Atrial septal defect (ASD) is a common congenital heart disease diagnosed during childhood. Persi... more Atrial septal defect (ASD) is a common congenital heart disease diagnosed during childhood. Persistently increased pulmonary blood flow and dilated right atrium (RA) and right ventricle (RV) result in multiple symptoms and morbidities in adulthood; untreated adults may develop exercise intolerance, congestive heart failure, atrial tachyarrhythmias, pulmonary hypertension (PH), embolic stroke, or even death [1,2]. Asymptomatic children with ASD are commonly referred for elective ASD closure around 3 to 6 years of age [2,3].
Abnormalities of coronary artery, congenital or acquired, are rare in the pediatric population, b... more Abnormalities of coronary artery, congenital or acquired, are rare in the pediatric population, but they frequently present unexpectedly. They may result in life-threatening conditions if unrecognized; however, in infants and children, preclinical coronary abnormalities usually do not present with the typical clinical manifestations seen in adults with myocardial ischemia. Timely diagnosis of silent myocardial ischemia is frequently challenging in children. Myocardial infarction may occur in anomalous left coronary artery from pulmonary artery (ALCAPA), right ventricle-dependent coronary artery seen in pulmonary atresia with intact ventricular septum (PA/IVS), and coronary aneurysm complicated in Kawasaki disease. On the other hand, some coronary artery abnormalities tend to present with unexpected ventricular arrhythmia or sudden cardiac death (SCD). These include aberrant aortic origin of coronary artery (AAOCA) and acquired coronary stenosis after arterial switch operation (ASO) ...
Heart transplant remains an important treatment option for end-stage heart failure in children wh... more Heart transplant remains an important treatment option for end-stage heart failure in children who have failed maximum medical management. Although the outcome of heart transplant has significantly improved due to advances in perioperative management and immunosuppression, commonly, it is not a permanent solution. We still encounter multiple problems in managing these patients before and after transplant, not only with hemodynamic derangement, but also with functional deterioration of multiple organ systems. Shortage of donor hearts in association with wait-list mortality remains a major ongoing problem, especially for infants. Importantly, transplant for patients with congenital heart disease has unique challenges, including complexity of surgical reconstruction, coagulation abnormalities, allosensitization, and specific problems related to single ventricular palliation. Even after successful transplant, chronic complications emerge as inevitable challenges, including rejection, in...
Journal of Cardiovascular Development and Disease, 2021
Ventricular wall stress (WS) is an important hemodynamic parameter to represent myocardial oxygen... more Ventricular wall stress (WS) is an important hemodynamic parameter to represent myocardial oxygen demand and ventricular workload. The normalization of WS is regarded as a physiological feedback signal that regulates the rate and extent of ventricular hypertrophy to maintain myocardial homeostasis. Although hypertrophy is an adaptive response to increased biomechanical stress, persistent hypertrophic stimulation forces the stressed myocardium into a progressive maladaptive process called ventricular remodeling, consisting of ventricular dilatation and dysfunction in conjunction with the development of myocyte hypertrophy, apoptosis, and fibrosis. The critical determinant of this pathological transition is not fully understood, but an energetic mismatch due to uncontrolled WS is thought to be a central mechanism. Despite extensive basic investigations conducted to understand the complex signaling pathways involved in this maladaptive process, clinical diagnostic studies that translat...
Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital ro... more Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell–matrix interactions, including thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, periostin, and fibulins. Fibulin family members consist of eight ECM glycoproteins characterized by a tandem array of calcium-binding epidermal growth factor-like modules and a common C-termi...
Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder presenting with hy... more Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder presenting with hypertrophic cardiomyopathy, Wolf-Parkinson-White syndrome, skeletal myopathy, and mild intellectual disability. Early morbidity and mortality due to heart failure or sudden death are known in Danon disease, more in males than in females. Here, we present a 17-year-old female adolescent with Danon disease and severe concentric hypertrophy with normal left ventricular (LV) systolic function, who has been complaining of intermittent headache and weakness for about 3 years, initially diagnosed with hemiplegic migraine. Subsequently, her neurological manifestation progressed to transient ischemic attack (TIA) and eventually to ischemic stroke confirmed by CT scan with 1-day history of expressive aphasia followed by persistent left side weakness and numbness. Detailed echocardiogram for the first time revealed a small LV apical thrombus with unchanged severe biventricular hypertrophy and normal...
Journal of Cardiovascular Development and Disease, 2017
Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomy... more Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic m...
For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and... more For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.
Journal of the American College of Cardiology, Jan 7, 2017
The American College of Cardiology Adult Congenital and Pediatric Cardiology (ACPC) Section had a... more The American College of Cardiology Adult Congenital and Pediatric Cardiology (ACPC) Section had attempted to create quality metrics (QM) for ambulatory pediatric practice, but limited evidence made the process difficult. The ACPC sought to develop QMs for ambulatory pediatric cardiology practice. Five areas of interest were identified, and QMs were developed in a 2-step review process. In the first step, an expert panel, using the modified RAND-UCLA methodology, rated each QM for feasibility and validity. The second step sought input from ACPC Section members; final approval was by a vote of the ACPC Council. Work groups proposed a total of 44 QMs. Thirty-one metrics passed the RAND process and, after the open comment period, the ACPC council approved 18 metrics. The project resulted in successful development of QMs in ambulatory pediatric cardiology for a range of ambulatory domains.
Background Transforming growth factor-β (TGF-β) is a multi-factorial peptide growth factor that h... more Background Transforming growth factor-β (TGF-β) is a multi-factorial peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and tissue repair. Quantification of biologically active TGF-β levels in tissues is crucial to illustrate mechanisms involved in various physiological and pathological processes, but direct measurement of bioactive TGF-β level in the tissue has been hampered by lack of reliable methods. Here, we introduced mink lung epithelial cell bioassay to quantify both active and total TGF-β levels in serum and protein lysates from solid organs in the mouse model. Findings Mink lung epithelial cells were stably transfected with plasminogen activator inhibitor-1 promoter/luciferase construct, in which bioactive TGF-β level was represented by luciferase activity. Serum total TGF-β levels were comparable between the bioassay and enzyme-linked immunosorbent assay (ELISA), but active TGF-β levels measured by ELISA were signi...
Atrial septal defect (ASD) is a common congenital heart disease diagnosed during childhood. Persi... more Atrial septal defect (ASD) is a common congenital heart disease diagnosed during childhood. Persistently increased pulmonary blood flow and dilated right atrium (RA) and right ventricle (RV) result in multiple symptoms and morbidities in adulthood; untreated adults may develop exercise intolerance, congestive heart failure, atrial tachyarrhythmias, pulmonary hypertension (PH), embolic stroke, or even death [1,2]. Asymptomatic children with ASD are commonly referred for elective ASD closure around 3 to 6 years of age [2,3].
Abnormalities of coronary artery, congenital or acquired, are rare in the pediatric population, b... more Abnormalities of coronary artery, congenital or acquired, are rare in the pediatric population, but they frequently present unexpectedly. They may result in life-threatening conditions if unrecognized; however, in infants and children, preclinical coronary abnormalities usually do not present with the typical clinical manifestations seen in adults with myocardial ischemia. Timely diagnosis of silent myocardial ischemia is frequently challenging in children. Myocardial infarction may occur in anomalous left coronary artery from pulmonary artery (ALCAPA), right ventricle-dependent coronary artery seen in pulmonary atresia with intact ventricular septum (PA/IVS), and coronary aneurysm complicated in Kawasaki disease. On the other hand, some coronary artery abnormalities tend to present with unexpected ventricular arrhythmia or sudden cardiac death (SCD). These include aberrant aortic origin of coronary artery (AAOCA) and acquired coronary stenosis after arterial switch operation (ASO) ...
Heart transplant remains an important treatment option for end-stage heart failure in children wh... more Heart transplant remains an important treatment option for end-stage heart failure in children who have failed maximum medical management. Although the outcome of heart transplant has significantly improved due to advances in perioperative management and immunosuppression, commonly, it is not a permanent solution. We still encounter multiple problems in managing these patients before and after transplant, not only with hemodynamic derangement, but also with functional deterioration of multiple organ systems. Shortage of donor hearts in association with wait-list mortality remains a major ongoing problem, especially for infants. Importantly, transplant for patients with congenital heart disease has unique challenges, including complexity of surgical reconstruction, coagulation abnormalities, allosensitization, and specific problems related to single ventricular palliation. Even after successful transplant, chronic complications emerge as inevitable challenges, including rejection, in...
Journal of Cardiovascular Development and Disease, 2021
Ventricular wall stress (WS) is an important hemodynamic parameter to represent myocardial oxygen... more Ventricular wall stress (WS) is an important hemodynamic parameter to represent myocardial oxygen demand and ventricular workload. The normalization of WS is regarded as a physiological feedback signal that regulates the rate and extent of ventricular hypertrophy to maintain myocardial homeostasis. Although hypertrophy is an adaptive response to increased biomechanical stress, persistent hypertrophic stimulation forces the stressed myocardium into a progressive maladaptive process called ventricular remodeling, consisting of ventricular dilatation and dysfunction in conjunction with the development of myocyte hypertrophy, apoptosis, and fibrosis. The critical determinant of this pathological transition is not fully understood, but an energetic mismatch due to uncontrolled WS is thought to be a central mechanism. Despite extensive basic investigations conducted to understand the complex signaling pathways involved in this maladaptive process, clinical diagnostic studies that translat...
Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital ro... more Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell–matrix interactions, including thrombospondins, SPARC (Secreted Protein Acidic and Rich in Cystein), tenascins, osteopontin, periostin, and fibulins. Fibulin family members consist of eight ECM glycoproteins characterized by a tandem array of calcium-binding epidermal growth factor-like modules and a common C-termi...
Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder presenting with hy... more Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder presenting with hypertrophic cardiomyopathy, Wolf-Parkinson-White syndrome, skeletal myopathy, and mild intellectual disability. Early morbidity and mortality due to heart failure or sudden death are known in Danon disease, more in males than in females. Here, we present a 17-year-old female adolescent with Danon disease and severe concentric hypertrophy with normal left ventricular (LV) systolic function, who has been complaining of intermittent headache and weakness for about 3 years, initially diagnosed with hemiplegic migraine. Subsequently, her neurological manifestation progressed to transient ischemic attack (TIA) and eventually to ischemic stroke confirmed by CT scan with 1-day history of expressive aphasia followed by persistent left side weakness and numbness. Detailed echocardiogram for the first time revealed a small LV apical thrombus with unchanged severe biventricular hypertrophy and normal...
Journal of Cardiovascular Development and Disease, 2017
Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomy... more Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic m...
For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and... more For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes.
Journal of the American College of Cardiology, Jan 7, 2017
The American College of Cardiology Adult Congenital and Pediatric Cardiology (ACPC) Section had a... more The American College of Cardiology Adult Congenital and Pediatric Cardiology (ACPC) Section had attempted to create quality metrics (QM) for ambulatory pediatric practice, but limited evidence made the process difficult. The ACPC sought to develop QMs for ambulatory pediatric cardiology practice. Five areas of interest were identified, and QMs were developed in a 2-step review process. In the first step, an expert panel, using the modified RAND-UCLA methodology, rated each QM for feasibility and validity. The second step sought input from ACPC Section members; final approval was by a vote of the ACPC Council. Work groups proposed a total of 44 QMs. Thirty-one metrics passed the RAND process and, after the open comment period, the ACPC council approved 18 metrics. The project resulted in successful development of QMs in ambulatory pediatric cardiology for a range of ambulatory domains.
Background Transforming growth factor-β (TGF-β) is a multi-factorial peptide growth factor that h... more Background Transforming growth factor-β (TGF-β) is a multi-factorial peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and tissue repair. Quantification of biologically active TGF-β levels in tissues is crucial to illustrate mechanisms involved in various physiological and pathological processes, but direct measurement of bioactive TGF-β level in the tissue has been hampered by lack of reliable methods. Here, we introduced mink lung epithelial cell bioassay to quantify both active and total TGF-β levels in serum and protein lysates from solid organs in the mouse model. Findings Mink lung epithelial cells were stably transfected with plasminogen activator inhibitor-1 promoter/luciferase construct, in which bioactive TGF-β level was represented by luciferase activity. Serum total TGF-β levels were comparable between the bioassay and enzyme-linked immunosorbent assay (ELISA), but active TGF-β levels measured by ELISA were signi...
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Papers by Takeshi Tsuda