Prospective cohort study of retinal vessel diameters and risk of hypertension
BMJ 2004; 329 doi: https://doi.org/10.1136/bmj.38124.682523.55 (Published 08 July 2004) Cite this as: BMJ 2004;329:79
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
The Beaver Dam Eye Study, by Wong et al (1), is very similar to
another project coordinated by the same researcher and published somewhere
else (2). The methodology differed a little, but the results are the same.
Anyway, when it comes outside the experimental field, these findings
are difficult to implement.
First, those who had the lowest arteriole:venule ratio (eg: the
smallest retinal arteriolar diameter) were the same who were in the pre-
hypertension stratum or, in other words, the same who already were at
greater risk of developing hypertension. Second, the ophtalmological
evaluation used in these studies cannot be established as a routine in any
assistence service because of its cost. Third, despite the little body of
evidence demonstrating the potential beneficial effects of ACE inhibitors
on the microcirculation – besides the anti-hypertensive effect -, thiazide
-type diuretics still are the first-line anti-hypertensive drugs,
according to the ALLHAT (3) and the JNC VII (4).
So, in the clinical scenario, nothing changes. The control of risk
factors for the development of hypertension continues to be the rule and
the accurate blood pressure measurement, the guideline.
References
1- Wong TY, Shankar A, Klein R, et al. Prospective cohort study of
retinal vessel diameters and risk of hypertension. BMJ, 2004; 329: 79
doi:10.1136/bmj.38124.682523.55 (Published 2 June 2004)
2- Wong TY, Klein R, Sharrett AR, et al for the Atherosclerosis Risk
in Communities Study. Retinal Arteriolar Diameter and Risk for
Hypertension. Ann Intern Med 2004;140:248-255
3- The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. Major outcomes in high-risk hypertensive patients
randomized to angiotensin-converting enzyme inhibitor or calcium channel
blocker vs diuretic. JAMA 2002; 288:2981-97
4- The Seventh report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure – The JNC 7
Report. JAMA 2003; 289:2560-72
Competing interests:
None declared
Competing interests: No competing interests
As a contact lens pratitioner I was in the unique position in 1998 of
using the first of the electronic fundus cameras in a practice routinely
dispensing sodium ascorbate for (a) reduction of infection risk - mainly
Post- Adnoviral Keratitis (PVK) (b) allergy seen as Giant Papillary
Conjunctivitis (GPC) and (c) diabetic complications, all in a patient base
returning unusually except in contact lens practise, for 6 monthly eye
examinations. Diabetic need for extra vitamin C is little dealt with in
textbooks of management of diabetics (Cheraskin E - Vitamin C Who needs
it? Pub 1993.) (1)
Although the fundi were not imaged at every visit it had become
obvious from anterior segment examinations that scurvy (any state in which
supplemental vitamin C improves the pericorneal vasculature) was leading
to reductions of vessel lumen, congestion and hyperaemia in almost every
case. Microaneurysms and incipient microaneurysms were gradually
eliminated as dosages increased. It was judged that over 90% of patients
could be improved but some needed over 10,000mgs/day supplemented with
vitamin E. According to the received wisdom, the physicians consulted by
these patients continued to doubt the necessity for such large doses and a
degree of friction existed.
Serendipitously, two years later, when comparing optic disc images
to detect primary open angle glaucoma (POAG) in the procedure I had
earlier named Sequential Photometric Overlays Alerting Glaucoma (SPOAG)in
'Optometry Today'it was noticed that those patients taking supplemental
ascorbate were showing reductions of retinal arterial cholesterol,
typically seen at stressed points e.g. bifurcations.
CardioRetinometry appears to confirm the original work by Paterson
(1939/40) and later, Willis & Fishman (1955)(2-8) – all naming low
Vitamin C as being associated with death from Coronary Heart Disease
(CHD). Pauling/Rath theory (Lipoprotein alpha is a surrogate for vitamin
C) appears also to be well confirmed (9-14)
It was decided to research this and a company was formed
(AntiCoronary Clinics (UK) Ltd) both to explore the possibilities of a
study aided by local physicians and to determine if it could be
financially viable as no grant could be anticipated from competing sources
of funding especially as the method apppeared to have advantages over
electron beam tomography (EBT) and angiography. The method appeared to be
demonstrating more atheroma than EBT and it is confidently anticipated
that CardioRetinometry will prove to be a better surrogate outcome
predictor of reduced CHD risk than any current diagnostic procedure.
CardioRetinometry has already also demonstrated reductions of
cholesterol in the retinal venules and it is believed by the author that
cholesterol in the firt post capillary venules and veins, deposited
against the current received wisdom, is the precursor of arterioscleosis
and essential hypertension.
A research grant application is now in the pipeline.
Sydney J Bush
PhD. DOpt. (IOSc London)
References and End Notes:
1.) Cheraskin E MD. DMD. - Vitamin C Who needs it? Pub Arlington 1993.
Five textbooks on diabetic management fail to mention vitamin C.p98.
2.) J. C. Paterson (1939 - 1940) CAPILLARY RUPTURE WITH 2. INTIMAL
HEMORRHAGE IN THE CAUSATION OF CEREBRAL VASCULAR LESIONS,
3.) J. C. Paterson (1940) Arch Path, Vol 29, 1940, Pg 345-354 : SOME
FACTORS IN THE CAUSATION OF INTIMAL HEMORRHAGES AND IN THE PRECIPITATION
OF CORONARY THROMBI,
4.) J. C. Paterson (1941) Canad. M. A. J., Feb 1941, Pg 114-120
5.) G.C. Willis, An Experimental Stdy of the Intimal Ground Substance in
Atherosclerosis, Canad. M. A. J. Vol 69, 1953, p. 17-22
6.) G. C. Willis, A. W. Light, W.S. Cow, Serial Arteriography in
Atherosclerosis Canad. M. A. J. Dec 1954, Vol 71, 1954, p. 562-568
7.) G. C. Willis, S. Fishman, Ascorbic Acid Content of Human Arterial
Tissue. Canad. M. A. J., April 1, 1955, Vol 72, Pg 500-503
8.) G.C. Willis, The Reversibility of Atherosclerosis, Canad. M. A. J.,
July 15, 1957, Vol 77., Pg 106-109
9.) Pauling L. Rath M. Hypothesis: Lipoprotein(a) is a surrogate for
ascorbate.Proc Natl Acad Sci U S A. 1990 Aug;87(16):6204-7Linus Pauling
Institute of Science and Medicine, Palo Alto, CA 94306.
Cardiologist Matthias Rath. M.D.) Joint worker with Linus Pauling co-
writer of Unified Theory of Human Cardiovascular Disease Leading the Way
to the Abolition of This Disease as a Cause of Human Mortality. J. of
Orthomolecular Medicine 7:5-15 (1992a)
10.)Rath M. Pauling L. Solution to the Puzzle of Human Cardiovascular
Disease: Its Primary Cause is Ascorbate Deficiency Leading to the
Deposition of Lipoprotein Alpha and Fibrinogen/Fibrin in the Vascular
Wall. J. of Orthomolecular Medicine 6:125-34(1991a)
10.) Rath M. Pauling L. Apoprotein(a) is an Adhesive Protein. J. of
Orthomolecular Medicine 6:139-43(1991b)
11.) Rath M. Pailing L. Plasma Induced Proteolysis and the Role of
Lipoprotein alpha, Lysine and Synthetic Lysine Analogues J. of
Orthomolecular Medicine 7:17-23(1992b)
12.) Rath M. Lipoprotein alpha Reduction by Ascorbate. J. of
Orthomolecular Medicine 7:81-82(1992c)
13.) Rath M. Reducing the Risk of Cardiovascular Disease with Nutritional
Supplements. J. of Orthomolecular Medicine 7:153-62(1992e)
14.) Rath M. Cationic-anionic and Anionic-cationic Oligopeptides in
Apoprotein(a) and Other Proteins as Modulators of Protein Action and of
Biological Communication. J. of Applied Nutrition 44:62-9(1992f)
Competing interests:
AntiCoronary Clinics (UK) Ltd. 20-22 Brook St. Hull HU2 8LA
Competing interests: No competing interests
Recently, in a large prospective cohort study with 2451 normotensive
people and 10 years follow-up, the potentially important role of the
narrowing of the small blood vessels in the pathogenesis of hypertension
was clearly determined.(1)
Wong et al. showed that people with smaller retinal arteriolar
diameters were more likely to develop hypertension over a 10 year period,
than people with larger arteriolar diameters, independent of known risk
factors for hypertension. They also found that the combined exposure to
higher pre-existing blood pressure at baseline and narrowed arterioles was
associated with a higher risk of hypertension, than the effect of either
alone.
This finding supports the importance of microvascular rarefaction (or
rarification or rarefication) in hypertension, which refers to the
functional and structural remodeling of the arterioles, microvasculature
and venules in response to increased blood pressure, and ultimately
involves the obliteration of pre-existing blood vessels.(2-4)
Microvascular rarefaction has been observed even in very early stages
of the development of hypertension. The ensuing reduction in blood vessels
not only may contribute to hypertensive lesions of target organs, but may
also maintain or even amplify the increased blood pressure by augmenting
the peripheral vascular resistance, leading to further increases in blood
pressure and the maintenance of the hypertensive state, thus creating a
vicious circle.(2)
Therefore, the findings by Wong et al. deserve further attention, as
does the recognition of the value of specifically targeting the
microcirculation in the prevention and treatment of hypertension and its
complications.(1)
1. Wong TY, Shankar A, Klein R, Klein BE, Hubbard LD. Prospective
cohort study of retinal vessel diameters and risk of hypertension. BMJ
2004;329:79.
2. Boudier HA. [Hypertension and microcirculation]. Arch Mal Coeur
Vaiss 2002;95 Spec No 6:17-22.
3. Boudier HA. Arteriolar and capillary remodelling in
hypertension. Drugs 1999;58 Spec No 1:37-40.
4. Vicaut E. Microcirculation and arterial hypertension. Drugs
1999;58 Spec No 1:1-10.
Competing interests:
None declared
Competing interests: No competing interests
The Study conducted by Wong et.al.shows a relation between
microvascular changes in retina and risk of developing hypertension.They
included in their Study 47-80 year old people.We know in this age group
vascular,microcirculatory changes are very common and prevalence of
hypertension is very high.Blood flow within the eye decreases with
increasing age and retinal arterial blood flow decreases 6%-11% per decade
after 40 years of age.Another Study revealed that 62.4% of men and 77.3%
of women older than 75 years have hypertension.Therefore,it is very
deficult to conclde that retinal vascular narrowing causes hypertension or
vise versa.
Aging causes structural and functional changes of the blood
vessels.Aging blood vessels have greater wall thikness.Endothelial cells
become flattened,rounded and increase in volume, also accumulation of
collagen smooth muscle cells and mononuclear macrophage-like cells
contributes to increase vessel wall thickness thus decreses the
diameter.Endothelial cells produce biochemical compounds:endothelin
derived relaxing factor(EDRF)-nitric oxide(NO),prostacycline and
endothelin derived contractin factor(EDCF)-endothelin.Production of EDRF
decreases and EDCF increases with aging.In older age vascular tone
increases not only because of narrowing of small vessels but also because
of biochemical derangements, leading to increase blood pressure.
Atherosclerosis and arteriosclerosis are also age related disorders
responsible for retinal vascular changes and hypertension in persons
older than 65 years of age. We also know that involutional sclerosis of
retinal blood vessels can occure without hypertension.
So, microvascular changes in retina have multifactoral aetiology and
depend on multiple biophysical and biochemical factors and may occure with
or without hypertension.
Competing interests:
None declared
Competing interests: No competing interests
Am I alone in thinking that the photographs showing
narrowed and normal retinal arteriolar diameter in this
paper are the wrong way round? And is the fact that
noone else has commented a sad reflection on the
inability of non specialists medical practitioners to
distinguish between a retinal arteriole and a retinal
venule any more, and the lack of undergraduate
medical training in ophthalmology which has led to this
state of affairs?
Competing interests:
None declared
Competing interests: No competing interests
Wong et al. addressed an interesting issue in their study on the
association between retinal vessel diameters and risk of hypertension (1).
However, I see some points which would have deserved discussion.
First, there is evidence that the level of blood pressure (BP) is one
of the strongest predictors for the risk of progression towards
hypertension. Thus, in the Framingham cohort study (2), subjects with a
normal BP (120-129/80-84 mmHg) had a two-fold to four-fold increased risk
of hypertension compared with subjects with optimum BP (BP<120(80
mmHg). Subjects with a high normal BP (135-139/85-89 mmHg) had a five-fold
to twelve-fold raised odds. These figures were obtained only after four
years of follow-up (2)! Surprisingly, the odds ratios found in the study
by Wong et al. were lower despite a longer follow-up period. Moreover,
with increasing retinal arteriole narrowing, the risk difference between
normal and prehypertensive subjects disappeared. Do these findings suggest
that among patients in the first quartile of arteriole/venule ratio, BP is
no longer a determinant of hypertension risk? This raises questions about
the validity of the findings by Wong et al.
Second, again in the Framingham cohort study (2), the change in
weight was a clear determinant of the risk of hypertension: a 5% weight
gain was associated with a 20-30% increased odds of the incidence of
hypertension. Weight change was not measured into the study by Wong et al.
This change would have been a pertinent variable to consider for the
multivariate analysis.
Thus, I am not sure of the clinical pertinence of this study: before
assessing arteriolar narrowing among my patients, I would prefer to
carefully measure their blood pressure and to follow their change in
weight in order to evaluate their risk of hypertension (and other health
risks).
1. Wong TY, Shankar A, Klein R, Klein BE, Hubbard LD. Prospective
cohort study of retinal vessel diameters and risk of hypertension. BMJ
2004; 329(7457): 79
2. Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of
frequency of progression to hypertension in non-hypertensive participants
in the Framingham Heart Study: a cohort study. Lancet 2001; 358(9294):
1682-1686
Competing interests:
None declared
Competing interests: No competing interests
Re: Emperor's new clothes?
I have to agree with Dr Clarke at my old medical school, but my
excuse is that I considered it so obvious that the images had been
transposed that it was unworthy of comment.
As to lack of ability to differentiate between retinal arterioles and
venules I must agree that the difference should be apparent to anyone with
6/60 in this case.
What I find noteworthy however is the degree of retinal atheroma in
these images which has passed without comment. The non-surgical reversal
of such atheroma by nutritional prophylactic cardioretinometry (NPCRet) is
not difficult. I should also anticipate some improvements and restoration
of the lumen in such cases with NPCRet.
In my letter of 23rd July I redefined scurvy as "Any state in which
supplementary vitamin C improves the pericorneal vasculature." and this
has passed without challenge. I should hasten to add that because scurvy
exists in two forms, ephemeral and - more difficult to spot - chronic
subclinical, this definition only applies to the most obvious which is the
ephemeral form. Approximately ninety free radical diseases are now thought
to be rooted in Chronic Subclinical Scurvy although Denham Harman, whose
modesty is inversely proportional to the importance of his so fundamental
free radical theory, never made a great point of this after fathering the
Free Radical Theory of Aging and Disease an astonishing fifty years ago
this month. Indeed, that he is still waiting for a Nobel Prize is most
curious.
Because it is so difficult to diagnose, chronic subclinical scurvy is
perhaps, best defined as "That state in which retinal atheroma can be
proven by sequential imaging to be improved by Nutritional Prophylactic
CardioRetinometry (NPCRet)."
I have not carried out any serious veterinary ophthalmological
research but would welcome comments on the relative state of the retinal
vessels in animals that, perhaps, like the goat, are said to produce up to
100 grams of vitamin C endogenously/day. I doubt there is any cholesterol
visible in their arteries until they become old and feeble. The mouse eye
is frustratingly small as a model that, tantalisingly, produces up to 20
grams/day in 70Kg terms. This animal would be interesting for it
produces so much ascorbate as to be immune to the Sterne strain of
respiratory anthrax.
As I stated in July; Chronic Unbalanced Circadian Atheroma is
advanced as the principal aetiological factor in coronary heart disease.
It is diagnosable from the retinal atheroma and any subject in the Wong
presentation to whom the fundii belong, would be very suitable for NPCRet
in its therapeutic form. Such cases (and I have many hundreds of such
images) often belong to people with low to normal cholesterol levels for
whom statins are irrelevant. Sadly, my invitations to their medical
practitioners to cooperate in NPCRet are largely ignored.
Competing interests:
AntiCoronary Clinics (UK) Ltd
Competing interests: No competing interests