Journal of Hypertension:
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
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: email@example.com
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 . 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 .
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 . 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) . 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 .
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 . 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 ; third, never-treated male patients with primary hypertension revealed greater wall-to-lumen ratio of retinal arterioles than normotensive controls ; and finally, patients with subclinical organ damage such as increased urinary albumine excretion  and intima–media thickening of carotid arteries  were found to have parallel increases in wall-to-lumen ratio of retinal arterioles.
In the present issue of the journal, Rizzoni et al. 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 . 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 .
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. 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 . In contrast to the previous study by our group , Rizzoni et al. included individuals on antihypertensive treatment and also hypertensive patients with concomitant diabetes mellitus . 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 . 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 . 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 . 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.
Conflicts of interest
There are no conflicts of interest.
1. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension
2. Heagerty AM, Aalkjaer C, Bund SJ, Korsgaard N, Mulvany MJ. Small artery structure in hypertension. Dual processes of remodeling and growth. Hypertension
3. Schiffrin EL. Remodeling of resistance arteries in essential hypertension and effects of antihypertensive treatment. Am J Hypertens
4. Park JB, Schiffrin EL. Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. J Hypertens
5. Schiffrin EL, Deng LY. Relationship between small-artery structure and systolic, diastolic and pulse pressure in essential hypertension. J Hypertens
6. Rizzoni D, Porteri E, Boari GE, De Ciuceis C, Sleiman I, Muiesan ML, et al. Prognostic significance of small-artery structure in hypertension. Circulation
7. Mathiassen ON, Buus NH, Sihm I, Thybo NK, Morn B, Schroeder AP, et al. Small artery structure is an independent predictor of cardiovascular events in essential hypertension. J Hypertens
8. De Ciuceis C, Porteri E, Rizzoni D, Rizzardi N, Paiardi S, Boari GE, et al. Structural alterations of subcutaneous small-resistance arteries may predict major cardiovascular events in patients with hypertension. Am J Hypertens
9. Harazny JM, Ritt M, Baleanu D, Ott C, Heckmann J, Schlaich MP, et al. Increased wall:lumen ratio of retinal arterioles in male patients with a history of a cerebrovascular event. Hypertension
10. Ritt M, Harazny JM, Ott C, Schlaich MP, Schneider MP, Michelson G, Schmieder RE. Analysis of retinal arteriolar structure in never-treated patients with essential hypertension. J Hypertens
11. Ritt M, Harazny JM, Ott C, Schneider MP, Schlaich MP, Michelson G, Schmieder RE. Wall-to-lumen ratio of retinal arterioles is related with urinary albumin excretion and altered vascular reactivity to infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine. J Hypertens
12. Baleanu D, Ritt M, Harazny J, Heckmann J, Schmieder RE, Michelson G. Wall-to-lumen ratio of retinal arterioles and arteriole-to-venule ratio of retinal vessels in patients with cerebrovascular damage. Invest Ophthalmol Vis Sci
13. Rizzoni D, Porteri E, Duse S, De Ciuceis C, Rosei CA, La Boria E, et al
. Relationship between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles evaluated noninvasively by scanning laser Doppler flowmetry. J Hypertens
14. Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by angiotensin receptor antagonist losartan. Circulation
15. Rizzoni D, Muiesan ML, Porteri E, Castellano M, Zulli R, Bettoni G, et al. Effects of long-term antihypertensive treatment with lisinopril on resistance arteries in hyperensive patients with left ventricular hypertrophy. J Hypertens
16. Schiffirn EL, Deng LY. Structure and function of resistance arteries of hypertensive patients treated with a beta-blocker or a calcium channel antagonist. J Hypertens
17. Schofield I, Malik R, Izzard A, Austin C, Heagerty A. Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation
18. 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 noninsulin-dependent diabetes mellitus. Circulation
19. Harazny JM, Raff U, Welzenbach J, Ott C, Ritt M, Lehmann M, et al. New software analyses increase the reliability of measurement of retinal arterioles morphology by scanning laser Doppler flowmetry. J Hypertens
This article has been cited 1 time(s).
Cardiovascular DiabetologyVildagliptin in addition to metformin improves retinal blood flow and erythrocyte deformability in patients with type 2 diabetes mellitus - results from an exploratory studyCardiovascular Diabetology
© 2012 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read