Kenji Suda - Academia.edu (original) (raw)

Papers by Kenji Suda

Circulation, May 3, 2011

Background-Some patients with Kawasaki disease develop giant coronary aneurysms and coronary sten... more Background-Some patients with Kawasaki disease develop giant coronary aneurysms and coronary stenosis, leading to ischemic heart disease. The aim of this study was to determine the long-term prognosis of patients with Kawasaki disease with giant aneurysms. Methods and Results-From our institutional database, 76 patients (57 men and 19 women) who developed giant aneurysms after January 1, 1972, were identified. Information on patient demographics, catheter and surgical interventions, and most recent status was collected from medical charts and patients' contacts. From these data, we calculated the survival rate and cumulative coronary intervention rate. The average age at onset was 2.9Ϯ2.9 years, and the median observational period was 19 years. During this period, 7 patients died and 1 patient underwent a heart transplantation, resulting in 95%, 88%, and 88% survival rates at 10, 20, and 30 years after the onset of KD, respectively. On the other hand, catheter and surgical coronary interventions (median, 1 intervention; range, 1 to 7 interventions) were performed to alleviate coronary ischemia in 46 patients (61%) at 1 month to 21 years (mode at 1 month) after onset, resulting in 28%, 43%, and 59% cumulative coronary intervention rates at 5, 15, and 25 years after onset, respectively. Conclusions-The long-term survival of patients with Kawasaki disease complicated by giant coronary aneurysms is moderately good with multiple catheter and surgical interventions. Further research should focus on the prevention of coronary vascular remodeling and on the indications for and effectiveness of percutaneous and surgical coronary interventions. (Circulation. 2011;123:1836-1842.) Key Words: aneurysm Ⅲ coronary artery disease Ⅲ mucocutaneous lymph node syndrome Ⅲ outcome assessment K awasaki disease (KD), a systemic vasculitis with an unknown origin, is the most common acquired cardiovascular disease in developed countries. 1,2 Although intravenous immunoglobulin infusion is an effective treatment for this disease, some patients still develop coronary aneurysms. 3-5 These coronary aneurysms undergo remodeling over time, 6 leading to intimal thickening and calcification. 7,8 The result of this pathological change in coronary arteries is stenosis adjacent to the aneurysms or occlusion of the coronary arteries, resulting in ischemic heart disease. 9,10

Renal Replacement Therapy, Oct 30, 2017

Background: The treatment of Kawasaki disease is controversial when intravenous immunoglobulin th... more Background: The treatment of Kawasaki disease is controversial when intravenous immunoglobulin therapy fails, although it typically relies on combinations of prednisolone, infliximab, cyclosporine, and plasma exchange therapy. The goal of the treatment is no longer merely to reduce mortality but also to decrease the sequelae of coronary artery lesions, which are the most common and potentially life-threatening complications. Recently, plasma exchange therapy has been used to treat intravenous immunoglobulin-unresponsive Kawasaki disease with coronary artery lesions. When performed before coronary artery dilatation, the outcomes for plasma exchange are known to be excellent; however, when dilatation is already present, sequelae persist. Methods: Between December 2006 and April 2015, we treated ten patients with Kawasaki disease complicated by coronary artery lesions that received plasma exchange because intravenous immunoglobulin therapy had proven to be ineffective. Here, we retrospectively review the efficacy and safety of plasma exchange therapy in such unresponsive cases against coronary artery lesions in patients with Kawasaki disease when plasma exchange performed after coronary artery dilatation. Results: In nine of the ten patients (90.0%), the body temperature was confirmed to be < 37.5°C at an average of 2.7 ± 1. 4 days after starting plasma exchange. Serum C-reactive protein levels decreased significantly from 9.9 ± 4.9 mg/dL before exchange to 1.9 ± 2.9 mg/dL after exchange (P < 0.05). One year after plasma exchange treatment, the coronary artery lesions had regressed to within normal limits in six of the ten patients. Although lesions remained in three patients, all three of these patients were asymptomatic. In addition, there were no stenosis of the coronary artery in nine of the ten patients. One patient died due to a ruptured giant coronary aneurysm 1 day after starting plasma exchange. Conclusions: In conclusion, plasma exchange may be effective in not only regressing coronary artery lesions but also preventing sequelae in patients with Kawasaki disease when plasma exchange is performed after coronary artery dilatation.

European Journal of Pediatrics, Aug 3, 2013

Circulation Journal, 2020

2DE two-dimensional echocardiography ACEI angiotensin converting enzyme inhibitor ACS acute coron... more 2DE two-dimensional echocardiography ACEI angiotensin converting enzyme inhibitor ACS acute coronary syndrome AMI acute myocardial infarction AP angina pectoris APV average peak velocity ARB angiotensin II receptor blocker baPWV brachial-ankle pulse wave velocity BCG Bacille de Calmette et Guérin BMS bare metal stent BNP brain natriuretic peptide CAA coronary artery aneurysm(s)

Journal of Cardiology, Jun 1, 2020

Background: Growth differentiation factor 15 (GDF 15) is a member of the transforming growth fact... more Background: Growth differentiation factor 15 (GDF 15) is a member of the transforming growth factorbeta superfamily and is considered to be a useful biomarker for severity of heart failure (HF) in repaired congenital heart disease (CHD). The aim of this study was to determine the clinical implication of GDF 15 in children with unrepaired CHD. Methods: Subjects included 69 patients (14 years old) who had unrepaired CHD with left to right shunt and underwent cardiac catheterization. Demographic and hemodynamic data, including oxygen demand-supply relationship, were collected from medical records. Severity of HF was evaluated using modified Ross score. Serum GDF 15 levels were determined using enzyme-linked immunosorbent assay and correlated with patients' demographics, hemodynamic data, and blood chemistry data. Results: Subjects had median age of 71 (range 1-173) months and simple acyanotic CHDs with mean pulmonary to systemic flow ratio of 2.0 (1.0-5.6), median N-terminal pro type Brain natriuretic peptide (NT-pro-BNP) of 162.8 (17.1-8789) pg/mL, and median GDF 15 of 242.1 (13.6-1116.7) pg/mL. GDF 15 significantly positively correlated with the modified Ross score, mean pulmonary artery pressure, oxygen extraction rate (OER), and Ln NT-pro-BNP, but negatively correlated with age, oxygen delivery and its components, and estimated glomerular filtration rate (eGFR). Multiple linear regression analysis revealed significant correlation of GDF 15 levels with the modified Ross score, OER, and eGFR. Conclusions: GDF 15 mainly reflects oxygen demand-supply relationship and can be used as a diagnostic marker of HF in unrepaired CHD with left to right shunt for a wide range of age and diagnoses.

Journal of Nuclear Cardiology, Apr 17, 2018

International Journal of Cardiology, Feb 1, 2015

Journal of Nuclear Cardiology, Jul 7, 2022

International Journal of Cardiology, 2015

Circulation, Apr 28, 2015

A 22-year-old male patient, who was suffered from Kawasaki disease (KD) at 1 year and 1 month of ... more A 22-year-old male patient, who was suffered from Kawasaki disease (KD) at 1 year and 1 month of age and left with bilateral axillary arterial aneurysms (AAA) and regressed coronary aneurysm, visited us because of left hand edema and itchiness. He has been taking aspirin for thromboprophylaxis of AAA and well without any vascular event for these 20 years and does not have any sign of inflammatory disease. Digital subtraction angiography of bilateral arms revealed complete occlusion of left AAA with multiple collateral arteries supplying blood flow to the distal arm and persistent giant right AAA with 12 mm in diameter with only mild stenosis proximal to this AAA. To determine if the active inflammatory process is going on the axillary artery wall, the patient underwent positron emission tomography (PET) using fluorodeoxyglucose (FDG) with co-registration of multi-detector x-ray computed tomography, PET indeed showed significant FDG uptake inside and part of the outer wall of the left AAA and only minimum FDG uptake at the right AAA. For left arm ischemia, he underwent resection of the left AAA and successful axilla-brachial artery bypass surgery using a reversed autologous saphenous vein graft that relieved his symptoms. Histological examination of the resected wall of AAA showed significant intimal thickening and the immunohistochemistry study labeling CD68, as the marker of macrophages, showed relatively dense staining of the intimal thickening of left AAA wall compatible with FDG uptake. This is the first documentation of persistent inflammation of peripheral arterial wall long after KD using FDG-PET that must have resulted in peripheral arterial remodeling.

Journal of the American College of Cardiology, Mar 1, 2018

Metformin is a commonly used glucose-lowering drug. However, apart from glycemic measures, no bio... more Metformin is a commonly used glucose-lowering drug. However, apart from glycemic measures, no biomarker for its presence or dose has been identified. RESEARCH DESIGN AND METHODS A total of 237 biomarkers were assayed in baseline serum from 8,401 participants (2,317 receiving metformin) in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Regression models were used to identify biomarkers for metformin use. RESULTS Growth differentiation factor 15 (GDF15) was strongly linked to metformin, such that the odds of metformin use per SD increase in level varied from 3.73 (95% CI 3.40, 4.09) to 3.94 (95% CI 3.59, 4.33) depending on the other included variables. For the remaining 25 linked biomarkers, the odds ranged from 0.71 to 1.24. A 1.64 ng/mL higher GDF15 level predicted a 188-mg higher metformin dose (P < 0.0001). CONCLUSIONS GDF15 levels are a biomarker for the use of metformin in people with dysglycemia, and its concentration reflects the dose of metformin. Metformin is currently the most widely used glucose-lowering agent in the world that effectively lowers glucose levels; reduces incident diabetes (1); modestly reduces weight; and may reduce the occurrence of ischemic heart disease, mortality, and some malignancies (2). Whereas its glucometabolic effects are partially due to activation of the AMP-activated protein kinase (3), some of its other effects may be mediated by novel pathways. To identify nonglycemic biomarkers for such pathways, we screened a large panel of 237 markers, covering major physiological pathways that were assayed in baseline serum samples collected in 8,401 participants (;28% of whom were receiving various doses of metformin) in the recently completed Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. RESEARCH DESIGN AND METHODS The ORIGIN trial recruited 12,537 people with diabetes, impaired glucose tolerance, or impaired fasting glucose levels who had additional cardiovascular (CV) risk factors (4). Prior to randomization, 8,494 participants (68%) provided baseline blood samples that were spun, separated, aliquoted, frozen (within 2 h of collection), and transported to the Population Health Research Institute Biobank in Hamilton, Ontario, Canada, where they were stored in nitrogen vapor-cooled tanks at 2160°C.

Circulation, 2015

Introduction: Kawasaki disease (KD) is well known vasculitis that primarily affects small to midd... more Introduction: Kawasaki disease (KD) is well known vasculitis that primarily affects small to middle sized arteries such as coronary arteries and/or peripheral arteries. However, little evidence showed inflammation of large vasculature such as the aorta in patients with KD. Measurements of 18F-fluorodeoxyglucose (FDG) uptake evaluated by positron emission tomography (PET) and X-ray computed tomography (CT) could be useful to identify inflammatory activity of the vessel wall. Hypothesis: We hypothesized that aortic inflammation continues long after KD. Methods: FDG-PET/CT was performed in 19 patients with a history of KD. Of 19 patients, 11 patients still had persistent coronary and/or systemic vascular aneurysms (KD-An) and the remaining 8 revealed regression of arterial aneurysms (KD-Reg). Patients suffered from KD at 2.8 ± 3.2 years old and underwent FDG-PET at 22.2 ± 8.0 years old. FDG-PET was also performed in 5 control with age 14.1 ± 2.6 years old. Vascular inflammation was mea...

Annals of neurology, 2015

The diagnosis of mitochondrial disorders (MDs) is occasionally difficult because patients often p... more The diagnosis of mitochondrial disorders (MDs) is occasionally difficult because patients often present with solitary, or a combination of, symptoms caused by each organ insufficiency, which may be the result of respiratory chain enzyme deficiency. Growth differentiation factor 15 (GDF-15) has been reported to be elevated in serum of patients with MDs. In this study, we investigated whether GDF-15 is a more useful biomarker for MDs than several conventional biomarkers. We measured the serum levels of GDF-15 and fibroblast growth factor 21 (FGF-21), as well as other biomarkers, in 48 MD patients and in 146 healthy controls in Japan. GDF-15 and FGF-21 concentrations were measured by enzyme-linked immunosorbant assay and compared with lactate, pyruvate, creatine kinase, and the lactate-to-pyruvate ratio. We calculated sensitivity and specificity and also evaluated the correlation based on two rating scales, including the Newcastle Mitochondrial Disease Rating Scale (NMDAS). Mean GDF-15...

Circulation, Apr 28, 2015

The patient, 42-year-old male, was suffered from Kawasaki disease (KD) at 4 month of age and left... more The patient, 42-year-old male, was suffered from Kawasaki disease (KD) at 4 month of age and left with giant left coronary artery aneurysm (CAA) and occluded giant right CAA. When he visited us at 40 years of age after long interval, a multi-detector X-ray computed tomography revealed persistent giant CAA with 12 mm in diameter at segment 6 with low density area inside of it, stenosis distal to this CAA, persistent giant CAA with 12 mm in diameter at segment 11, and total occlusion of right coronary artery orifice with recanalization. Positron emission tomography using fluorodexoy glucose (FDG-PET) with co-registration of x-ray computed tomography showed significant FDG uptake around the left coronary orifice of the aortic wall and extending to the proximal left CAA wall with 1.48 of target-to-background ratio, indicating persistent inflammation. He has 2 risk factors of atherosclerosis, dyslipidemia and a history of smoking and, since then he has been placed on 2 mg of oral pitavastatin. With the treatment, his LDL-cholesterol has decreased (105 at baseline vs. 74 mg/dL on treatment) though HDL-cholesterol did not change significantly (31 at baseline vs. 30 mg/dl on treatment). FDG-PET after 2 years of treatment indeed showed alleviation of coronary inflammation with significantly smaller area and lower uptake of FDG on the coronary wall with 1.28 of target-to-background ratio. This case indicates that statin can alleviate persistent coronary artery inflammation long after KD and FDG-PET can be a useful monitoring tool of this process.

Circulation, 2015

Objective: We report four patients with incomplete Kawasaki disease (KD) successfully treated by ... more Objective: We report four patients with incomplete Kawasaki disease (KD) successfully treated by antibiotics without intravenous immunoglobulin (IVIG) treatment with ≦ 5 days of fever but left with coronary artery lesion. Result: The patients were 2 babies and 2 young children age ranged from 2 months to 2 years old and 9 months. They showed fever and other signs of KD, but did not fulfill diagnostic criteria. The numbers of symptoms compatible with KD were 2 or 3 and included conjunctival injection, oral or lip injection, and eruption. Within 5 days, they became afebrile by antibiotics without IVIG treatment. However, they were noted to have coronary artery aneurysm (CAA) on day from 7 to 33 of illness. All patients had been placed on antithrombotic treatment including aspirin or aspirin plus warfarin and, fortunately, showed regression of CAA within 2 years. Conclusions: This case series indicates that there are patients with incomplete KD successfully treated by antibiotics witho...

Circulation, 2011

Background: A risk for acute coronary events in adults with a history of Kawasaki disease (KD) is... more Background: A risk for acute coronary events in adults with a history of Kawasaki disease (KD) is still speculative. Methods: We conducted a nationwide questionnaire survey to test the hypothesis t...

Cardiology in the Young, 2016

Transcatheter closure of atrial septal defects has become more common because of its high success... more Transcatheter closure of atrial septal defects has become more common because of its high success rate and low morbidity; however, this treatment for patients with atrial septal aneurysms is still challenging.

Journal of the American College of Cardiology, 2019

Circulation Journal, 2016

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp... more Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp therapy can subdue the inflammation in KD and reduce the occurrence of CAL. 2-4 However, approximately 20% of KD patients show resistance to a single course of IVIG therapy. 5 Many studies have shown that these IVIG-resistant patients have a greater risk of CAL. 6-8 Currently, several scoring systems that combine multiple clinical parameters are used to awasaki disease (KD) is an acute febrile illness of childhood characterized by systemic vasculitis of unknown origin. 1 Coronary artery lesions (CAL) constitute the most critical complication of KD and can lead to myocardial infarction (MI) and death or chronic distress in adulthood. High-dose intravenous immunoglobulin (IVIG) K

International Journal of Cardiology, 2013

Circulation, May 3, 2011

Background-Some patients with Kawasaki disease develop giant coronary aneurysms and coronary sten... more Background-Some patients with Kawasaki disease develop giant coronary aneurysms and coronary stenosis, leading to ischemic heart disease. The aim of this study was to determine the long-term prognosis of patients with Kawasaki disease with giant aneurysms. Methods and Results-From our institutional database, 76 patients (57 men and 19 women) who developed giant aneurysms after January 1, 1972, were identified. Information on patient demographics, catheter and surgical interventions, and most recent status was collected from medical charts and patients' contacts. From these data, we calculated the survival rate and cumulative coronary intervention rate. The average age at onset was 2.9Ϯ2.9 years, and the median observational period was 19 years. During this period, 7 patients died and 1 patient underwent a heart transplantation, resulting in 95%, 88%, and 88% survival rates at 10, 20, and 30 years after the onset of KD, respectively. On the other hand, catheter and surgical coronary interventions (median, 1 intervention; range, 1 to 7 interventions) were performed to alleviate coronary ischemia in 46 patients (61%) at 1 month to 21 years (mode at 1 month) after onset, resulting in 28%, 43%, and 59% cumulative coronary intervention rates at 5, 15, and 25 years after onset, respectively. Conclusions-The long-term survival of patients with Kawasaki disease complicated by giant coronary aneurysms is moderately good with multiple catheter and surgical interventions. Further research should focus on the prevention of coronary vascular remodeling and on the indications for and effectiveness of percutaneous and surgical coronary interventions. (Circulation. 2011;123:1836-1842.) Key Words: aneurysm Ⅲ coronary artery disease Ⅲ mucocutaneous lymph node syndrome Ⅲ outcome assessment K awasaki disease (KD), a systemic vasculitis with an unknown origin, is the most common acquired cardiovascular disease in developed countries. 1,2 Although intravenous immunoglobulin infusion is an effective treatment for this disease, some patients still develop coronary aneurysms. 3-5 These coronary aneurysms undergo remodeling over time, 6 leading to intimal thickening and calcification. 7,8 The result of this pathological change in coronary arteries is stenosis adjacent to the aneurysms or occlusion of the coronary arteries, resulting in ischemic heart disease. 9,10

Renal Replacement Therapy, Oct 30, 2017

Background: The treatment of Kawasaki disease is controversial when intravenous immunoglobulin th... more Background: The treatment of Kawasaki disease is controversial when intravenous immunoglobulin therapy fails, although it typically relies on combinations of prednisolone, infliximab, cyclosporine, and plasma exchange therapy. The goal of the treatment is no longer merely to reduce mortality but also to decrease the sequelae of coronary artery lesions, which are the most common and potentially life-threatening complications. Recently, plasma exchange therapy has been used to treat intravenous immunoglobulin-unresponsive Kawasaki disease with coronary artery lesions. When performed before coronary artery dilatation, the outcomes for plasma exchange are known to be excellent; however, when dilatation is already present, sequelae persist. Methods: Between December 2006 and April 2015, we treated ten patients with Kawasaki disease complicated by coronary artery lesions that received plasma exchange because intravenous immunoglobulin therapy had proven to be ineffective. Here, we retrospectively review the efficacy and safety of plasma exchange therapy in such unresponsive cases against coronary artery lesions in patients with Kawasaki disease when plasma exchange performed after coronary artery dilatation. Results: In nine of the ten patients (90.0%), the body temperature was confirmed to be < 37.5°C at an average of 2.7 ± 1. 4 days after starting plasma exchange. Serum C-reactive protein levels decreased significantly from 9.9 ± 4.9 mg/dL before exchange to 1.9 ± 2.9 mg/dL after exchange (P < 0.05). One year after plasma exchange treatment, the coronary artery lesions had regressed to within normal limits in six of the ten patients. Although lesions remained in three patients, all three of these patients were asymptomatic. In addition, there were no stenosis of the coronary artery in nine of the ten patients. One patient died due to a ruptured giant coronary aneurysm 1 day after starting plasma exchange. Conclusions: In conclusion, plasma exchange may be effective in not only regressing coronary artery lesions but also preventing sequelae in patients with Kawasaki disease when plasma exchange is performed after coronary artery dilatation.

European Journal of Pediatrics, Aug 3, 2013

Circulation Journal, 2020

2DE two-dimensional echocardiography ACEI angiotensin converting enzyme inhibitor ACS acute coron... more 2DE two-dimensional echocardiography ACEI angiotensin converting enzyme inhibitor ACS acute coronary syndrome AMI acute myocardial infarction AP angina pectoris APV average peak velocity ARB angiotensin II receptor blocker baPWV brachial-ankle pulse wave velocity BCG Bacille de Calmette et Guérin BMS bare metal stent BNP brain natriuretic peptide CAA coronary artery aneurysm(s)

Journal of Cardiology, Jun 1, 2020

Background: Growth differentiation factor 15 (GDF 15) is a member of the transforming growth fact... more Background: Growth differentiation factor 15 (GDF 15) is a member of the transforming growth factorbeta superfamily and is considered to be a useful biomarker for severity of heart failure (HF) in repaired congenital heart disease (CHD). The aim of this study was to determine the clinical implication of GDF 15 in children with unrepaired CHD. Methods: Subjects included 69 patients (14 years old) who had unrepaired CHD with left to right shunt and underwent cardiac catheterization. Demographic and hemodynamic data, including oxygen demand-supply relationship, were collected from medical records. Severity of HF was evaluated using modified Ross score. Serum GDF 15 levels were determined using enzyme-linked immunosorbent assay and correlated with patients' demographics, hemodynamic data, and blood chemistry data. Results: Subjects had median age of 71 (range 1-173) months and simple acyanotic CHDs with mean pulmonary to systemic flow ratio of 2.0 (1.0-5.6), median N-terminal pro type Brain natriuretic peptide (NT-pro-BNP) of 162.8 (17.1-8789) pg/mL, and median GDF 15 of 242.1 (13.6-1116.7) pg/mL. GDF 15 significantly positively correlated with the modified Ross score, mean pulmonary artery pressure, oxygen extraction rate (OER), and Ln NT-pro-BNP, but negatively correlated with age, oxygen delivery and its components, and estimated glomerular filtration rate (eGFR). Multiple linear regression analysis revealed significant correlation of GDF 15 levels with the modified Ross score, OER, and eGFR. Conclusions: GDF 15 mainly reflects oxygen demand-supply relationship and can be used as a diagnostic marker of HF in unrepaired CHD with left to right shunt for a wide range of age and diagnoses.

Journal of Nuclear Cardiology, Apr 17, 2018

International Journal of Cardiology, Feb 1, 2015

Journal of Nuclear Cardiology, Jul 7, 2022

International Journal of Cardiology, 2015

Circulation, Apr 28, 2015

A 22-year-old male patient, who was suffered from Kawasaki disease (KD) at 1 year and 1 month of ... more A 22-year-old male patient, who was suffered from Kawasaki disease (KD) at 1 year and 1 month of age and left with bilateral axillary arterial aneurysms (AAA) and regressed coronary aneurysm, visited us because of left hand edema and itchiness. He has been taking aspirin for thromboprophylaxis of AAA and well without any vascular event for these 20 years and does not have any sign of inflammatory disease. Digital subtraction angiography of bilateral arms revealed complete occlusion of left AAA with multiple collateral arteries supplying blood flow to the distal arm and persistent giant right AAA with 12 mm in diameter with only mild stenosis proximal to this AAA. To determine if the active inflammatory process is going on the axillary artery wall, the patient underwent positron emission tomography (PET) using fluorodeoxyglucose (FDG) with co-registration of multi-detector x-ray computed tomography, PET indeed showed significant FDG uptake inside and part of the outer wall of the left AAA and only minimum FDG uptake at the right AAA. For left arm ischemia, he underwent resection of the left AAA and successful axilla-brachial artery bypass surgery using a reversed autologous saphenous vein graft that relieved his symptoms. Histological examination of the resected wall of AAA showed significant intimal thickening and the immunohistochemistry study labeling CD68, as the marker of macrophages, showed relatively dense staining of the intimal thickening of left AAA wall compatible with FDG uptake. This is the first documentation of persistent inflammation of peripheral arterial wall long after KD using FDG-PET that must have resulted in peripheral arterial remodeling.

Journal of the American College of Cardiology, Mar 1, 2018

Metformin is a commonly used glucose-lowering drug. However, apart from glycemic measures, no bio... more Metformin is a commonly used glucose-lowering drug. However, apart from glycemic measures, no biomarker for its presence or dose has been identified. RESEARCH DESIGN AND METHODS A total of 237 biomarkers were assayed in baseline serum from 8,401 participants (2,317 receiving metformin) in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Regression models were used to identify biomarkers for metformin use. RESULTS Growth differentiation factor 15 (GDF15) was strongly linked to metformin, such that the odds of metformin use per SD increase in level varied from 3.73 (95% CI 3.40, 4.09) to 3.94 (95% CI 3.59, 4.33) depending on the other included variables. For the remaining 25 linked biomarkers, the odds ranged from 0.71 to 1.24. A 1.64 ng/mL higher GDF15 level predicted a 188-mg higher metformin dose (P < 0.0001). CONCLUSIONS GDF15 levels are a biomarker for the use of metformin in people with dysglycemia, and its concentration reflects the dose of metformin. Metformin is currently the most widely used glucose-lowering agent in the world that effectively lowers glucose levels; reduces incident diabetes (1); modestly reduces weight; and may reduce the occurrence of ischemic heart disease, mortality, and some malignancies (2). Whereas its glucometabolic effects are partially due to activation of the AMP-activated protein kinase (3), some of its other effects may be mediated by novel pathways. To identify nonglycemic biomarkers for such pathways, we screened a large panel of 237 markers, covering major physiological pathways that were assayed in baseline serum samples collected in 8,401 participants (;28% of whom were receiving various doses of metformin) in the recently completed Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. RESEARCH DESIGN AND METHODS The ORIGIN trial recruited 12,537 people with diabetes, impaired glucose tolerance, or impaired fasting glucose levels who had additional cardiovascular (CV) risk factors (4). Prior to randomization, 8,494 participants (68%) provided baseline blood samples that were spun, separated, aliquoted, frozen (within 2 h of collection), and transported to the Population Health Research Institute Biobank in Hamilton, Ontario, Canada, where they were stored in nitrogen vapor-cooled tanks at 2160°C.

Circulation, 2015

Introduction: Kawasaki disease (KD) is well known vasculitis that primarily affects small to midd... more Introduction: Kawasaki disease (KD) is well known vasculitis that primarily affects small to middle sized arteries such as coronary arteries and/or peripheral arteries. However, little evidence showed inflammation of large vasculature such as the aorta in patients with KD. Measurements of 18F-fluorodeoxyglucose (FDG) uptake evaluated by positron emission tomography (PET) and X-ray computed tomography (CT) could be useful to identify inflammatory activity of the vessel wall. Hypothesis: We hypothesized that aortic inflammation continues long after KD. Methods: FDG-PET/CT was performed in 19 patients with a history of KD. Of 19 patients, 11 patients still had persistent coronary and/or systemic vascular aneurysms (KD-An) and the remaining 8 revealed regression of arterial aneurysms (KD-Reg). Patients suffered from KD at 2.8 ± 3.2 years old and underwent FDG-PET at 22.2 ± 8.0 years old. FDG-PET was also performed in 5 control with age 14.1 ± 2.6 years old. Vascular inflammation was mea...

Annals of neurology, 2015

The diagnosis of mitochondrial disorders (MDs) is occasionally difficult because patients often p... more The diagnosis of mitochondrial disorders (MDs) is occasionally difficult because patients often present with solitary, or a combination of, symptoms caused by each organ insufficiency, which may be the result of respiratory chain enzyme deficiency. Growth differentiation factor 15 (GDF-15) has been reported to be elevated in serum of patients with MDs. In this study, we investigated whether GDF-15 is a more useful biomarker for MDs than several conventional biomarkers. We measured the serum levels of GDF-15 and fibroblast growth factor 21 (FGF-21), as well as other biomarkers, in 48 MD patients and in 146 healthy controls in Japan. GDF-15 and FGF-21 concentrations were measured by enzyme-linked immunosorbant assay and compared with lactate, pyruvate, creatine kinase, and the lactate-to-pyruvate ratio. We calculated sensitivity and specificity and also evaluated the correlation based on two rating scales, including the Newcastle Mitochondrial Disease Rating Scale (NMDAS). Mean GDF-15...

Circulation, Apr 28, 2015

The patient, 42-year-old male, was suffered from Kawasaki disease (KD) at 4 month of age and left... more The patient, 42-year-old male, was suffered from Kawasaki disease (KD) at 4 month of age and left with giant left coronary artery aneurysm (CAA) and occluded giant right CAA. When he visited us at 40 years of age after long interval, a multi-detector X-ray computed tomography revealed persistent giant CAA with 12 mm in diameter at segment 6 with low density area inside of it, stenosis distal to this CAA, persistent giant CAA with 12 mm in diameter at segment 11, and total occlusion of right coronary artery orifice with recanalization. Positron emission tomography using fluorodexoy glucose (FDG-PET) with co-registration of x-ray computed tomography showed significant FDG uptake around the left coronary orifice of the aortic wall and extending to the proximal left CAA wall with 1.48 of target-to-background ratio, indicating persistent inflammation. He has 2 risk factors of atherosclerosis, dyslipidemia and a history of smoking and, since then he has been placed on 2 mg of oral pitavastatin. With the treatment, his LDL-cholesterol has decreased (105 at baseline vs. 74 mg/dL on treatment) though HDL-cholesterol did not change significantly (31 at baseline vs. 30 mg/dl on treatment). FDG-PET after 2 years of treatment indeed showed alleviation of coronary inflammation with significantly smaller area and lower uptake of FDG on the coronary wall with 1.28 of target-to-background ratio. This case indicates that statin can alleviate persistent coronary artery inflammation long after KD and FDG-PET can be a useful monitoring tool of this process.

Circulation, 2015

Objective: We report four patients with incomplete Kawasaki disease (KD) successfully treated by ... more Objective: We report four patients with incomplete Kawasaki disease (KD) successfully treated by antibiotics without intravenous immunoglobulin (IVIG) treatment with ≦ 5 days of fever but left with coronary artery lesion. Result: The patients were 2 babies and 2 young children age ranged from 2 months to 2 years old and 9 months. They showed fever and other signs of KD, but did not fulfill diagnostic criteria. The numbers of symptoms compatible with KD were 2 or 3 and included conjunctival injection, oral or lip injection, and eruption. Within 5 days, they became afebrile by antibiotics without IVIG treatment. However, they were noted to have coronary artery aneurysm (CAA) on day from 7 to 33 of illness. All patients had been placed on antithrombotic treatment including aspirin or aspirin plus warfarin and, fortunately, showed regression of CAA within 2 years. Conclusions: This case series indicates that there are patients with incomplete KD successfully treated by antibiotics witho...

Circulation, 2011

Background: A risk for acute coronary events in adults with a history of Kawasaki disease (KD) is... more Background: A risk for acute coronary events in adults with a history of Kawasaki disease (KD) is still speculative. Methods: We conducted a nationwide questionnaire survey to test the hypothesis t...

Cardiology in the Young, 2016

Transcatheter closure of atrial septal defects has become more common because of its high success... more Transcatheter closure of atrial septal defects has become more common because of its high success rate and low morbidity; however, this treatment for patients with atrial septal aneurysms is still challenging.

Journal of the American College of Cardiology, 2019

Circulation Journal, 2016

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp... more Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp therapy can subdue the inflammation in KD and reduce the occurrence of CAL. 2-4 However, approximately 20% of KD patients show resistance to a single course of IVIG therapy. 5 Many studies have shown that these IVIG-resistant patients have a greater risk of CAL. 6-8 Currently, several scoring systems that combine multiple clinical parameters are used to awasaki disease (KD) is an acute febrile illness of childhood characterized by systemic vasculitis of unknown origin. 1 Coronary artery lesions (CAL) constitute the most critical complication of KD and can lead to myocardial infarction (MI) and death or chronic distress in adulthood. High-dose intravenous immunoglobulin (IVIG) K

International Journal of Cardiology, 2013