Myocardial T-Lymphocytes as a Prognostic Risk-Stratifying Marker of Dilated Cardiomyopathy　- Results of the Multicenter Registry to Investigate Inflammatory Cell Infiltration in Dilated Cardiomyopathy in Tissues of Endomyocardial Biopsy (INDICATE Study).

BACKGROUND: Dilated cardiomyopathy (DCM) associated with inflammation is diagnosed by endomyocardial biopsy; patients with this have a poorer prognosis than patients without inflammation. To date, standard diagnostic criteria have not been established.Methods and Results: This study analyzed clinical records and endomyocardial biopsy samples of 261 patients with DCM (201 males, median left ventricular ejection fraction; 28%) from 8 institutions in a multicenter retrospective study. Based on the European Society of Cardiology criteria and CD3 (T-lymphocytes) and CD68 (macrophages) immunohistochemistry, 48% of patients were categorized as having inflammatory DCM. For risk-stratification, we divided patients into 3 groups using Akaike Information Criterion/log-rank tests, which can determine multiple cut-off points: CD3+-Low, <13/mm2(n=178, 68%); CD3+-Moderate, 13-24/mm2(n=58, 22%); and CD3+-High, ≥24/mm2(n=25, 10%). The survival curves for cardiac death or left ventricular assist device implantation differed significantly among the 3 groups (10-year survival rates: CD3+-Low: 83.4%; CD3+-Moderate: 68.4%; CD3+-High: 21.1%; Log-rank P<0.001). Multivariate Cox analysis revealed CD3+count as a potent independent predictive factor for survival (fully adjusted hazard ratio: CD3+-High: 5.70, P<0.001; CD3+-Moderate: 2.64, P<0.01). CD3+-High was also associated with poor left ventricular functional and morphological recovery at short-term follow up. CONCLUSIONS: Myocardial CD3+T-lymphocyte infiltration has a significant prognostic impact in DCM and a 3-tiered risk-stratification model could be helpful to refine patient categorization.

Case Report: Acute Eosinophilic Myocarditis With a Low-Flow Heart Failure With Preserved Ejection Fraction Phenotype.

Eosinophilic myocarditis is a rare subtype of myocarditis characterized by myocardial eosinophilic infiltration, and it is potentially fatal if left untreated. Although endomyocardial biopsy (EMB) is a cornerstone for the histological diagnosis of acute eosinophilic myocarditis (AEM), as it is an invasive procedure and has a low diagnostic accuracy, the diagnosis of AEM with hemodynamic instability remains challenging. We describe a case of AEM presenting as low-flow heart failure with preserved ejection fraction (HFpEF), with rapid progression to cardiogenic shock. The constellation of peripheral eosinophilia, increased left ventricular wall thickness, and HFpEF raised the suspicion of AEM. Contrast-enhanced computed tomography (CT) scan revealed heterogeneous hypoenhancement localized in the basal-to-mid septal and mid anterolateral walls of the left ventricle, strongly suggestive of acute inflammation. Based upon these findings, we performed CT-guided EMB, which lead to a definitive diagnosis. Subsequent high-dose corticosteroids allowed a rapid and dramatic recovery and normalization of cardiac structure and function. This case highlights the clinical importance of assessing AEM as a rare cause of HFpEF and the usefulness of CT-guided EMB in patients with hemodynamic instability.

Serum tenascin-C predicts resistance to steroid combination therapy in high-risk Kawasaki disease: a multicenter prospective cohort study.

BACKGROUND: Tenascin-C (TN-C) is an extracellular matrix glycoprotein related to tissue inflammation. Our previous retrospective study conducted in 2016 revealed that the serum tenascin-C level was higher in patients with Kawasaki disease (KD) who were resistant to intravenous immunoglobulin (IVIG) and developed coronary artery lesions (CALs). The present study is a prospective cohort study to assess if the serum level of tenascin-C could be used as a novel biomarker to predict the risk of resistance to initial treatment for high-risk patients. METHODS: A total of 380 KD patients were registered and provided serum samples for tenascin-C measurement before commencing their initial treatment. Patients who did not meet the inclusion criteria were excluded from analysis; of the 181 remaining subjects, there were 144 low-risk patients (Kobayashi score: ≤4 points) and 37 high-risk patients (Kobayashi score: ≥5 points). The initial treatments for low-risk patients and high-risk patients were conventional therapy (IVIG with aspirin) and prednisolone combination therapy, respectively. The patient clinical and laboratory data, including the serum tenascin-C level, were compared between initial treatment responders and non-responders. RESULTS: In the low-risk patients, there was no significant difference in the median levels of serum tenascin-C between the initial therapy responders and non-responders. However, in the high-risk patients, the median serum tenascin-C level in initial therapy non-responders was significantly higher than that in initial therapy responders (175.8 ng/ml vs 117.6 ng/ml). CONCLUSIONS: Serum tenascin-C could be a biomarker for predicting the risk of high-risk patients being non-responsive to steroid combination therapy. TRIAL REGISTRATION: This study was a prospective cohort study. It was approved by the ethics committee of each institute and performed in accordance with the Declaration of Helsinki.

A New Mouse Model of Chronic Myocarditis Induced by Recombinant Bacille Calmette-Guèrin Expressing a T-Cell Epitope of Cardiac Myosin Heavy Chain-α.

Dilated cardiomyopathy (DCM) is a potentially lethal disorder characterized by progressive impairment of cardiac function. Chronic myocarditis has long been hypothesized to be one of the causes of DCM. However, owing to the lack of suitable animal models of chronic myocarditis, its pathophysiology remains unclear. Here, we report a novel mouse model of chronic myocarditis induced by recombinant bacille Calmette-Guérin (rBCG) expressing a CD4+ T-cell epitope of cardiac myosin heavy chain-α (rBCG-MyHCα). Mice immunized with rBCG-MyHCα developed chronic myocarditis, and echocardiography revealed dilation and impaired contraction of ventricles, similar to those observed in human DCM. In the heart, CD62L-CD4+ T cells were increased and produced significant amounts of IFN-γ and IL-17 in response to cardiac myosin. Adoptive transfer of CD62L-CD4+ T cells induced myocarditis in the recipient mice, which indicated that CD62L-CD4+ T cells were the effector cells in this model. rBCG-MyHCα-infected dendritic cells produced proinflammatory cytokines and induced MyHCα-specific T-cell proliferation and Th1 and Th17 polarization. This novel chronic myocarditis mouse model may allow the identification of the central pathophysiological and immunological processes involved in the progression to DCM.

Radionuclide Imaging of Cardiac Amyloidosis and Sarcoidosis: Roles and Characteristics of Various Tracers.

Amyloidosis and sarcoidosis are systemic diseases that affect multiple organ systems. Accurate diagnosis of cardiac amyloidosis and sarcoidosis is particularly important because cardiac involvement can be fatal. Amyloidosis is characterized by the deposition of amyloid fibrils, and cardiac amyloidosis is classified into amyloid immunoglobulin light chain (AL) and amyloid transthyretin (ATTR) types. Radionuclide tracers for amyloidosis include (a) bone tracers, (b) amyloid-directed molecules, and (c) PET amyloid agents. Bone tracers are particularly sensitive in detection of ATTR type amyloidosis, whereas PET amyloid agents show a higher affinity for the AL type. In sarcoidosis, gallium 67 (67Ga) citrate scintigraphy and fluorine 18 (18F) fluorodeoxyglucose (FDG) PET are pivotal to diagnosis of cardiac sarcoidosis, and 18F-FDG PET/CT has particularly high efficacy in detection of sarcoidosis and monitoring of response to therapy. A major limitation of 18F-FDG is physiologic uptake in the myocardium, which can remain in approximately 20% of patients even after elaborate preparation (eg, prolonged fasting >12-18 hours, modification to a high-fat and low-carbohydrate diet, and injection of unfractionated heparin). This limitation has led to a search for potential new tracers. Recently introduced tracers that show promise include those used in somatostatin receptor imaging and cellular proliferation imaging, which provide detectability as high as that for 18F-FDG without requiring dietary restrictions and have potential for monitoring disease activity. ©RSNA, 2020.

Myocardial Native T1 Predicts Load-Independent Left Ventricular Chamber Stiffness In Patients With HFpEF.

OBJECTIVES: This study sought to evaluate the potential of cardiac magnetic resonance T1 mapping to detect load-independent left ventricular (LV) chamber stiffness by histological confirmation. BACKGROUND: Accurate noninvasive diagnosis of LV diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) remains challenging. METHODS: Nineteen HFpEF patients (14 female, 65 ± 16 years of age) without primary cardiomyopathy were prospectively enrolled. Cine, late gadolinium enhancement cardiac magnetic resonance, and triple-slice T1 mapping using a modified Look-Locker inversion recovery sequence were performed at 3-T. Extracellular volume (ECV) was quantified from pre- and post-contrast T1 values of the blood and myocardium with hematocrit correction. LV stiffness constant (beta) was assessed by calculating the slope of the end-diastolic pressure-volume relationship curve during vena cava occlusion. Biopsy samples were used for quantification of collagen volume fraction (CVF) and myocardial cell size. RESULTS: Six patients showed focal scar on late gadolinium enhancement. There was no significant difference in histological CVF between patients with and without focal myocardial scarring (p = 0.2). Septal ECV rather than native T1 was a better surrogate marker for detecting histological CVF (r = 0.54; p = 0.02, and r = 0.44; p = 0.06, respectively). Global native T1 and ECV, but not native T1 and ECV in the septal myocardium, correlated well with the beta of passive LV stiffness, and had similar ability for predicting LV stiffness to histological CVF (r = 0.54, 0.50, 0.53, all p < 0.05, respectively). When the beta ≥0.054 was considered as moderately increased LV stiffness, global native T1 ≥1,362 ms provided 88% sensitivity and 64% specificity with the C-statistic of 0.81 (95% confidence interval: 0.56 to 0.95). CONCLUSIONS: Myocardial native T1 provides comparable ability in predicting LV stiffness to ECV and histological CVF and may be useful for monitoring patients with HFpEF who have renal dysfunction, allergy to gadolinium, or wheezing that can simulate asthma. Our feasibility study shows the potential of native T1 to allow for insight of heterogeneous pathophysiology and better risk stratification of HFpEF.

Correction to: Performance of 99mTc-aprotinin scintigraphy for diagnosing light chain (AL) cardiac amyloidosis confirmed by endomyocardial biopsy.

This prospective study was conducted according to the principles outlined within the Declaration of Helsinki, and approved by the Ethics Review Board of National Center for Global Health and Medicine (NCGM-G-00839-01, NCGM-G-00839-02).

Performance of 99mTc-aprotinin scintigraphy for diagnosing light chain (AL) cardiac amyloidosis confirmed by endomyocardial biopsy.

BACKGROUND: Light chain (AL) cardiac amyloidosis is associated with a poor prognosis. Diagnosing at an early stage is critical for treatment and the management of cardiac complication. PURPOSE: We aimed to evaluate the diagnostic performance of 99mTc-aprotinin images in patients with AL cardiac amyloidosis. METHODS AND RESULTS: 99mTc-aprotinin scintigraphy and endomyocardial biopsy were performed in 10 patients with suspected amyloidosis. Endomyocardial biopsy showed amyloid deposits in 5 of 10 patients. 99mTc-aprotinin (planer image) was positive in 4 of 5 patients who had amyloid deposits in endomyocardial biopsy. On the other hand, all 5 patients without amyloid deposits were negative in planer image. 99mTc-aprotinin (SPECT/CT image) was positive in all 5 patients who had amyloid deposits. CONCLUSIONS: 99mTc-aprotinin scintigraphy is valuable for the non-invasive diagnosis of AL cardiac amyloidosis.

Postconditioning Accelerates Myocardial Inflammatory Resolution Demonstrated by 14C-Methionine Imaging and Attenuates Ventricular Remodeling After Ischemia and Reperfusion.

BACKGROUND: Methionine uptake after myocardial infarction has been proven to reflect myocardial inflammation. The effect of postconditioning on the post-infarction inflammatory process, however, remains to be elucidated.Methods and Results:In control (n=22) and postconditioning rats (n=23), the left coronary artery was occluded for 30 min, followed by reperfusion for 1, 3, 7, and 14 days. Postconditioning was performed immediately following the reperfusion. 14C-methinine (0.74 MBq) and 201Tl (14.8 MBq) were injected 20 and 10 min prior to sacrifice, respectively. One minute before sacrifice, 150-180 MBq of 99 mTc-MIBI was injected immediately following the re-occlusion of the left coronary artery to verify the area at risk, and left ventricular triple-tracer autoradiography was performed. To examine the ventricular remodeling, echocardiography was performed 2 months after reperfusion in both groups (n=6 each). In the control rats, the methionine uptake ratios on days 1, 3, 7, and 14 were 0.74±0.12, 1.85±0.16, 1.48±0.10, 1.25±0.04, respectively. With postconditioning, methionine uptake was similar on day 3 (1.90±0.21), but was lower on day 7 (1.23±0.22, P<0.05) and day 14 (1.08±0.09, P<0.005). Echocardiography revealed that postconditioning reduced the ventricular end-diastolic (0.97±0.16 to 0.78±0.12 cm, P<0.05) and systolic (0.85±0.21 to 0.55±0.23 cm, P<0.05) dimensions and improved ventricular percentage fractional shortening (12±6.2 to 29±12 %, P=0.01). CONCLUSIONS: 14C-methinine imaging revealed that postconditioning accelerated resolution of inflammation and attenuated ventricular remodeling.

A multicenter trial of extracorporeal cardiac shock wave therapy for refractory angina pectoris: report of the highly advanced medical treatment in Japan.

We have previously demonstrated that cardiac shock wave therapy (CSWT) effectively improves myocardial ischemia through coronary neovascularization both in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris (AP). In this study, we further addressed the efficacy and safety of CSWT in a single-arm multicenter study approved as a highly advanced medical treatment by the Japanese Ministry of Health, Labour and Welfare. Fifty patients with refractory AP [mean age 70.9 ± 12.6 (SD) years, M/F 38/12] without the indications of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were enrolled in 4 institutes in Japan. Ischemic myocardial regions in the left ventricle (LV) were identified by drug-induced stress myocardial perfusion imaging (MPI). Shock waves (200 shots/spot at 0.09 mJ/mm2) were applied to 40-60 spots in the ischemic myocardium 3 times in the first week. The patients were followed up for 3 months thereafter. Forty-one patients underwent CSWT and completed the follow-up at 3 months. CSWT markedly improved weekly nitroglycerin use [from 3.5 (IQR 2 to 6) to 0 (IQR 0 to 1)] and the symptoms [Canadian Cardiovascular Society functional class score, from 2 (IQR 2 to 3) to 1 (IQR 1 to 2)] (both P < 0.001). CSWT also significantly improved 6-min walking distance (from 384 ± 91 to 435 ± 122 m, P < 0.05). There were no significant changes in LV ejection fraction evaluated by echocardiography and LV stroke volume evaluated by cardiac magnetic resonance imaging (from 56.3 ± 14.7 to 58.8 ± 12.8%, P = 0.10, and from 52.3 ± 17.4 to 55.6 ± 15.7 mL, P = 0.15, respectively). Percent myocardium ischemia assessed by drug-induced stress MPI tended to be improved only in the treated segments (from 16.0 ± 11.1 to 12.1 ± 16.2%, P = 0.06), although no change was noted in the whole LV. No procedural complications or adverse effects related to the CSWT were noted. These results of the multicenter trial further indicate that CSWT is a useful and safe non-invasive strategy for patients with refractory AP with no options of PCI or CABG.

Successful Inflammation Imaging of Non-Human Primate Hearts Using an Antibody Specific for Tenascin-C.

Inflammation after myocardial infarction (MI) may be a major factor influencing ventricular remodeling, leading to congestive heart failure and arrhythmia. Therefore, inflammation in the heart needs to be monitored. Tenascin-C (TNC) is an extracellular matrix molecule not normally expressed, but it is strongly upregulated when associated with active inflammation. Based on this characteristic, we successfully imaged in vivo inflammatory lesions in rat models using 111Indium (111In)-labeled anti-TNC antibodies. The aim of the present study was to further assess the applicability of this molecular imaging probe to detect inflammatory activity in primate hearts.We generated an MI model of cynomolgus monkeys (Macaca fascicularis) by coronary artery ligation and performed dual-isotope single-photon emission computed tomography (SPECT) imaging with an 111In-labeled anti-TNC antibody Fab' fragment (111In-TNC Fab') and 99mtechnetium methoxy-isobutyl isonitrile (99mTc-MIBI). Dual autoradiography was used to compare the uptake of 111In-TNC Fab' with histology and immunostaining for TNC. Dual-isotope SPECT showed the regional myocardial uptake of 111In-TNC Fab' complementary to a defect in the perfusion image by 99mTc-MIBI. The high radioactivity of 111In-TNC Fab' by autoradiography corresponded to immunostaining for TNC, which was observed in inflammatory lesions at the border zone between the infarcted and non-infarcted areas of the left ventricle and at the epi/pericarditis lesions of the right ventricle. These results demonstrate the potential of 111In-TNC-Fab' imaging to monitor myocardial injury and inflammation and suggest the feasibility of the non-invasive detection of cardiac inflammation following acute MI in a preclinical stage before testing in humans.

Tenascin-C accelerates adverse ventricular remodelling after myocardial infarction by modulating macrophage polarization.

AIMS: Tenascin-C (TN-C) is an extracellular matrix protein undetected in the normal adult heart, but expressed in several heart diseases associated with inflammation. We previously reported that serum TN-C levels of myocardial infarction (MI) patients were elevated during the acute stage, and that patients with high peak TN-C levels were at high risk of left ventricular (LV) remodelling and poor outcome, suggesting that TN-C could play a significant role in the progression of ventricular remodelling. However, the detailed molecular mechanisms associated with this process remain unknown. We aimed to elucidate the role and underlying mechanisms associated with TN-C in adverse remodelling after MI. METHODS AND RESULTS: MI was induced by permanent ligation of the coronary artery of TN-C knockout (TN-C-KO) and wild type (WT) mice. In WT mice, TN-C was expressed at the borders between intact and necrotic areas, with a peak at 3 days post-MI and observed in the immediate vicinity of infiltrating macrophages. TN-C-KO mice were protected from ventricular adverse remodelling as evidenced by a higher LV ejection fraction as compared with WT mice (19.0 ± 6.3% vs. 10.6 ± 4.4%; P < 0.001) at 3 months post-MI. During the acute phase, flow-cytometric analyses showed a decrease in F4/80+CD206lowCD45+ M1 macrophages and an increase in F4/80+CD206highCD45+ M2 macrophages in the TN-C-KO heart. To clarify the role of TN-C on macrophage polarization, we examined the direct effect of TN-C on bone marrow-derived macrophages in culture, observing that TN-C promoted macrophage shifting into an M1 phenotype via Toll-like receptor 4 (TLR4). Under M2-skewing conditions, TN-C suppressed the expression of interferon regulatory factor 4, a key transcription factor that controls M2-macrophage polarization, via TLR4, thereby inhibiting M2 polarization. CONCLUSION: These results suggested that TN-C accelerates LV remodelling after MI, at least in part, by modulating M1/M2-macrophage polarization.

Hereditary cardiac amyloidosis associated with Pro24Ser transthyretin mutation: a case report.

BACKGROUND: Transthyretin amyloidosis is a systemic disorder caused by extracellular deposition of insoluble amyloid fibrils in peripheral and autonomic nerves, heart, kidney, gastrointestinal tract, and other organs. Hereditary transthyretin amyloidosis is an autosomal dominant disease. More than 120 mutations have been reported in the transthyretin gene with considerable phenotypic heterogeneity and geographic diversity. Among them, a sporadic case of hereditary transthyretin amyloidosis with cardiac-predominant phenotype is very rare, progressive, and potentially fatal if left undiagnosed. However, a clinical diagnosis of cardiac amyloidosis still remains challenging due to non-specific symptoms, and less sensitivity and specificity of medical examinations. CASE PRESENTATION: A 60-year-old Japanese man with a history of embolic stroke and hypertrophic cardiomyopathy visited our department for heart failure. The present case exhibited only cardiomyopathy without any clinical signs of systemic amyloidosis manifested as carpal tunnel syndrome, polyneuropathy, or autonomic dysfunction. An echocardiogram revealed severe asymmetric left ventricular hypertrophy, biatrial dilatation, pericardial effusion, and preserved left ventricular ejection fraction of 50% with severe diastolic dysfunction. Technetium pyrophosphate scintigraphy indicated marked diffuse myocardial uptake of technetium pyrophosphate, strongly suggesting transthyretin cardiac amyloidosis, which was firmly confirmed by a left ventricular endomyocardial biopsy. Genetic analysis demonstrated a transthyretin C70T (Pro24Ser) heterozygous mutation. Tafamidis, a transthyretin stabilizer, was started. His cardiac symptoms remained unchanged for 12 months. CONCLUSIONS: Here we report the case of a patient with hereditary cardiac amyloidosis associated with a Pro24Ser mutation in transthyretin, which is the first case reported in Japan. Technetium pyrophosphate scintigraphy was extremely useful for definitive diagnosis. Thus, we propose that the nuclear imaging technique should be taken into account even for an exploratory diagnosis of transthyretin cardiac amyloidosis.

A case of biopsy-proven eosinophilic myocarditis related to tetanus toxoid immunization.

Vaccine-associated myocarditis is an extremely rare, yet potentially lethal disease, which requires early diagnosis and prompt treatment. However, its pathogenesis remains elusive. We report the first case of biopsy-proven eosinophilic myocarditis related to tetanus toxoid immunization, with unique histopathologic findings, characterized by perivascular eosinophilic infiltrates with myocyte necrosis and abundant interstitial lymphocytic infiltrates with myocyte necrosis, separately. A systemic high-dose corticosteroid treatment had a dramatic beneficial effect on hemodynamic instability and resulted in complete recovery. This case highlights the value of endomyocardial biopsy in establishing a definite diagnosis and understanding the pathogenesis of vaccine-associated myocarditis.

A case of cardiac sarcoidosis mimicking cardiac amyloidosis on cardiovascular magnetic resonance.

A 52-year-old male visited our hospital with abnormal electrocardiogram and exertional fatigue. The electrocardiogram showed first-degree atrioventricular block, complete right bundle branch block, and inverted T waves in Leads II, III, aVF, V3, and V4. Echocardiography showed biventricular wall thickening involving granular sparkling of the interventricular septum. Late gadolinium enhancement on cardiovascular magnetic resonance (CMR) was found at the circumferential right ventricular wall and patchy regions of the left ventricle. Although these findings strongly suggested cardiac amyloidosis, he was finally diagnosed with systemic sarcoidosis due to the following. First, endomyocardial biopsy revealed non-caseating epithelioid granuloma with giant cells. Second, 18 F-fluorodeoxyglucose positron emission tomography showed uptake in bilateral hilar lymph nodes, para-aortic lymph nodes, and the biventricular wall of the heart. Although echocardiography and CMR are very useful tools for diagnosis of cardiomyopathies, their specificity and accuracy need to be considered.

Steroid pulse therapy was effective for cardiac sarcoidosis with ventricular tachycardia and systolic dysfunction.

A 32-year-old man presented with palpitation. He was diagnosed with pulmonary sarcoidosis by lung biopsy. The electrocardiogram showed first-degree atrioventricular block and complete right bundle branch block (CRBBB). We planned to examine laboratory data, echocardiography, Holter monitoring, and gallium-67 scintigraphy. Before he went through all these exams, he developed ventricular tachycardia. After defibrillation was performed, his electrocardiogram revealed complete atrioventricular block. We observed elevation of serum angiotensin-converting enzyme levels. In addition, both of gallium-67 scintigraphy and 18F-fluorodeoxyglucose positron emission tomography showed abnormal uptake in the ventricular septum. We diagnosed the patient with cardiac sarcoidosis associated with these arrhythmias. We started treatment with methylprednisolone pulse therapy (1 g daily). After 3 days of steroid pulse therapy, we administered prednisolone 30 mg daily. On day 15, electrocardiogram changed from complete atrioventricular block to first-degree atrioventricular block and CRBBB. He was discharged with no progression with cardiac sarcoidosis for 2 years.

Serum Tenascin-C as a Novel Predictor for Risk of Coronary Artery Lesion and Resistance to Intravenous Immunoglobulin in Kawasaki Disease　- A Multicenter Retrospective Study.

BACKGROUND: Tenascin-C (TN-C) is an extracellular matrix glycoprotein that is heavily upregulated at sites of inflammation. We conducted a retrospective study to assess the utility of TN-C as a novel biomarker to predict the risk of developing coronary artery lesions (CAL) and resistance to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD).Methods and Results:We collected blood samples of 111 KD patients (IVIG-responder: 89, IVIG-resistant: 22; CAL: 8) and 23 healthy controls, and measured the serum levels of TN-C. TN-C levels on admission were significantly higher in patients than in healthy controls and in patients during convalescence after IVIG administration (69.6 vs. 20.4 vs. 39.7 ng/ml, respectively; P<0.001), and correlated positively with C-reactive protein (P<0.001), neutrophil (percentage; P=0.005), and ALT (P<0.001), and negatively with platelet count (P=0.023) and sodium level (P=0.025). On admission, TN-C levels in patients who later developed CAL were significantly higher than in those without CAL (P=0.010), and significantly higher in IVIG-resistant subjects than in IVIG-responders (P=0.003). The accuracy of TN-C testing for the prediction of IVIG resistance was comparable to that of the Kobayashi score. CONCLUSIONS: Serum TN-C could be a biomarker for predicting the risk of developing CAL and IVIG resistance during the acute phase of KD. (Circ J 2016; 80: 2376-2381).