Moyamoya disease (MMD) is known as a progressive steno-occlusive intracranial angiopathy with small, fragile, and multiple collateral formation (1). The prevalence of MMD was found to be 16.1 per 100,000 in the Republic of Korea, when calculated with the 2011 population (2). The MMD is usually known to involve intracranial arteries, but systemic involvement of endothelial hyperplasia was raised in an autopsy study (3). Also, the renal artery is often involved with this disease in around 8% of the cases (4). It has been reported that the systemic arterial involvement in MMD can be a manifestation of certain genetic mutation such as ACTA 2 (5). Up to date, coronary artery disease in MMD has been described sporadically in several case reports, and the association between MMD and coronary heart disease (CHD) has been constantly suggested in the literature (6, 7, 8, 9, 10, 11, 12, 13, 14). However, to the best of our knowledge, there have been no reports determining the prevalence of symptomatic CHD in MMD. In this study, we retrospectively reviewed the adult patients in MMD registry to determine the prevalence of CHD. Also, we explored the potential risk factors and analyzed the characteristics of CHD in MMD.

The baseline characteristics of the patients are described in Table 1. Twenty one (4.6%) out of 456 patients were diagnosed as symptomatic CHD. The detailed information on these patients with CHD are described in Table 2. The median follow-up period was 32 months (range, 1-192). During the follow-up period, one patient was admitted to emergency room and dead upon arrival. The sudden death could have been caused by coronary heart disease, but there was no definite evidence associated with it as a cause of death, because medical examination could not be performed. Thus, we excluded the patient from CHD group. The median age at CHD diagnosis was 44 yr (range, 27-59). Three (Patient No. 7, 13, and 14) of them were unilateral disease and 4 (Patient No. 2, 3, 15, and 16) were hemorrhagic subtype of MMD.

The treatment for CHD were as follows: 11 medical treatments (5 variant angina with mild degree of stenosis, 6 stable angina), 4 coronary artery bypass graft (CABG), and 6 percutaneous coronary intervention (PCI). One patient (Patient No. 7) who underwent CABG surgery had a postoperative ischemic stroke.

The patients with CHD were older in age (median, 46; range, 20-63) when diagnosed with MMD than the patients who were diagnosed as MMD without CHD (median age, 39; range, 20-76; P=0.003, Mann-Whitney U-test). The patients with MMD and CHD had higher percentage of DM than the MMD patients without the CHD (23.8% vs. 8.2%, P=0.031 Fisher's exact test). Multivariate analyses using multiple logistic regression test showed that only the age factor was associated in those with both CHD and MMD (P=0.021, OR, 1.053; 95% CI, 1.008-1.110). Other variables, such as gender, hyperlipidemia, hypertension, smoking, and subtype of MMD (hemorrhagic vs. ischemic vs. atypical vs. asymptomatic) were not statistically different between those with and without CHD (Table 3).

Coronary computed tomography angiography (CTA) was available for 7 patients, and 4 patients showed no calcification of affected coronary artery (Fig. 1), and one patient showed aneurysmal dilatation.

Several of the previous reported articles demonstrated CHD in MMD, and most of them were reported from East Asian countries (7, 8, 9, 10, 11, 12, 13, 14, 16). Ikeda demonstrated that MMD is involved with the extra-cranial vessels as well as the intracranial vessels, and there are systemic etiologic factors, which cause intimal thickening in the systemic vessels (3). Histopathologic studies of the involved internal carotid arteries in MMD showed fibrocellular thickening of the intima and proliferated smooth muscle cells (SMC) as the cause of the arterial occlusion (17, 18). Also, the SMC proliferation is part of the mechanism of atherosclerosis in CHD, which is similar to the histopathology of MMD (19, 20). Several mutant genes which can cause stenosis in both MMD and CHD have already been reported (5, 17).

Both MMD and CHD can cause life-threatening events. If these two diseases had significant association, screening test should be performed to reduce the morbidity and mortality. In our adult MMD registry, 4.6% showed CHD. However, this percentage could be underestimated because only the symptomatic patients who underwent diagnostic study at our hospital were retrospectively included. The prevalence of CHD in the Asian population is known to be less than 1% person per year in the population of 65 or less years of age (21), which could be significant.

In this study, all of the CHD were developed at relatively young age (<65 yr), and Framingham scores were low at the initial diagnosis of MMD. Also, half of the patients showed no calcification on CTA, which reflects the atherosclerotic burden of the coronary artery. These findings support the idea that MMD is a causative factor of CHD rather than pure atherosclerosis (16, 22).

Previous case reports about CHD in MMD described the minimal atherosclerotic burden on the affected coronary artery (10, 16), and half of our data supported this except the coronary artery lesions were heterogeneous in this study. The prevalence was not high enough to designate MMD as the main culprit. Also, in this study the classic risk factors for atherosclerosis, such as old age and diabetes, were associated with CHD in MMD. Therefore, we hypothesized that the underlying endothelial hyperplasia in the coronary artery is not so significant in the most cases of MMD, but smaller atherosclerotic burden seemed to be causing the symptomatic CHD in MMD patients at younger age than normal population. In our study, 5 (23.8%) of 21 CHD patients were diagnosed as variant angina, and this proportion was high compared with general CHD patients. In 1998, Ikeda et al., reported variant angina associated with MMD, and 2 (22.2%) out of 9 MMD patient were diagnosed as variant angina (23). There seems to be an association between MMD and variant angina. However, there has been no evidence that supports this idea, considering the mechanism of variant angina and MMD.

Several limitations must be noted in this study. First, this was an uncontrolled, retrospective study. Therefore, the data cannot provide the exact prevalence of CHD in MMD. Also, not all of the patients underwent coronary CTA, which could have provided more information about atherosclerotic components, such as calcium score or plaque content. The MMD is a rare disease and there is no adequate evidence regarding the association between CHD and MMD, which makes it difficult to perform a prospective, controlled study. This study also reflects mainly the patients who were treated in our hospital. Since we have considered those with CHD treated in other hospitals, there are some loss of data from outside medical records. Therefore, the prevalence suggested in this study might be underestimated.

In conclusion, MMD does not seem to be the main culprit of CHD, but it can lead to CHD with small atherosclerosis probably due to the underlying endothelial proliferation. The screening test for CHD in the MMD patients with older age is in need, and DM might have a role for this matter. The future study with a larger sample size is warranted to reveal the general characteristics of CHD in MMD and to determine the usefulness of coronary screening test in MMD.