lipid

Xanthelasmata, arcus corneae, and ischaemic vasculardisease and death in general population: prospectivecohort study
BMJ 14 July 2011
د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2011

Abstract

Objective To test the hypothesis that xanthelasmata and arcus corneae,individually and combined, predict risk of ischaemic vascular disease and death in the general population.
Design Prospective population based cohort study.
Setting The Copenhagen City Heart Study.
Participants 12 745 people aged 20-93 years free of ischaemic vascular disease at baseline and followed from 1976-8 until May 2009 with 100% complete follow-up.
Main outcome measures Hazard ratios for myocardial infarction,ischaemic heart disease, ischaemic stroke, ischaemic cerebrovascular disease, and death; odds ratios for severe atherosclerosis.

Results 563 (4.4%) of participants had xanthelasmata and 3159 (24.8%)

had arcus corneae at baseline. During 33 years’ follow-up (mean 22 years), 1872 developed myocardial infarction, 3699 developed ischaemic heart disease, 1498 developed ischaemic stroke, 1815 developed ischaemic cerebrovascular disease, and 8507 died.


Multifactorially adjusted hazard/odds ratios for people with versus those without
xanthelasmata were 1.48 (95% confidence interval 1.23 to 1.79) for
myocardial infarction, 1.39 (1.20 to 1.60) for ischaemic heart disease,
0.94 (0.73 to 1.21) for ischaemic stroke, 0.91 (0.72 to 1.15) for ischaemic
cerebrovascular disease, 1.69 (1.03 to 2.79) for severe atherosclerosis,
and 1.14 (1.04 to 1.26) for death.

The corresponding hazard/odds ratios for people with versus those without arcus corneae were non-significant.
In people with versus those without both xanthelasmata and arcus corneae, hazard/odds ratios were 1.47 (1.09 to 1.99) for myocardial
infarction, 1.56 (1.25 to 1.94) for ischaemic heart disease, 0.87 (0.57 to 1.31) for ischaemic stroke, 0.86 (0.58 to 1.26) for ischaemic cerebrovascular disease, 2.75 (0.75 to 10.1) for severe atherosclerosis,
and 1.09 (0.93 to 1.28) for death.

In all age groups in both women and men, absolute 10 year risk of myocardial infarction, ischaemic heart disease, and death increased in the presence of xanthelasmata. The highest absolute 10 year risks of ischaemic heart disease of 53% and 41% were found in men aged 70-79 years with and without xanthelasmata. Corresponding values in women were 35% and 27%.

Conclusion

Xanthelasmata predict risk of myocardial infarction, ischaemic heart disease, severe atherosclerosis, and death in the general population, independently of well known cardiovascular risk factors,including plasma cholesterol and triglyceride concentrations.
In contrast,arcus corneae is not an important independent predictor of risk.

Introduction

Xanthelasmata palpebrarum are sharply demarcated, yellowish flat plaques on the upper or lower eyelids, most often near the inner canthus. Xanthelasmata represent areas of macrophages containing lipids, of which the major constituent is cholesteryl esters but the exact pathophysiology is not known. Arcus corneae is a grey-white-yellowish opacity located near the periphery of the cornea but separated from the limbic margin by a clear corneal zone.


Arcus corneae represents deposits of cholesteryl ester rich lipid particles, which are thought to be selectively trapped in the extracellular matrix in
the stroma of the cornea. Although xanthelasmata and arcus corneae both consist mainly of cholesteryl esters, on average half of people presenting with xanthelasmata and arcus corneae have relatively low lipid concentrations.

For both xanthelasmata and arcus corneae, lipids originate from plasma lipoproteins. Furthermore, similar mechanisms may be involved in the formation of xanthelasmata and atherosclerotic plaques, and formation of arcus corneae can be induced by experimental hypercholesterolaemia. These findings suggest that xanthelasmata and arcus corneae are markers of proatherogenic changes in the vessels and thus markers of atherosclerosis.

Although most, but not all, studies have reported increased concentrations of plasma total cholesterol or low density lipoprotein cholesterol, decreased high density lipoprotein cholesterol, or both in people with xanthelasmata,most of these case-control studies did not find any association between xanthelasmata and cardiovascular disease.

Similarly, arcus corneae is a well known sign of

hyperlipidaemia, and some studies suggest that arcus corneae is a risk factor for cardiovascular disease, although a recent study showed that this association was mainly due to an association between arcus corneae and increasing age.

Probably because of these inconsistent results, xanthelasmata and arcus corneae are often considered benign phenomena and may not elicit further examination. However, large prospective studies examining the question of whether xanthelasmata and arcus corneae in themselves predict risk of ischaemic vascular disease and death in the general population are lacking. This is clinically important, because the visual diagnosis of xanthelasmata and arcus corneae is easy and inexpensive and can be made even in settings without access to blood samples for lipid profiles.

We tested the hypothesis that xanthelasmata and arcus corneae, individually and combined, predict risk of myocardial infarction, ischaemic heart disease, ischaemic stroke, ischaemic
cerebrovascular disease, severe atherosclerosis, and death in the general population. We studied 12 745 participants from the Copenhagen City Heart Study cohort, of whom 563 (4.4%) had xanthelasmata and 3159 (24.8%) had arcus corneae at baseline, and followed them from 1976 until May 2009.

Methods

Participants
The Copenhagen City Heart Study is a prospective
cardiovascular study of the Danish general population started in 1976-8 with follow-up examinations in 1981-3, 1991-4, and2001-3. We invited 19 329 white women and men of Danish descent stratified into age groups of five years from 20 years to 80 years or older and drawn randomly from the Copenhagen Central Person Registry. Data came from a self administered questionnaire, a physical examination, and blood samples.

Ischaemic heart disease, ischaemic

cerebrovascular disease, and death


We defined ischaemic heart disease as fatal or
non-fatal myocardial infarction or characteristic symptoms of angina pectoris, including revascularisation procedures; death
from other causes led to censoring. We determined time to ischaemic heart disease from the date of study entry until the first date of a diagnosis of either myocardial infarction or angina . Diagnosis of myocardial infarction followed the changing definitions over time.

After 2000, the diagnosis was based on: either typical rise and fall of biochemical markers of
myocardial necrosis (troponin or creatine kinase MB) with at least one of ischaemic symptoms, development of pathological Q waves on the electrocardiogram, and electrocardiographic changes indicative of ischaemia or coronary artery intervention;
or pathological findings of an acute, healed, or healing
myocardial infarction, with later changes as indicated.

We gathered potential cases with ischaemic cerebrovasculardisease, including ischaemic stroke, from the national Danish Patient Registry and the national Danish Causes of Death Registry .We requested hospital records, and experienced neurologists reviewed all potential cases. We validated possible stroke events (in patients admitted to hospital as well as non-admitted) by using the WHO definition of stroke: an acute disturbance of focal or global cerebral function with symptoms lasting longer than 24 hours or leading to death with presumably no other reasons than of vascular origin.

To distinguish between infarction (ischaemic stroke), intracerebral haemorrhage, and subarachnoid haemorrhage, a computed tomography or magnetic resonance scan, autopsy, spinal fluid examination, or surgical description was needed. The event was
diagnosed as an ischaemic stroke if the scan did not show an infarction or haemorrhage but the person had symptoms that met the criteria of the definition of stroke.

We did not apply the diagnosis of stroke in cases in which a scan showed signs of previous cerebrovascular disease but no history of any symptoms was present. The diagnostic criteria for ischaemic cerebrovascular disease were ischaemic stroke, transient ischaemic attack (focal neurological symptoms lasting less than 24 hours), or amaurosis fugax (transient blindness in one eye only).
Information on date of death came from the national Danish Central Person Registry, which is 100% complete.

Severe atherosclerosis

Ankle brachial index, a drop in blood pressure in the legs that predicts severe atherosclerosis, was determined in the 2001-3 examination of the Copenhagen City Heart Study in 2773
participants who had also participated in the baseline examination (1976-8) and had complete information on all relevant variables including xanthelasmata and arcus corneae.


A standard brachial systolic and diastolic blood pressure was recorded on both arms, and systolic ankle blood pressure of the posterior tibial artery on both legs was obtained by Doppler
(Huntleigh Mini Dopplex Doppler D900, Huntleigh, UK). The ankle brachial index was the lowest ankle systolic blood pressure divided by the highest brachial systolic blood pressure. Severe atherosclerosis was an ankle brachial index below 0.9.

Lipid profile

In people with xanthelasmata or arcus corneae at baseline,plasma concentrations of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and triglycerides at baseline were higher than in those without these traits. High density lipoprotein cholesterol and apolipoprotein A1 were lower in people with xanthelasmata than in those without xanthelasmata, and lipoprotein(a) was higher in those with arcus corneae than in those without arcus corneae.

Ischaemic heart disease, ischaemic

cerebrovascular disease, and death
During a follow-up of up to 33 years (mean follow-up 22 years), 1872 participants developed myocardial infarction, 3699 developed ischaemic heart disease, 1498 developed ischaemic stroke, 1815 developed ischaemic cerebrovascular disease, and 8507 died. For myocardial infarction, ischaemic heart disease, ischaemic stroke, ischaemic cerebrovascular disease, and total death, the incidence rates in events per 10 000 person years were 121, 226, 64, 74, and 414 in people with xanthelasmata and 65, 134, 53, 65, and 293 in those without xanthelasmata .

We calculated the absolute 10 year risk of ischaemic heart disease in people with xanthelasmata and found that it approaches or exceeds 20% in several age groups of both sexes.
People with an absolute 10 year risk of ischaemic heart disease above 20% are generally considered to be at high risk, and recommendations for treatment include both lifestyle changes and treatment to reduce low density lipoprotein cholesterol.

The absolute 10 year risk estimates for myocardial infarction,ischaemic heart disease, and total death as a function of presence of xanthelasmata stratified for age and sex allows clinicians to use presence of xanthelasmata together with age and sex in the
assessment of risk in individual patients.

Presence of arcus corneae was associated with an increased risk of myocardial infarction, ischaemic heart disease, and total death after adjustment for only age and sex. However, arcus corneae did not remain a risk predictor after multifactorial adjustment.
In support of these findings, a recent prospective study with eight years of follow-up reported a trend towards a significant association between arcus corneae and cardiovascular disease after adjustment for age and sex, which disappeared after additional adjustment for well known cardiovascular risk factors.

Thus, presence of arcus corneae seems to reflect an adverse cardiovascular risk profile—probably in particular an unfavourable lipid profile. This is supported by the higher prevalence of arcus corneae in men, who have a larger inherent
risk of cardiovascular disease.


Implications for clinicians and policymakers
The results from this study suggest that xanthelasmata are acutaneous marker of atherosclerosis independent of lipid concentrations and thus should be considered in clinical practice as an independent and additional risk factor for myocardial infarction and ischaemic heart disease. Today, most people with xanthelasmata are seen by dermatologists, when they want their xanthelasmata removed for cosmetic reasons.

Because of the lack of consensus on the clinical importance of xanthelasmata,some of these people may not have been managed according to their increased risk of cardiovascular disease. The findings from our study could be of particular value in societies where access to laboratory facilities, and thus lipid profile measurement, is difficult.

In this setting, presence of xanthelasmata may be a

useful predictor of underlying atherosclerotic disease. An easy registration of presence of xanthelasmata along with age and sex makes it possible to assess the risk of myocardial infarction and ischaemic heart disease and thus to make sure that people at increased risk are managed accordingly with lifestyle changes and treatment to reduce low density lipoprotein cholesterol.

Strengths and limitations of study

Our study has several strengths. We studied
a homogeneous white general population of 100% Danes; we had a 66% participation rate and up to 33 years of complete follow-up. For all participants, complete information on all variables was
available at baseline, and we had sufficient statistical power to examine even the association between xanthelasmata and risk of ischaemic vascular disease and total death in different subgroups of our study population.

Moreover, no participants were using lipid lowering treatment at baseline in 1976-8, so none of the lipid profiles of the participants are biased by effects
of treatment. This makes this study unique in its ability to evaluate the association between xanthelasmata, arcus corneae, lipid concentrations, and risk of cardiovascular disease.

A limitation to the generalisability of our study is that we examined only white people. The prevalence of xanthelasmata and arcus corneae, as well as the association with risk of cardiovascular disease, may differ among different ethnicities.

Therefore, our findings may not necessarily translate to populations of other ethnicities. Another limitation is that the diagnosis of xanthelasmata and arcus corneae was based on visual inspection. Overlooking mild cases of xanthelasmata and arcus corneae is of course a possibility, which could have led to an underestimation of risk of disease and death. The opposite situation—misclassification of people free of xanthelasmata and arcus corneae—is probably less likely, as both of these deposits are relatively easy to diagnose visually and the investigators were specifically trained for this.

Furthermore, the prevalence of xanthelasmata and arcus corneae in our study corresponds well with previous reports in the literature.
Finally, although we have adjusted for a large number of covariates, unmeasured confounders may still have influenced our results. In particular, low density lipoprotein cholesterol, high density lipoprotein cholesterol, lipoprotein(a), and apolipoproteins were not measured at baseline in 1976-8 and thus were not adjusted for.


However, we adjusted for total cholesterol (that is, cholesterol in low density lipoprotein, high
density lipoprotein, remnants, and lipoprotein(a)) and for non-fasting triglycerides. In addition, we adjusted for baseline measurements of all confounders, although some confounders
may have changed during the follow-up period of up to 33 years.

Conclusion

We have shown that xanthelasmata predict increased risk of myocardial infarction, ischaemic heart disease, and total death independently of well known cardiovascular risk factors,including plasma cholesterol and triglyceride concentrations.
In contrast, arcus corneae is not an important independent risk predictor.

What is already known on this topic

Xanthelasmata and arcus corneae are associated with increased concentrations of plasma total or low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein, or both . Most previous studies have shown no associations between xanthelasmata or arcus corneae and risk of myocardial infarction and ischaemic heart disease, but the results are inconsistent, and few prospective studies exist.
Consensus on the clinical importance of xanthelasmata and arcus corneae is absent.

What this study adds

Xanthelasmata, but not arcus corneae, predicts increased risk of myocardial infarction, ischaemic heart disease, and total death independently of well known cardiovascular risk factors, including plasma cholesterol and triglyceride concentrations
People with xanthelasmata and relatively low lipid concentrations are at an increased risk of myocardial infarction, ischaemic heart disease, and early death, independent of their lipid profiles Arcus corneae is not an important independent risk predictor
BMJ 14 July 2011