Author + information
- Received August 31, 2011
- Revision received November 28, 2011
- Accepted December 5, 2011
- Published online March 1, 2012.
- Andrew M. Kahn, MD, PhD⁎,⁎ (, )
- Matthew J. Budoff, MD†,
- Lori B. Daniels, MD, MAS⁎,
- Susan Jimenez-Fernandez, MD‡,
- Amber S. Cox, BS§,
- John B. Gordon, MD∥ and
- Jane C. Burns, MD‡
- ↵⁎Reprint requests and correspondence:
Dr. Andrew M. Kahn, Division of Cardiology, Mail Code 7411, University of California San Diego Medical Center, 9444 Medical Center Drive, La Jolla, California 92037-7411
Objectives The goal of this study was to assess coronary artery calcification in patients ≥10 years or age with a history of Kawasaki disease (KD).
Background Patients with a history of KD and coronary artery aneurysms are at risk for late morbidity from coronary artery events. It is unknown whether patients with KD with acutely normal or transiently dilated coronary arteries also have increased risk of late coronary artery complications. Coronary calcium scoring using noncontrast computed tomography is a well-established tool for risk-stratifying patients with atherosclerotic coronary artery disease, but there are limited data on its role in evaluating patients with a history of KD.
Methods We performed coronary artery calcium (CAC) volume scoring using a low radiation dose computed tomography protocol on 70 patients (median age 20.0 years) with a remote history of KD (median interval from acute KD to imaging 14.8 years). Forty-four (63%) patients had no history of coronary dilation, 12 (17%) had a history of transient dilation, and 14 (20%) had coronary aneurysms.
Results All of the patients with normal coronary artery internal diameter during the acute phase of KD and 11 of 12 patients with transient dilation had CAC scores of zero. Coronary calcification was observed in 10 of the 14 patients with coronary aneurysms, with the degree of calcification ranging from mild to severe and occurring years after the patients' acute KD.
Conclusions Coronary calcification was not observed in patients with a history of KD and normal coronary arteries during the acute phase. Therefore, CAC scanning may be a useful tool to screen patients with a remote history of KD or suspected KD and unknown coronary artery status. Coronary calcification, which may be severe, occurs late in patients with coronary aneurysms. The pathophysiology and clinical implications of coronary calcification in patients with aneurysms are currently unknown and warrant further study.
Kawasaki disease (KD), the most common cause of acquired heart disease in children, is an acute vasculitis associated with the formation of coronary aneurysms in 25% of untreated cases and 5% of patients treated with intravenous immunoglobulin (1–3). Patients with a history of KD and aneurysm formation are at risk for coronary artery thrombosis, stenosis, myocardial infarction, and death (2,4–7). Patients with aneurysms are known to deposit calcium in the arterial wall in sites of antecedent inflammation, and such dramatic calcifications can be noted on chest radiographs decades after the acute disease (8). Those with a history of KD without aneurysm formation have a benign course in the short term, but whether they are at increased risk for coronary and myocardial complications later in life is currently unknown (9). As a result, there is a need for better tools to identify patients at increased risk and to help risk-stratify patients for appropriate medical treatments such as antiplatelet, anticoagulation, and lipid-lowering therapies and invasive treatments such as percutaneous coronary intervention and coronary artery bypass surgery (CABG) (5,6).
Coronary artery calcium (CAC) scoring using computed tomography (CT) has a proven role in detecting and managing atherosclerotic coronary artery disease (CAD) and is highly predictive of mortality (10–12). This examination uses a relatively low radiation dose, requires no contrast, is inexpensive, and provides a single score that can be useful in patient management (10,13). For atherosclerotic CAD, the CT CAC score risk-stratifies patients more accurately than traditional risk factors (11).
Thus far, the role of CAC scoring in the management of patients with a history of KD has not been systematically studied. In 1 study of 18 patients (mean age 12.8 years) with a history of KD investigated using electron-beam CT, elevated CAC scores were only observed in those patients with coronary aneurysms, and the patient with the highest CAC score suffered sudden cardiac death (14). In another study of 79 patients with KD and a history of abnormal coronary arteries acutely, electron-beam CT was used to assess the presence of qualitative calcification (15). We report here the results of CAC scoring using multislice CT in a diverse population of patients with a distant history of KD both with and without coronary aneurysms.
A total of 70 patients were enrolled from 2 separate cohorts. We enrolled 44 patients (age ≥10 years) recruited from those originally diagnosed, treated, and followed up by the Kawasaki Disease Research Center at the University of California, San Diego Medical Center and Rady Children's Hospital (cohort 1). In addition, we enrolled 26 patients who were self-referred for our study or responded to recruiting efforts (cohort 2), the majority of whom became aware of the study via word-of-mouth and locally held informational symposia. For cohort 2, a total of 23 of the patients had a known history of KD. In the remaining 3 patients, the diagnosis of KD was based on the presence of proximal coronary artery aneurysms diagnosed using CT or coronary angiography independently reviewed by 2 cardiologists and a history of a KD-compatible illness obtained through interview of the patient or his or her parents. This study was approved by the institutional review board of the University of California, and all patients or their parents provided written informed consent.
The coronary artery status at the time of the patient's acute KD presentation was determined from the initial evaluation using echocardiography and by repeat imaging with echocardiography, invasive coronary angiography, or computed tomography angiography (CTA) where available. For those patients with coronary artery abnormalities, subsequent coronary artery status was determined by the most recent clinically indicated CTA or invasive coronary angiography results. Data from 1 of these 2 tests were available for all of the patients with coronary aneurysms. Patients were grouped into 4 categories: 1) no history of coronary artery dilation (American Heart Association risk level I) (9); 2) transient coronary artery dilation that subsequently resolved (American Heart Association risk level 2); 3) persistent coronary artery aneurysms <8 mm in diameter; or 4) persistent giant coronary aneurysms ≥8 mm in diameter. Major adverse cardiac events (MACE) were defined as a history of CABG, myocardial infarction, or percutaneous coronary intervention.
Risk factors for CAD
All patients completed a standardized questionnaire that documented current medications and assessed risk factors for atherosclerotic CAD: physician-diagnosed hypertension, diabetes mellitus, hyperlipidemia, family history of early atherosclerotic CAD (defined as disease diagnosed at <55 years-of-age in a first-degree relative), and current smoking. Height and weight were obtained at the time of CT scanning, and body mass index (BMI [in kilograms per meters squared]) was computed.
CT scanning protocol
Patients were scanned during a single breath-hold using a 64-slice Discovery CT750 HD scanner (GE Healthcare, Milwaukee, Wisconsin) with a customized protocol designed to minimize the administered radiation dose. All but 3 of the patients were scanned using a tube energy of 100 kVp (instead of the tube energy of 120 kVp traditionally used for calcium scoring) in gated axial mode. The tube current was adjusted on the basis of the BMI to give adequate signal-to-noise ratio while minimizing the net current, using the empirically determined formula: tube current (mA) = 11 × BMI. The time of imaging during the cardiac cycle was adjusted on the basis of heart rate, imaging at 75% of the R-R interval for heart rate <75 beats/min, and at 50% of the R-R interval for heart rate >75 beats/min. The slice thickness was 2.5 mm, the gantry rotational period was 0.35 s, and the scan length was adjusted from the scout images to encompass the entire heart. The median radiation dose–length product was 42 mGy·cm, which, using a conversion factor of 0.014 mSv/mGy·cm, corresponds to a median effective radiation dose of 0.59 mSv (16). The minimum, first quartile, third quartile, and maximum doses were 0.32, 0.49, 0.68, and 1.46 mSv, respectively (of note, the maximum dose was for 1 of the 3 patients scanned using 120 kVp). The minimum, first quartile, median, third quartile, and maximum effective radiation doses divided by body mass were 0.0064, 0.0086, 0.0095, 0.011, and 0.020 mSv/kg, respectively.
CTA was performed in selected patients when clinically indicated using the scanner described earlier. Oral and/or intravenous metoprolol was administered as needed to decrease the patients' heart rate, with a goal heart rate of <60 beats/min. A timing bolus with 10 ml of iodinated contrast and subsequent sequential imaging and analysis of a single slice at the level of the left main coronary artery were used to determine the optimal imaging time. Iodinated contrast was injected with a triple-phase technique (contrast, contrast/saline mix, and saline) with the dose, mixture, and flow rate adjusted for the patients' BMI. The tube voltage and current were also adjusted for the patients' BMI. Images were obtained during a single breath-hold using prospective gating with imaging centered at 75% of the R-R interval and a slice thickness of 0.625 mm.
Images for CAC scoring were reconstructed using a 512 × 512 matrix and analyzed offline using a Ziostation workstation (Ziosoft, Inc., Redwood City, California). For each patient, the total coronary calcium volume was calculated using a minimum threshold of 147 HU, following the work of Nakazato et al. (17), to adjust for the lower tube energy, and a minimum volume of 2.5 mm3. For the 3 patients scanned using 120 kVp, the traditional 130-HU threshold was used (18). Regions of calcification of the coronary arteries were manually identified on the workstation, and the total volume of coronary calcification was calculated for each patient. Regions of coronary arteries with stents were excluded from scoring due to artifacts from the stents. CTA images were viewed, reconstructed, and analyzed using a Vitrea workstation (Vital Images, Inc., Minnetonka, Minnesota).
For each group of patients, medians and quartiles were calculated for all continuous parameters studied. Spearman rank order correlation was used to assess the correlation between continuous variables. For all tests, a 2-sided p value <0.05 was considered statistically significant.
Patients ranged in age from 10.3 to 59.8 years with a median age of 20.0 years. The median interval from the onset of KD to the time of imaging was 14.8 years. Of the 70 patients, 44 (63%) had no history of coronary dilation, 12 (17%) had a history of transient dilation, and 14 (20%) had aneurysms. Six patients (9%) had giant (≥8 mm in diameter) aneurysms (Table 1).
Diabetes mellitus, hypertension, and current smoking were each present in <10% of the patients. A history of hyperlipidemia was present in 16% of the patients, and 36% had a family history of early CAD. The majority (38 patients [54%]) had no risk factors for CAD, 23 (33%) had 1 risk factor, and 9 (13%) had ≥2 risk factors. Of the 38 patients with 1 coronary risk factor, 25 (66%) had a family history of early CAD. Five patients were receiving statin medications, and 2 patients were receiving niacin. Six of the patients were receiving systemic anticoagulation: 5 patients were on warfarin and 1 patient was on dabigatran.
CAC volume scores
Table 2 displays the CAC scores as a function of coronary artery status. No calcification was detected in any of the patients whose coronary artery internal diameter was always assessed as normal. Of the patients with transient coronary dilation, only 1 patient had calcification. For patients with aneurysms <8 mm in diameter and for those with giant aneurysms, a wide range of calcium scores was observed (see examples shown in Figs. 1B, 2, and 3)⇓⇓; scores ranged from zero to >8,000 mm3, indicative of severe calcification.
Overall, 59 (84%) of the patients studied had no coronary calcification, and 11 (16%) had calcification. The majority of the patients with calcification (8 of 11) had ≤1 cardiac risk factor: 4 had none and 4 had only 1 risk factor. Of these 11 patients with calcification, 9 had a history of MACE (6 had undergone CABG, 2 had myocardial infarctions, and 1 had undergone percutaneous coronary intervention with stent placement). Of the 14 patients with coronary aneurysms, 9 had MACE, all but 1 of whom had a positive CAC score. The 1 patient with a MACE and a CAC score of zero was a 19-year-old man with giant coronary aneurysms who suffered a myocardial infarction 6 years after KD onset while not taking anticoagulation medication. Of the 5 patients taking warfarin, all had aneurysms and 4 of them had positive CAC scores. The 1 patient taking warfarin without calcification was studied 6 years after his episode of acute KD.
The CAC scan from the 1 patient with transient coronary dilation during his acute KD and a positive CAC score is shown in Figure 1A. This 33-year-old man with no cardiac risk factors and a history of KD at 5 years of age presented with unstable angina. Results of invasive angiography demonstrated a 90% left main coronary artery stenosis, which was treated with urgent CABG.
An analysis of the CAC scores as a function of the time since the patients' episodes of acute KD revealed that all patients with positive CAC scores had their acute KD at least 10 years before their scan (Fig. 4). However, the degree of calcification did not correlate with the time since acute KD (rs = 0.05, p = 0.88).
Patients with no acute coronary abnormalities
Every patient who had normal-appearing coronary arteries in the acute KD phase had no coronary calcification, consistent with the previous findings of Dadlani et al. (14). Subclinical pathology in such patients has been assessed by measuring coronary flow reserve, which yielded mixed results, with some studies showing impaired coronary flow reserve (19,20) and others showing no difference from controls (21,22). The absence of calcification in our patients does not exclude the possibility of impaired endothelial function as well as structural damage to the arterial wall and hence some subclinical pathology. Autopsy studies have raised concerns that abnormal remodeling of the arterial wall can occur in the absence of documented changes during the acute illness (23,24). Long-term, longitudinal studies of patients with normal echocardiograms during the acute illness are needed to address this question.
Patients with transient coronary dilation
In this study, the number of patients with transient coronary artery dilation was relatively small. Only 1 of these patients had coronary calcification. However, this condition was associated with a significant clinical outcome requiring urgent CABG. Although it is conceivable that this patient's CAD was not due to his KD, this was a relatively young man with no risk factors for atherosclerotic CAD, and hence this possibility seems unlikely. Had he undergone calcium scoring, this patient could have been identified as a high-risk patient and had earlier, elective intervention. In the previous study by Dadlani et al. (14), in which the patients were younger and imaged sooner (mean age 12.8 years; mean elapsed time since acute KD 8.6 years), there were only 4 patients with transient dilation, and none had coronary calcification. Given the relatively small number of patients studied, and the presence of significant calcification in 1 patient, this is a category that merits further study and for which the utility and implications of CT CAC scoring remain unclear.
Patients with aneurysms
From our data and consistent with previous work (8,14,15), it seems clear that patients with aneurysms have a high likelihood of developing calcification of their coronary arteries. Our data suggest that it may take approximately 10 years for significant calcification to develop. By comparison, in the study by Kaichi et al. (15), for coronary arteries with initial diameters ≥6 mm, the prevalence of coronary calcification was 12% at 5 years, 44% at 10 years, and 94% at 20 years. Once calcification does develop, in our data, the CAC volumes did not correlate with the elapsed times since the initial episodes of KD.
Radiation dose from CAC scoring
Although the effects of radiation at small doses are unknown with certainty, minimizing the radiation dose is desirable and considered good medical practice. Radiation doses are of particular concern in younger patients, in whom there may be greater risk from radiation (25). We used a customized protocol specifically designed to minimize the radiation administered while still providing diagnostic data. The median radiation dose of 0.59 mSv used in this study is much lower than that previously reported for CAC scoring using multidetector CT (13). By comparison, the average annual radiation dose from natural sources in the United States is approximately 3 mSv (26). Hence, on average, this examination is equivalent to just 2.4 months of natural radiation exposure and imparts a lower dose than invasive angiography, CTA, and cardiac nuclear stress testing (26).
Mechanism of calcification
The underlying mechanisms causing coronary arteries to calcify in KD patients are currently unclear; possibilities include inflammatory, immunologic, treatment-related, or hemodynamic factors or some combination of these. Calcification may be the long-term result of damage from the initial inflammatory insult associated with coronary aneurysm formation. Alternatively, recent patient-specific modeling of hemodynamics in a patient with giant aneurysms demonstrated that the presence of aneurysms resulted in abnormal flow patterns with markedly increased flow recirculation times and reduced wall shear stress within the aneurysms (27). Correlating regions of hemodynamic abnormalities with those that develop increased calcification may help clarify the possible connection. Recently, Zhu et al. (28) found that vascular calcification is associated with up-regulation of alkaline phosphatase and the sodium-dependent phosphate transporter PiT-1, which are known osteocytic molecules. What role genetics may play and whether up-regulation of these proteins is occurring in some patients with KD is currently unknown. Vascular calcification has also been associated with warfarin use (29). In our study, only 5 patients were receiving warfarin. Although 4 of these 5 had positive CAC scores, these were also patients with aneurysms for whom ≥10 years had elapsed since their episode of acute KD. Hence, due to the small number of patients receiving warfarin and the presence of confounding factors, no clear conclusions regarding the effects of warfarin use can be drawn from our study data.
The use of CT calcium scoring with a low-radiation protocol may contribute to the management of patients with a history of KD and unknown coronary artery status. In such patients, the finding of coronary calcification suggests significant coronary pathology and should prompt further clinical evaluation, typically with CTA to evaluate for the presence of coronary aneurysms and stenoses.
For patients with aneurysms who develop severe calcification, the clinical implications are currently unclear. In the case of atherosclerotic heart disease, high calcium scores identify patients at increased risk of cardiovascular events and mortality, probably because these patients have more extensive vascular pathology (12). However, for a given coronary lesion, CT data have shown that the lack of calcification or the presence of spotty calcification are associated with increased events, possibly because these plaques have higher lipid content and hence are more prone to rupture (30–33).
The coronary lesions in KD have a different pathophysiology than coronary atherosclerosis, and their natural history into adulthood is largely unknown (34). Postmortem case report literature has documented that extensive arterial wall dystrophic calcification occurs in coronary artery aneurysms late after KD (35). A frequent cause of coronary events in patients with KD is thrombus formation within aneurysms and subsequent coronary occlusion. In addition, patients may experience stenoses at the distal portions of the aneurysms. Future longitudinal clinical study will be required to determine whether the degree of calcification in patients with a history of KD is a risk factor for events or is protective. Hence, using CT CAC scoring to assess the degree of calcification may be useful in risk-stratifying patients with KD and aneurysms. However, due to the time required for calcification to develop, our data suggest that the potential utility of such scanning would probably be restricted to patients for whom approximately ≥10 years have elapsed since having acute KD.
Study strengths and limitations
Strengths of this study include our study population, which included patients with a range of KD pathology, ages, and elapsed time since their acute KD occurred. Also, the CT protocol used a very low radiation dose while still providing diagnostic data in all patients. This study also has several limitations. The patients in cohort 2 were self-referred to this study or responded to recruiting efforts and hence may not be representative of KD patients overall. In addition, 1 of the patients had stents in his coronary arteries. Because these regions are likely to be among the most diseased segments and were necessarily excluded from calcium scoring, this fact likely resulted in an underestimation of the calcium scores for this patient. Finally, the relatively small sample size, particularly for the transiently dilated patients, limits our ability to draw conclusions or make recommendations about the use of CAC scoring in this group of patients.
We used low-dose noncontrast CT scanning to assess coronary calcification in patients with a remote history of KD. Our primary findings were that patients with no coronary artery dilation had no calcification and that those with aneurysms developed significant calcification approximately 10 years after their episode of acute KD. The pathophysiology and clinical implications of coronary calcification in this population will require further study.
This work was supported in part by a grant from the National Institutes of Health, Heart, Lung, and Blood Institute to Dr. Burns (RO1-HL69413), a grant from the American Heart Association National Affiliate (09SDG2010231) to Dr. Daniels, and a grant from the Macklin Foundation. The Ziostation workstation was provided to the University of California San Diego, without charge, via a research agreement with Ziosoft, Inc. Ms. Cox is a former employee of Vital Images, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body mass index
- coronary artery bypass surgery
- coronary artery calcium
- coronary artery disease
- computed tomography
- computed tomography angiography
- Kawasaki disease
- major adverse cardiac events
- Received August 31, 2011.
- Revision received November 28, 2011.
- Accepted December 5, 2011.
- American College of Cardiology Foundation
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