We found a positive association between CD and MI, AP, heart failure, brain haemorrhage and ischaemic stroke. This risk increase was seen in the first 20–25 years after diagnosis of CD, but not after that. Furthermore, the risk of vascular disease did not differ between individuals with CD and individuals hospitalised for non‐CD reasons.
In contrast with previous studies,9,10,11
we used a matched prospective analysis, internally stratified for a number of factors, including age and sex. This means that our findings are independent of sex, age and calendar year. Female sex is a risk factor in CD,17
whereas male sex is linked to an increased risk of cardiovascular disease.18
Nevertheless, cardiovascular disease is the prime cause of death among women in the Western world.19
We found an increased risk for vascular disease also after taking DM into account. DM is an important risk factor for cardiovascular death, especially in women.20
This is to our knowledge the first study on vascular disease distinguishing between CD diagnosed in childhood and CD diagnosed in adulthood, although it failed to show any association between childhood CD and later vascular disease other than heart failure.
As opposed to earlier research,9,10,11
we excluded individuals with vascular disease before diagnosis of CD or within 1 year after diagnosis of CD. This is important as there is otherwise a risk that ascertainment bias in individuals with CD will contribute to all kinds of morbidity. Still, there remains a risk of ascertainment bias in this study, as cases were identified through hospital discharge diagnoses. In recent years, some patients with stable angina have undergone coronary angiogram as outpatients. However, a low ascertainment of these patients would affect our risk estimates only if the prevalence of coronary angiogram at diagnosis of heart failure differentiates between individuals with and without CD. Currently in Sweden, the perceived need to undergo angiogram is not influenced by the presence of CD. Confirmation of the vascular diagnoses through CT, ultrasound, angiogram and EEG would have been desirable, but is not possible since the Swedish IPR does not contain data on most investigative procedures. Our end points usually entail hospital admission; this is especially so for MI and stroke.
The IPR does not contain data on smoking, body weight or body mass index. Smoking is of major importance to the risk of cardiovascular death.21
Given that smoking and body mass index are negatively associated with CD,11,22,23
inclusion of these variables in our statistical models would probably have increased the risk estimates for vascular disease. Instead, we were able to adjust for SEI (which is indeed strongly linked to smoking habits, other lifestyle factors in Sweden24
and in this study also to CD) in a subset of individuals, and this only affected our risk estimates marginally.
In 1999, Ivarsson et al25
reported a prevalence of diagnosed CD in adults slightly above 1/1000. Since the population in Sweden is about nine million (although a larger number of individuals have been at risk of CD between 1964 and 2003), we assume that a large proportion of Swedish individuals with diagnosed CD have been included in this study, although not all individuals with CD are hospitalised. False‐negative diagnosis in subjects with actual CD is probably uncommon compared with the number of reference individuals without CD, and should not affect the risk estimates.
Individuals identified through a hospital discharge register may suffer from more severe CD than the average individual with CD. However, many individuals were probably hospitalised when undergoing small‐bowel biopsy. This is especially so for small children, but also for adults in the first half of the study period. However, in post‐hoc analyses where reference individuals were restricted to those being hospitalised within 1 year before or after study entry, CD was not associated with an increased risk of later vascular disease. Instead, there was a negative association with CD of later heart failure. Hence, we cannot rule out that the association seen between CD and later vascular disease in the main analyses of this study is due to ascertainment bias and our choice of reference group. Still, it must be remembered that hospitalised‐reference individuals are sicker than the general population. The most common diagnosis at hospital admission in this subset of reference individuals with vascular disease was DM—another autoimmune disease. The identification of individuals with and without CD in this study may explain why our study results differ from those in the West et al
's study. Other explanations include different smoking patterns and blood pressure levels in Sweden and England,26
and the larger number of study participants in our study.
Swedish doctors generally perform small intestinal biopsy before confirming the diagnosis of CD.27
This could explain the high specificity for CD found in the IPR; in a study on CD and lymphoma, >85% of patients with an IPR diagnosis of CD and lymphoma had a correct diagnosis of CD.28
Although every study carries a risk of misclassification of end points, this should not be a major drawback of this study. Misclassification only affects risk ratios marginally, provided it is not differential with regard to the exposure variable—in this case CD. We find such misclassification unlikely. Besides, we calculated the risk of vascular disease listed as main diagnosis in order to increase the specificity of our end points. This resulted in similar risk estimates. MI, AP and heart failure were studied in detail through patient charts in a study of some 900 Swedish individuals with ICD‐8 diagnoses.29
For these diagnoses, the specificity was 87–100% (36/36 patients with a main diagnosis of MI actually had MI; 17/18 had AP; and 15/17 had heart failure).29
Suggested mechanism of action
The increased risk of vascular disease seen among patients with CD in this study could be due to ascertainment bias, since we found no positive association between CD and later vascular disease when reference individuals were restricted to inpatients. The relationship between CD and vascular disease may be complicated since CD is linked with protective factors for vascular disease such as lower serum cholesterol levels11
and indications of lower blood pressure,10
but also with risks for vascular disease such as lower folate levels30
and higher homocysteine levels.4
Homocysteine levels in treated CD are only marginally increased,4
but it remains a biologically plausible possibility that low‐grade inflammation31,32
may result in a modest increase in the risk of vascular disease, if our results are not fully explained by ascertainment bias. In rheumatoid arthritis, another disease characterised by inflammation, the risk of death from coronary heart disease is increased by about 70%.12
Although most individuals with CD but on a gluten‐free diet will experience clinical remission, endoscopic abnormalities and histologic inflammation may persist for many years in up to three of four adults reporting diet compliance.3