DOACs in Patients With Giant Coronary Artery Aneurysms After Kawasaki Disease.

This case series examines outcomes among patients with giant coronary artery aneurysms after Kawasaki disease treated with direct oral anticoagulants (DOACs).

Exercise Stress Echocardiography in Kawasaki Disease Patients with Coronary Aneurysms.

The most significant sequelae of Kawasaki disease (KD) are coronary artery aneurysms, which can lead to risk of future myocardial ischemia. Exercise stress echocardiography allows for non-invasive assessment of myocardial dysfunction. We reviewed our single center experience with exercise stress echocardiography in patients with previous history of KD with coronary aneurysms. We reviewed the records of 53 KD patients who underwent exercise stress echocardiography from 2000 to 2020. Abnormal stress echocardiograms were defined as those showing no increase in biventricular systolic function post-exercise or regional wall motion abnormalities. Computed tomography angiography and cardiac magnetic resonance imaging were reviewed for patients with abnormal stress echocardiograms. Clinical data were reviewed and correlated with stress echocardiogram results. Of the 53 patients, three (5.7%) had an abnormal exercise stress echocardiogram. All three patients were classified as AHA Risk Level 4 or 5 by coronary Z-score (internal dimension normalized for body surface area) and were confirmed to have coronary aneurysms, stenosis, or myocardial tissue perfusion defects on advanced cardiac imaging that could account for the results seen on stress echocardiogram. Exercise stress echocardiography detected signs of myocardial ischemia in a subset of high-risk patients with Kawasaki disease and coronary aneurysms and may be considered as a useful screening tool for this complex patient cohort.

Long-term health outcomes in young adults after Kawasaki disease.

Background: We compared the long-term health of adults with prior Kawasaki disease (KD) to controls and determined whether outcomes varied by coronary artery (CA) status. Methods: We conducted a prospective cohort study of 258 KD subjects (mean 19 ± 9 years since KD) and 148 age-similar controls who completed extensive health questionnaires. KD subjects were divided into 2 groups, Cohort 1: 109 subjects followed since KD diagnosis at our institution; Cohort 2: 149 KD subjects diagnosed elsewhere. Results: KD subjects and controls were of similar age at the time of questionnaire completion (p = 0.50). Overall, 128 subjects (including 60 in Cohort 1) reported normal CAs during and after KD. Compared to controls, KD subjects with normal CAs reported several medical conditions with increased prevalence including migraine headaches, shortness of breath, and leg pain with walking, among others. When limited to Cohort 1, KD subjects were significantly more likely to report chest pain (47% vs 16%, p < 0.001) or palpitations (23% vs 10%, p = 0.01) compared to controls. Prevalence of depression was similar (7% vs 5%, p = 0.73). Conclusions: Despite always having normal CAs in the acute and subacute phases of KD, young adults with a history of KD with normal coronaries were more likely than controls to experience cardiovascular symptoms. These differences could be influenced by anxiety or depression, but report of depression was similar between groups. Whether these health differences reflect a heightened awareness of symptoms among KD subjects, or underlying vascular pathology (i.e. vasospasm, microvascular dysfunction, other) merits further study.

Falling Through the Cracks: The Current Gap in the Health Care Transition of Patients With Kawasaki Disease: A Scientific Statement From the American Heart Association.

Background Health care transition (HCT) is a period of high vulnerability for patients with chronic childhood diseases, particularly when patients shift from a pediatric to an adult care setting. An increasing number of patients with Kawasaki disease (KD) who develop medium and large coronary artery aneurysms (classified by the American Heart Association according to maximal internal coronary artery diameter Z-scores ≥5 and ≥10, respectively) are becoming adults and thus undergoing an HCT. However, a poor transition to an adult provider represents a risk of loss to follow-up, which can result in increasing morbidity and mortality. Methods and Results This scientific statement provides a summary of available literature and expert opinion pertaining to KD and HCT of children as they reach adulthood. The statement reviews the existing life-long risks for patients with KD, explains current guidelines for long-term care of patients with KD, and offers guidance on assessment and preparation of patients with KD for HCT. The key element to a successful HCT, enabling successful transition outcomes, is having a structured intervention that incorporates the components of planning, transfer, and integration into adult care. This structured intervention can be accomplished by using the Six Core Elements approach that is recommended by the American Academy of Pediatrics, the American Academy of Family Physicians, and the American College of Physicians. Conclusions Formal HCT programs for patients with KD who develop aneurysms should be established to ensure a smooth transition with uninterrupted medical care as these youths become adults.

Biomarkers of inflammation and fibrosis in young adults with history of Kawasaki disease.

BACKGROUND: Myocardial histology from autopsies of young adults with giant coronary artery aneurysms following Kawasaki disease (KD) shows bridging fibrosis beyond the territories supplied by the aneurysmal arteries. The etiology of this fibrosis is unknown, but persistent, low-level myocardial inflammation and microcirculatory ischemia are both possible contributing factors. To investigate the possibility of subclinical myocardial inflammation or fibrosis, we measured validated biomarkers in young adults with a remote history of KD. METHODS: We measured plasma calprotectin, galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and serum procollagen type 1C-terminal propeptide (P1CP) in 91 otherwise healthy young adults with a remote history of KD and in 88 age-similar, healthy controls. KD subjects were stratified by coronary artery aneurysm (CAA) status and history of remote myocardial infarction (MI). RESULTS: After correction for multiple testing, calprotectin, Gal-3, and GDF-15 levels were significantly higher in subjects with persistent CAA (n = 26) compared with KD subjects with remodeled CAA (n = 20, p = 0.005, 0.001, 0.0036, respectively). In a multivariable regression model with CA status as the main predictor and adjusting for sex, MI history, and interval from KD onset, CA status was a significant predictor (Persistent CAA vs KD Normal CA) of calprotectin, Gal-3, GDF-15 and sST2 levels (p = 0.004, <0.001, 0.007, and 0.049, respectively). CONCLUSIONS: These results suggest that ongoing inflammation and fibrosis may be occurring in individuals with persistent CAA. Longitudinal follow-up is needed to clarify the clinical significance of these elevated biomarker levels in this patient population that requires life-long monitoring.

Lifetime cardiovascular management of patients with previous Kawasaki disease.

Kawasaki disease (KD) is an inflammatory disorder of young children, associated with vasculitis of the coronary arteries with subsequent aneurysm formation in up to one-third of untreated patients. Those who develop aneurysms are at life-long risk of coronary thrombosis or the development of stenotic lesions, which may lead to myocardial ischaemia, infarction or death. The incidence of KD is increasing worldwide, and in more economically developed countries, KD is now the most common cause of acquired heart disease in children. However, many clinicians in the UK are unaware of the disorder and its long-term cardiac complications, potentially leading to late diagnosis, delayed treatment and poorer outcomes. Increasing numbers of patients who suffered KD in childhood are transitioning to the care of adult services where there is significantly less awareness and experience of the condition than in paediatric services. The aim of this document is to provide guidance on the long-term management of patients who have vascular complications of KD and guidance on the emergency management of acute coronary complications. Guidance on the management of acute KD is published elsewhere.

Circulating Markers of Inflammation Persist in Children and Adults With Giant Aneurysms After Kawasaki Disease.

BACKGROUND: The sequelae of Kawasaki disease (KD) vary widely with the greatest risk for future cardiovascular events among those who develop giant coronary artery aneurysms (CAA). We sought to define the molecular signature associated with different outcomes in pediatric and adult KD patients. METHODS: Molecular profiling was conducted using mass spectrometry-based shotgun proteomics, transcriptomics, and glycomics methods on 8 pediatric KD patients at the acute, subacute, and convalescent time points. Shotgun proteomics was performed on 9 KD adults with giant CAA and matched healthy controls. Plasma calprotectin was measured by ELISA in 28 pediatric KD patients 1 year post-KD, 70 adult KD patients, and 86 healthy adult volunteers. RESULTS: A characteristic molecular profile was seen in pediatric patients during the acute disease, which resolved at the subacute and convalescent periods in patients with no coronary artery sequelae but persisted in 2 patients who developed giant CAA. We, therefore, investigated persistence of inflammation in KD adults with giant CAA by shotgun proteomics that revealed a signature of active inflammation, immune regulation, and cell trafficking. Correlating results obtained using shotgun proteomics in the pediatric and adult KD cohorts identified elevated calprotectin levels in the plasma of patients with CAA. Investigation of expanded pediatric and adult KD cohorts revealed elevated levels of calprotectin in pediatric patients with giant CAA 1 year post-KD and in adult KD patients who developed giant CAA in childhood. CONCLUSIONS: Complex patterns of biomarkers of inflammation and cell trafficking can persist long after the acute phase of KD in patients with giant CAA. Elevated levels of plasma calprotectin months to decades after acute KD and infiltration of cells expressing S100A8 and A9 in vascular tissues suggest ongoing, subclinical inflammation. Calprotectin may serve as a biomarker to inform the management of KD patients following the acute illness.

The State of the Absorb Bioresorbable Scaffold: Consensus From an Expert Panel.

Significant progress has been made in the percutaneous coronary intervention technique from the days of balloon angioplasty to modern-day metallic drug-eluting stents (DES). Although metallic stents solve a temporary problem of acute recoil following balloon angioplasty, they leave behind a permanent problem implicated in very late events (in addition to neoatherosclerosis). BRS were developed as a potential solution to this permanent problem, but the promise of these devices has been tempered by clinical trials showing increased risk of safety outcomes, both early and late. This is not too dissimilar to the challenges seen with first-generation DES in which refinement of deployment technique, prolongation of dual antiplatelet therapy, and technical iteration mitigated excess risk of very late stent thrombosis, making DES the treatment of choice for coronary artery disease. This white paper discusses the factors potentially implicated in the excess risks, including the scaffold consideration and deployment technique, and outlines patient and lesion selection, implantation technique, and dual antiplatelet therapy considerations to potentially mitigate this excess risk with the first-generation thick strut Absorb scaffold (Abbott Vascular, Abbott Park, Illinois). It remains to be seen whether these considerations together with technical iterations will ultimately close the gap between scaffolds and metal stents for short-term events while at the same time preserving options for future revascularization once the scaffold bioresorbs.

Resource Utilization Associated with Extracardiac Co-morbid Conditions Following Congenital Heart Surgery in Infancy.

Congenital heart disease (CHD) is often associated with chronic extracardiac co-morbid conditions (ECC). The presence of ECC has been associated with greater resource utilization during the operative period; however, the impact beyond hospital discharge has not been described. This study sought to understand the scope of chronic ECC in infants with CHD as well as to describe the impact of ECC on resource utilization after discharge from the index cardiac procedure. IRB approved this retrospective study of infants <1 year who had cardiac surgery from 2006 and 2011. Demographics, diagnoses, procedures, STAT score, and ECC were extracted from the medical record. Administrative data provided frequency of clinic and emergency room visits, admissions, cumulative hospital days, and hospital charges for 2 years after discharge from the index procedure. Data were compared using Mann-Whitney Rank Sum Test with p < 0.05 considered significant. ECC occurred in 55% (481/876) of infants. Median STAT score was higher in the group with ECC (3 vs. 2, p < 0.001). Resource utilization after discharge from the index procedure as defined by median hospital charges (78 vs. 10 K, p < 0.001 and unplanned hospital days 4 vs. 0, p < 0.001) was higher in those with ECC, and increased with the greater number of ECC, even after accounting for surgical complexity. STAT score and the presence of multiple ECC were associated with higher resource utilization following the index cardiac surgical procedure. These data may be helpful in deciding which children might benefit from a cardiac complex care program that partners families and providers to improve health and decrease healthcare costs.

Usefulness of Calcium Scoring as a Screening Examination in Patients With a History of Kawasaki Disease.

Subsets of patients with a remote history of Kawasaki disease (KD) have coronary artery aneurysms with associated risks of late morbidity. In a pilot study, we previously showed that computed tomography (CT) coronary artery calcium (CAC) scoring detects late CAC in patients with aneurysms and a remote history of KD. We performed CT calcium volume scoring in 166 subjects (median age 19.5 years) with a remote history of KD (median interval from KD to CT 15.1 years). Coronary arteries were classified as normal (n = 100), transiently dilated (n = 23), persistently dilated (n = 10), remodeled aneurysm (n = 9), or aneurysm (n = 24) based on echocardiography. All subjects with coronary arteries classified as normal, persistently dilated, or remodeled aneurysm had zero CAC. Of the 24 subjects with coronary aneurysms, all but 5 had CAC (median volume 542 mm3; range 17 to 8,218 mm3). For subjects imaged ≥9 years after their acute KD (n = 144), the presence of CAC had a sensitivity of 95% and a specificity of 100% for detecting coronary artery abnormalities (defined as coronary artery aneurysm and/or stenosis). In conclusion, coronary calcification was not observed in subjects with a history of KD who had normal coronary arteries by echocardiography during the acute phase. Coronary calcification, which may be severe, occurs late in patients with coronary aneurysms. 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.

Management of sequelae of Kawasaki disease in adults.

Background: A growing population of young adults is presenting to cardiologists with late manifestations of Kawasaki disease (KD) that include cardiomyopathy, ischemia, and infarction. The management of these conditions differs in important ways from atherosclerotic heart disease, and yet there is little awareness in the adult cardiology community regarding the special challenges posed by the cardiovascular sequelae of KD. Methods: Observations were made on a population of 140 adult KD patients enrolled in the San Diego Adult KD Collaborative Study. Results: Coronary artery aneurysms resulting from KD in childhood are associated with a high risk of thrombosis and stenosis at the inlet or outlet of the aneurysm. These aneurysms are often highly calcified and may contain a large thrombus burden that may obscure the true size of the aneurysm. Pitfalls in the management of these patients stem largely from failure to recognize the nature of the lesions, which leads to attempts to dilate highly calcified stenotic segments and undersizing of stents. Intravascular ultrasound is helpful in appreciating the true dimensions of the aneurysm, which may be filled with thrombus. Thrombolysis and use of anti-platelet agents followed by systemic anti-coagulation are appropriate management strategies for patients presenting with acute infarction. Bypass grafting with the internal thoracic arteries can be a successful strategy, but care must be taken to avoid competitive flow through the native vessel leading to graft failure. In contrast to the individuals who developed coronary artery aneurysms, young adults who had documented normal echocardiograms associated with their acute KD in childhood and who have no evidence of calcium deposition in the arterial wall as assessed by computed tomography (CT) calcium score appear to have no increased cardiovascular risk in the medium term. Long-term outcomes for adults post-KD in childhood are still being defined. Conclusions: KD poses special management challenges for the adult cardiologist who must recognize the unique features of the cardiovascular lesions in this growing population of patients.

The Intersection of Medical Child Abuse and Medical Complexity.

Children with medical complexity and victims of medical child abuse may have similar clinical presentations. Atypical or unexplained signs and symptoms due to rare diseases may lead providers to suspect medical child abuse when not present. Conversely, medical child abuse may be the cause of or coexist with medical complexity. Careful consideration of whether or not medical child abuse is present is essential when assessing a child with medical complexity since either diagnosis has significant consequences for children and families.

The Spectrum of Cardiovascular Lesions Requiring Intervention in Adults After Kawasaki Disease.

OBJECTIVES: The aim of this study was to characterize the range of management issues raised by adults with cardiovascular sequelae from Kawasaki disease (KD) in childhood. BACKGROUND: Aneurysms resulting from vascular inflammation associated with KD in childhood may remain clinically silent until adulthood. Adults with large aneurysms, unstable angina, or myocardial infarction following KD in childhood present unique challenges to interventional cardiologists and cardiothoracic surgeons. METHODS: In an observational study of adults with histories of KD in childhood, data were collected regarding the medical histories and outcomes of 154 adult KD patients, of whom 21 underwent either percutaneous interventions or surgery. RESULTS: Of the 21 subjects with interventions, 11 had been diagnosed with KD in childhood, and 10 had histories of KD-compatible illnesses. Seventeen subjects were asymptomatic until experiencing acute cardiovascular symptoms: acute myocardial infarction (n = 12), angina (n = 2), end-stage congestive heart failure requiring cardiac transplantation (n = 1), and claudication (n = 2). CONCLUSIONS: Cardiovascular complications in these subjects illustrate the following points: 1) even small to moderate-sized aneurysms that "normalize" on echocardiography in childhood can lead to stenosis and thrombosis decades after the acute illness; 2) coronary interventions without intravascular ultrasound may result in clinically significant underestimation of vessel luminal diameter; 3) failure to assess the extent of calcification may lead to suboptimal procedural outcomes; and 4) patients with symptomatic peripheral aneurysms may benefit from endarterectomy or resection. Interventional cardiologists should be aware of the potential challenges in treating this growing population of adults.

Impact of caring for children with medical complexity and high resource use on family quality of life.

PURPOSE: This study examined the impact of caring for children with medical complexity (CMC) and high resource use on family quality of life (QoL). METHODS: Families of CMC enrolled in a complex care program completed the PedsQL Family Impact module (PedsQL FIM) and Healthcare Satisfaction module (PedsQL HCS) at enrollment then 1 and 2 years after enrollment. Tertiary center resource utilization and staff care coordination time were collected for the two years. RESULTS: PedsQL FIM scores were low at enrollment and did not improve over time. Social Functioning, Worry, and Daily Activities were the lowest domains. PedsQL HCS scores were higher at enrollment, but also failed to improve over the two years. Changes in resource use were not associated with changes in PedsQL FIM or HCS scores. Staff care coordination time was highest for patients with ≥ 10 hospital days per year. CONCLUSION: CMC families' low QoL did not appear to be related to healthcare satisfaction or a shift from inpatient to outpatient resource use. Less staff support for families of CMC who spent more time at home may have contributed to their continued low QoL. Further study is required to identify causes of and strategies for improving the low QoL of families of CMC.

Galectin-3 is a marker of myocardial and vascular fibrosis in Kawasaki disease patients with giant aneurysms.

BACKGROUNDS: Galectin-3 (Gal-3) is a multifunctional matricellular protein associated with heart failure and cardiovascular events. Gal-3 is required for transforming growth factor-ß pathway-mediated myofibroblast activation that is a key process in coronary artery aneurysm formation in Kawasaki Disease (KD). Autopsies from young adults late after KD onset (AKD) have demonstrated bridging fibrosis throughout the myocardium and arteries. In this study, we postulated that Gal-3 may participate in the pathogenesis of myocardial and vascular fibrosis and the remodeling of coronary artery aneurysms following acute KD. METHODS AND RESULTS: We measured plasma Gal-3 levels in 63 pediatric KD (PKD) and 81 AKD subjects. AKD subjects with giant aneurysms had significantly higher Gal-3 levels compared to the other adult groups (all p<0.05). All PKD groups had significantly higher Gal-3 levels than pediatric healthy controls (HC) (all p<0.05). Histological and immunohistochemical staining was performed on tissues from 10 KD autopsies and one explanted heart. Gal-3 positive staining was detected associated with acute inflammation and in spindle-shaped cells in the myocardium and arterial wall in KD subjects with giant aneurysms. CONCLUSIONS: AKD subjects with giant aneurysms and PKD subjects had significantly higher plasma Gal-3 levels than HC and Gal-3 expression was increased in the myocardium of KD subjects who died with either acute inflammation or marked myocardial fibrosis. Gal-3 may be a clinically useful biomarker that identifies a subset of KD patients at highest risk of myocardial and vascular fibrosis, and may be an attractive therapeutic target to prevent myocardial dysfunction in this subset.

Missed Kawasaki disease in childhood presenting as myocardial infarction in adults.

Kawasaki disease (KD) is an acute, self-limited vasculitis that occurs in young children and was first described by Japanese pediatrician Tomisaku Kawasaki in 1967. Although originally thought to be a rare condition, KD has become the most common cause of acquired heart disease in the pediatric population in developed countries. The majority of patients with KD appear to have a benign prognosis, but a subset of patients with coronary artery aneurysms are at risk for ischemic events and require lifelong treatment. In the 4 decades since the initial recognition of KD, the number of patients reaching adulthood has continued to grow. Adult cardiologists will be increasingly involved in the management of these patients. Currently, there are no established guidelines for the evaluation and treatment of adult patients who have had KD. We report 4 most probable cases of KD missed in childhood and presented as acute coronary syndrome in adulthood.

Role of TGF-ß Signaling in Remodeling of Noncoronary Artery Aneurysms in Kawasaki Disease.

Coronary artery aneurysms (CAA) remain an important complication of Kawasaki disease (KD), the most common form of pediatric acquired heart disease in developed countries. Potentially life-threatening CAA develop in 25% of untreated children and 5% of children treated with high-dose intravenous immunoglobulin during the acute phase of the self-limited vasculitis. Noncoronary artery aneurysms (NCAA) in extraparenchymal, muscular arteries occur in a minority of patients with KD who also have CAA, yet little is understood about their formation and remodeling. We postulated that activation of the transforming growth factor-ß (TGF-ß) pathway in KD may influence formation and remodeling of aneurysms in iliac, femoral, and axillary arteries, the most common sites for NCAA. We studied a resected axillary artery from one adult and endarterectomy tissue from the femoral artery from a second adult, both with a history of CAA and NCAA following KD in infancy. Histology of the axillary artery aneurysm revealed destruction of the internal elastic lamina and recanalization of organized thrombus, while the endarterectomy specimen showed dense calcification and luminal myofibroblastic proliferation. Immunohistochemistry for molecules in the TGF-ß signaling pathway revealed increased expression of TGF-ß2, TGF-ß receptor 2, and phosphorylated SMAD3. These findings suggest ongoing tissue remodeling of the aneurysms decades after the acute injury and demonstrate the importance of the TGF-ß signaling pathway in this process.

Acute myocardial ischemia in adults secondary to missed Kawasaki disease in childhood.

Coronary artery aneurysms that occur in 25% of untreated Kawasaki disease (KD) patients may remain clinically silent for decades and then thrombose resulting in myocardial infarction. Although KD is now the most common cause of acquired heart disease in children in Asia, the United States, and Western Europe, the incidence of KD in Egypt is unknown. We tested the hypothesis that young adults in Egypt presenting with acute myocardial ischemia may have coronary artery lesions because of KD in childhood. We reviewed a total of 580 angiograms of patients ≤40 years presenting with symptoms of myocardial ischemia. Coronary artery aneurysms were noted in 46 patients (7.9%), of whom 9 presented with myocardial infarction. The likelihood of antecedent KD as the cause of the aneurysms was classified as definite (n = 10), probable (n = 29), or equivocal (n = 7). Compared with the definite and probable groups, the equivocal group had more traditional cardiovascular risk factors, smaller sized aneurysms, and fewer coronary arteries affected. In conclusion, in a major metropolitan center in Egypt, 6.7% of adults aged ≤40 years who underwent angiography for evaluation of possible myocardial ischemia had lesions consistent with antecedent KD. Because of the unique therapeutic challenges associated with these lesions, adult cardiologists should be aware that coronary artery aneurysms in young adults may be because of missed KD in childhood.