima–media thickening of carotid arteries [12] were found to have parallel increases in wall-to-lumen ratio of retinal arterioles.

In the present issue of the journal, Rizzoni et al.[13] compared both methodologies, namely wall-to-lumen ratio of retinal arterioles assessed in vivo by SLDF versus media-to-lumen ratio of isolated subcutaneous small arteries and arterioles assessed in vitro using a myograph. In a cohort of participants with arterial hypertension and normotensive controls, a close linear relationship between wall-to-lumen ratio of retinal arterioles and media-to-lumen ratio of isolated subcutaneous small arteries and arterioles was observed [13]. These data provide for the first time evidence that changes of arterioles in the retinal vascular bed assessed in vivo by SLDF are similar and comparable to the changes of small arteries and arterioles in the subcutaneous tissue assessed ex vivo in patients with arterial hypertension. The strength of the relationship between wall-to-lumen ratio of retinal arterioles and media-to-lumen ratio of isolated subcutaneous small arteries and arterioles was confirmed by multiple linear regression analyses [13].

It is important to stress that the two methodologies have significant differences. First, in contrast to the ex-vivo examined media-to-lumen ratio of isolated subcutaneous small arteries and arterioles, the in-vivo wall-to-lumen ratio also includes the tunica intima and the tunica adventita of the vessel wall in the measurements [14,15]. Second, although the media-to-lumen ratio of isolated subcutaneous small arteries and arterioles is assessed outside the metabolic environment of the patients, with the small arteries and arterioles mounted on the myograph, the wall-to-lumen ratio of retinal arterioles is assessed in vivo under physiological conditions. Feedback-loop regulations of vascular tone, which impact small arteries and arterioles, are by nature not respected under ex-vivo conditions.

The data of the current study by Rizzoni et al.[13] confirms previous findings from our group that wall-to-lumen ratio of retinal arterioles is increased in patients with arterial hypertension compared to normotensive controls [10]. In contrast to the previous study by our group [10], Rizzoni et al. included individuals on antihypertensive treatment and also hypertensive patients with concomitant diabetes mellitus [13]. Calcium channel blockers [15,16] and diabetes mellitus [17,18] were found to modulate small artery and arteriolar morphology. Thus, the presence of these confounders might explain the lack of a correlation of blood pressure levels with media-to-lumen ratio of isolated subcutaneous small arteries and arterioles and wall-to-lumen ratio of retinal arterioles, respectively.

The interobserver and intraobserver reproducibility of measurement of wall-to-lumen ratio of retinal arterioles is slightly less than 10% in various different study cohorts, for example in primary hypertension stage 1 and 2, treatment resistant hypertension and hypertension coexisting with diabetes mellitus [19]. In their study, Rizzoni et al. analyzed reproducibility as well and found a fairly good reproducibility for the measurement of wall-to-lumen ratio of retinal arterioles by SLDF [13]. Nevertheless, the assessment of wall-to-lumen ratio of retinal arterioles by SLDF is still a semiautomatic measurement, and a fully automatic measurement would clearly be desirable.

In conclusion, the most novel finding of the current study by Rizzoni et al. is that wall-to-lumen ratio of retinal arterioles assessed noninvasively and in vivo by SLDF is closely related to in-vitro media-to-lumen ratio of isolated subcutaneous small arteries and arterioles in humans [13]. This report thus confirms the validity of analyzing early arteriolar changes in the retinal circulation in vivo by SLDF in patients with arterial hypertension. However, whether increased wall-to-lumen ratio of retinal arterioles is predictive with respect to cardiovascular outcome in patients with arterial hypertension, as it was previously demonstrated for increased media-to-lumen ratio of isolated subcutaneous small arteries and arterioles [6–8], remains to be elucidated in future prospective studies.

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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