“Yellow markings on the eyelids are a sign of increased risk of heart attack and other illnesses,” reported BBC News. These markings, called xanthelasmata, are mostly made up of cholesterol and can be treated cosmetically, but are also a warning sign of raised cholesterol.
This study examined the association between these deposits and heart disease, by recruiting 12,745 Danish people in the 1970s, 4.4% of whom had these eye signs. Thirty years later those with xanthelasmata were 48% more likely to have had a heart attack, 39% more likely to have heart disease and 14% more likely to have died.
This was a large, well-conducted study carried out over a long period. The findings will come as no surprise to the medical profession, as xanthelasmata are known to be cholesterol deposits. They suggest raised cholesterol levels, which is a well-known risk factor for cardiovascular disease. What these findings add is an idea of the strength of their association with cardiovascular disease outcomes.
The research highlights that people with these marks should have their cardiovascular risk assessed, taking into account other risk factors, such as age, BMI, smoking, diabetes, family history of heart attack or stroke and raised blood pressure. Together, this knowledge will allow doctors to assess a person’s risk of cardiovascular disease, and allow them to make lifestyle changes to help reduce their risk.
Where did the story come from?
The study was carried out by researchers from the Departments of Clinical Biochemistry and Cardiology from three hospitals in Denmark. Funding was provided by the Research Fund at Rigshospitalet, the Lundbeck Foundation, the Danish Medical Research Council and the Danish Heart Foundation.
The study was published in the peer-reviewed British Medical Journal .
The BBC provides good coverage of this research.
What kind of research was this?
This research followed a large population sample over many years to see whether the presence of two signs seen in or around the eye, called xanthelasmata and arcus corneae, were associated with the development of cardiovascular disease and death. Xanthelasmata are clearly defined yellowish flat plaques found on the upper or lower eyelids, often near to the inner corner of the eye. They are mainly made up of cholesterol. An arcus corneae is a greyish white ring or arc that can appear around the iris (the coloured part of the eye) and is also made up of cholesterol deposits.
This was a prospective cohort study, which is the most appropriate way of looking at whether a particular factor is associated with a disease outcome. This study benefits from having a large population sample (which means that a reasonable number had the two risk factors of interest) and a long follow-up time during which people could experience the outcomes of interest. The researchers say that most previous studies have not found a link between these signs and risk of heart attack or heart disease, but that few of the studies were prospective like this one.
What did the research involve?
The participants were all part of the Copenhagen City Heart Study, which was a prospective cohort study of the Danish general population starting in 1976-8 and carrying out follow-up examinations in 1981-3, 1991-4 and 2001-3. Participants (aged 20-93) were randomly drawn from the general population. This study analysed data from the 12,745 people (66% of those invited to participate) for whom complete information (including assessment for presence of xanthelasmata and arcus corneae) was available at the beginning of the study.
All participants in this sample were followed up to May 2009 using their Central Person Register number. The researchers identified all cardiovascular disease outcomes of coronary heart disease (including angina, fatal and non-fatal heart attack and revascularisation procedures, which are used to treat narrowed or obstructed arteries) and ischaemic stroke (caused by a blood clot). They did this using the Danish Patient Registry, where all diagnoses and hospital admissions were recorded using valid diagnostic criteria. This information was supported by examination of medical records from hospitals and GPs, and information from the national Danish Causes of Death Registry. They also had information available from medical records and follow-up examinations on various other cardiovascular risk factors, including BMI and lifestyle habits of smoking and alcohol.
The researchers then looked at whether people with xanthelasmata and arcus corneae were more likely to have cardiovascular disease outcomes than those without these signs. They took into account other cardiovascular risk factors, including gender, total cholesterol, BMI, high blood pressure, diabetes, physical inactivity, smoking, use of hormone replacement therapy and family history of heart disease, among others.
What were the basic results?
At the beginning of the study, between 1976 and 1978, 4.4% of participants (563 people) had xanthelasmata and 24.8% (3,159 people) had arcus corneae. Over the 33 years of follow-up, 3,699 had developed coronary heart disease, 1,872 had experienced a heart attack, 1,815 had experienced an ischaemic stroke or mini-stroke (1,498 of whom had a full stroke), and 8,507 had died.
After taking into account multiple known cardiovascular risk factors (including blood cholesterol and triglyceride levels, age, blood pressure, diabetes, family history and lifestyle factors), the presence of xanthelasmata was found to be associated with:
- a 48% increased risk of heart attack (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.23 to 1.79)
- a 39% increased risk of coronary artery disease (HR 1.39, 95% CI 1.20 to 1.60)
- a 14% increased risk of death (HR 1.14, 95% CI 1.04 to 1.26)
The researchers present the risk of these outcomes over a 10-year period for men and women of different ages with and without xanthelasmata. For men aged under 40, the 10-year risk of the different outcomes were:
- heart attack - 4.1% in those with xanthelasmata and 2.7% in those without
- heart disease - 7.5% in those with xanthelasmata and 5.4% in those without
- death - 8.6% in those with xanthelasmata and 2.7% in those without
In general, women had lower risks than men, and as people got older their risks increased.
There was no association of xanthelasmata with stroke. There was also no significant association between the presence of arcus corneae and any of the cardiovascular outcomes assessed.
How did the researchers interpret the results?
The researchers conclude that xanthelasmata predict risk of coronary artery disease, heart attack and death in the general population, independently of well known cardiovascular risk factors, including blood cholesterol and triglyceride concentrations.
They also conclude that arcus corneae is not an important independent predictor of risk.
This was a well-conducted cohort study that has examined the association between the cholesterol deposits of xanthelasmata and arcus corneae, and the later development of cardiovascular disease. It benefits from having a large sample that is representative of the Danish general population and 100% participant follow-up over 30 years. It has also been carried out prospectively, allowing thorough medical assessment of participants at the start of the study and the identification of cardiovascular disease outcomes during a long period of follow-up using national registries that are likely to be accurate.
There are some limitations to these findings. As the researchers highlight, the results are representative of a white European population, and so cannot be generalised to other ethnicities. They also note that although they took into account various cardiovascular risk factors that could influence the results in their analysis, these adjustments may not have completely removed their influence. They were only able to adjust their analyses for total cholesterol levels, as levels of the “good” and “bad” forms of cholesterol were not measured. The relative levels of these two forms of cholesterol are thought to be better indicators of cardiovascular risk than total cholesterol levels.
Xanthelasmata and arcus corneae are already recognised to be cholesterol deposits that could suggest raised cholesterol levels in the body. What this study adds is some quantification of how much of an association there is between these factors and a person’s risk of developing cardiovascular disease. One unexpected finding is that xanthelasmata were found to be associated with coronary heart disease and death independently of levels of cholesterol in the body. It may have been expected that as xanthelasmata are cholesterol deposits, any association between their presence and cardiovascular disease would have been due to raised fat levels in the body. However, in this study people with xanthelasmata were found to be at higher risk of heart attack even if total cholesterol levels in their blood were low.
Another interesting finding is that while xanthelasmata were independently associated with cardiovascular outcomes, arcus corneae were not. The researchers consider that the presence of arcus corneae is still associated with adverse cardiovascular risk. However, as expected, this reflected an unfavourable blood lipid profile and these raised blood lipids increased cardiovascular disease risk. The researchers have one theory that could explain the independent association between xanthelasmata and cardiovascular outcomes, which is that xanthelasmata may reflect a raised level of cholesterol deposition in body tissues but not in the blood. Further research may be able to identify why there is a difference between the risk associations with xanthelasmata and arcus corneae.
The overall message of the research is that it highlights that people with xanthelasmata should have their full cardiovascular risk profile assessed (including age, BMI, smoking, diabetes, blood pressure and family history of cardiovascular disease). With this knowledge, people at risk can be managed appropriately and potentially modifiable risk factors for heart disease, such as smoking, diet and physical activity, can be addressed.