Background Dilated cardiomyopathy, characterized by ventricular dilatation and decreased systolic... more Background Dilated cardiomyopathy, characterized by ventricular dilatation and decreased systolic contraction, is twofold to threefold more common as a cause of heart failure than hypertrophic cardiomyopathy and costs several billion dollars annually. The idiopathic form occurring early in life, with a 75% mortality in 5 years, is a common reason for transplantation. It is estimated that at least 20% of cases are familial. Methods and Results A family of 46 members spanning four generations underwent history and physical examinations, echocardiographic analysis, and blood sampling for genotyping. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of ≥2.7 cm/m 2 with an ejection fraction ≤50% in the absence of other potential causes. DNA from all members was analyzed by polymerase chain reaction for amplification of short tandem-repeat polymorphic markers located every 10 cM throughout the human genome. Assuming a penetrance of 90%, linkage analysis was performed to map the responsible chromosomal locus. Linkage analysis, after 412 markers were analyzed, indicated the locus to be on chromosome 1q32, with a peak multipoint logarithm of the odds score at D1S414 of 6.37. Conclusions The locus identified in this study for familial dilated cardiomyopathy, 1q32, is rich in candidate genes, such as MEF-2, renin, and helix loop helix DNA binding protein MYF-4. Identification of the genetic defect could provide insight into the molecular basis for the cardiac dilatory response in both familial and acquired disorders.
Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of... more Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands ...
Background: Maximal interventricular septal wall thickness is a key measurement in patients with ... more Background: Maximal interventricular septal wall thickness is a key measurement in patients with HCM, influencing decision making for ICD placement. Frequent MRIs are often obtained due to perceived inaccuracy of wall thickness with echocardiographic measurements. As children generally have good acoustic windows, we hypothesize that that in children there will be strong correlation between echocardiogram and MRI assessment of myocardial thickness and left ventricular dimensions. Methods: Using a cohort from the Pediatric Cardiomyopathy Biomarkers Study, protocolized echocardiograms and MRIs from 55 children (median age 13.8 yr, range 1-20 yr) were analyzed in a core lab for left ventricular end-diastolic (LVEDV) and end-systolic dimensions (LVESV), LV mass, and maximal interventricular septal wall thickness. Studies were obtained on average within 4 days of each other. Results: 51/55 pairs of echocardiograms and MRIs were analyzed for LVEDV and LVESV. No strong correlation was seen ...
Background: Children with dilated cardiomyopathy (DCM) are at high risk for morbidity and death. ... more Background: Children with dilated cardiomyopathy (DCM) are at high risk for morbidity and death. There are no validated serum biomarkers associated with clinical events. Objective: To evaluate cardiac biomarkers as predictors of clinical endpoints (heart failure, death, or transplant listing, heart transplant). Design / Methods: Patients (<21 years of age at DCM diagnosis) were enrolled at 15 North American pediatric cardiomyopathy centers within one year of diagnosis with collection of serum, echocardiograms and clinical data at enrollment and at intervals for up to 2 years. The main hypothesis was that heart failure, myocyte injury, and inflammatory biomarkers are associated with the primary study endpoint (heart failure, death, or transplant listing, or heart transplant) <90 days of enrollment. Results: Data from 74 subjects were analyzed, median age 2.1 years at enrollment [interquartile range (IQR 0.7-12.8)], 44 (55%) female, and 61 (76%) enrolled within 90 days of diagno...
Background: MRI can assess left ventricular (LV) hypertrophy and LV fibrosis as indicated by late... more Background: MRI can assess left ventricular (LV) hypertrophy and LV fibrosis as indicated by late gadolinium enhancement (LGE). LGE ≥15% of LV mass has been proposed as a threshold for prophylactic...
Introduction: Pediatric cardiomyopathy (CM) is a genetically heterogeneous high-risk condition, w... more Introduction: Pediatric cardiomyopathy (CM) is a genetically heterogeneous high-risk condition, with a large proportion of cases labeled as idiopathic. Hypothesis: A comprehensive sequencing approa...
BACKGROUND Understanding the overall variant burden in pediatric patients with left ventricular n... more BACKGROUND Understanding the overall variant burden in pediatric patients with left ventricular noncompaction (LVNC) has clinical implications. Whole exome sequencing (WES) allows detection of coding variants in both candidate cardiomyopathy genes and those included on commercial panels. Other lines of evidence, including in silico analysis, are necessary to reduce the overwhelming number of variants to those most likely having a phenotypic impact. METHODS Five families, including five pediatric probands with LVNC, 5 other affected, and 10 unaffected family members, had WES performed, followed by bioinformatics filtering and Sanger sequencing. Review of the HGMD, variant classification by ACMG guidelines, and clinical information were used to further refine complex genotypes. RESULTS One nonsense and eleven missense variants were identified. In Family 1, affected siblings carried digenic heterozygous variants: E1350K-MYH7 and A276V-ANKRD1. The proband also carried heterozygous W143X-NRG1. Four affected members of Family 2 carried K184Q-MYH7 while unaffected members did not. In Family 3, homozygous A161T-MYH7 and heterozygous P4935T-OBSCN variants were identified in the proband with the latter being absent in his unaffected brother. In Family 4, proband's father and half-sibling have mild hypertrabeculation and carry T3796I-PLEC. The proband, carrying T3796I-PLEC and V2878A-OBSCN, demonstrated higher trabeculation burden. The proband in Family 5 carried four variants, R3247W-PLEC, C92Y-ERG, T1233M-NCOR2, and E54K-HIST1H4B. Application of ACMG criteria and clinical data revealed that W143X-NRG1, P4935T-OBSCN, and V2878A-OBSCN likely have no phenotypic role. CONCLUSIONS We report nine variants, including novel T3796I-PLEC and biallelic A161T-MYH7, likely contributing to phenotypes ranging from asymptomatic hypertrabeculation to severe LVNC with heart failure.
BackgroundLimited data exist regarding left ventricular remodeling patterns observed in adult sur... more BackgroundLimited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy.MethodsAmong 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8‐14.4 years]; age at evaluation, 35.6 years [IQR, 29.5‐42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed.ResultsOverall, 28.2% of survivors (95% confidence interval [CI], 25.6%‐30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%‐3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%‐1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only ch...
Background: Genetic mutations in the LDB3-encoding the Z-band alternatively spliced PDZ motif-con... more Background: Genetic mutations in the LDB3-encoding the Z-band alternatively spliced PDZ motif-containing protein (ZASP) cause cardiomyopathy associated with arrhythmias and sudden cardiac death (SCD), although the underlying mechanism remains unclear. We have previously identified the common SNP rs34423165 (p.K251R in NM_001080115.1; p.K204R in NM_001080114.1) in a patient with significant family history of QT-prolongation and SCD associated with dilated cardiomyopathy (DCM). We hypothesized that rs34423165 may affect cardiac repolarization and specifically the delayed rectifier K+ channel. Methods and Results: The proband is an 18-year old female presenting with QT-prolongation (QTc = 510 ms) associated with mild LV dilatation. Three of six first relatives were affected, and two of them (father and uncle) died suddenly. The effects of ZASP4-K251R on the delayed rectifier K+ currents were studied using whole-cell mode of patch-clamp techniques. CHO cells expressing Kv7.1 and KCNE1 (IKs), Kv11.1 and KCNE2 ...
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 1996
Viral infections, particularly those caused by cytomegalovirus, are a major cause of postoperativ... more Viral infections, particularly those caused by cytomegalovirus, are a major cause of postoperative morbidity and mortality in heart transplant recipients. These infections have classically been diagnosed by history, physical examination, peripheral viral cultures, and serologic studies. These methods are often time-consuming and lack sensitivity. Positive viral cultures from the heart are rarely obtained, and viral myocarditis and acute cellular rejection are unable to be differentiated histologically. We have therefore used the polymerse chain reaction to diagnose possible viral infection in pediatric heart transplant recipients with findings consistent with acute unexplained rejection. Polymerase chain reaction was used as an aid to diagnose cytomegalovirus infection of cardiac tissue obtained by right ventricular endomyocardial biopsy and follow its long-term course. In addition, polymerase chain reaction was used to diagnose infection of the heart by other viruses in patients wi...
Sudden cardiac death is a significant problem in the United States, with an incidence reported to... more Sudden cardiac death is a significant problem in the United States, with an incidence reported to be greater than 300,000 persons per year (1). Interest in identifying the underlying cause of the death has been focused on cases of unexpected arrhythmogenic death, which is estimated to represent 5% of all sudden deaths (2). In cases in which no structural heart disease can be identified, the long QT syndrome and ventricular preexcitation are most commonly considered as likely causes. Recently, Brugada syndrome (also known by some investigators as idiopathic ventricular fibrillation, IVF), a disease associated with an electrocardiographic (ECG) abnormality of right bundle branch block with ST- elevation in the right precordial leads (V1–V3), has been added to the list of possible causes of sudden death in otherwise healthy, young individuals. The purpose of this chapter is to describe the clinical disorder and the genetics of this disease.
In 1992 a syndrome consisting of syncope episodes and/or sudden death in patients with a structur... more In 1992 a syndrome consisting of syncope episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram (ECG) displaying a pattern resembling right bundle branch block with ST segment elevation in leads V1 to V3 was described. The disease is genetically determined with an autosomal dominant pattern of transmission in 50% of the familial cases. Several different mutations have been identified affecting the structure and the function of the sodium channel gene SCN5A. These mutations result in loss of function of the sodium channel. The syndrome appears ubiquitous. The incidence of the disease is difficult to estimate worldwide, but it may cause 4 to 10 sudden deaths per 10,000 inhabitants per year in areas like Thailand and Laos. In these countries, the disease represents the most frequent cause of natural death in young adults. It is estimated that 20 to 50% of sudden deaths in patients with a normal heart result from this syndrome. The disease has been linked to the sudden infant death syndrome and to the sudden unexpected death syndrome by showing that the electrocardiogram and mutations are the same as in Brugada syndrome. The diagnosis is easily made by means of the ECG when it is typical. There exist, however, patients with concealed and intermittent electrocardiographic forms that make the diagnosis difficult. The ECG can be modulated by changes in autonomic balance, body temperature, glucose level, and the administration of drugs like antiarrhythmics, but also neuroleptic and antimalaria drugs.
Background Dilated cardiomyopathy, characterized by ventricular dilatation and decreased systolic... more Background Dilated cardiomyopathy, characterized by ventricular dilatation and decreased systolic contraction, is twofold to threefold more common as a cause of heart failure than hypertrophic cardiomyopathy and costs several billion dollars annually. The idiopathic form occurring early in life, with a 75% mortality in 5 years, is a common reason for transplantation. It is estimated that at least 20% of cases are familial. Methods and Results A family of 46 members spanning four generations underwent history and physical examinations, echocardiographic analysis, and blood sampling for genotyping. Diagnostic criteria, detected by echocardiography, consisted of ventricular dimension of ≥2.7 cm/m 2 with an ejection fraction ≤50% in the absence of other potential causes. DNA from all members was analyzed by polymerase chain reaction for amplification of short tandem-repeat polymorphic markers located every 10 cM throughout the human genome. Assuming a penetrance of 90%, linkage analysis was performed to map the responsible chromosomal locus. Linkage analysis, after 412 markers were analyzed, indicated the locus to be on chromosome 1q32, with a peak multipoint logarithm of the odds score at D1S414 of 6.37. Conclusions The locus identified in this study for familial dilated cardiomyopathy, 1q32, is rich in candidate genes, such as MEF-2, renin, and helix loop helix DNA binding protein MYF-4. Identification of the genetic defect could provide insight into the molecular basis for the cardiac dilatory response in both familial and acquired disorders.
Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of... more Introduction: Pediatric cardiomyopathies are genetically heterogeneous diseases with high risk of death or cardiac transplant. Despite progress in identifying causes, the majority of cases remain idiopathic. Currrently, genetic testing is not performed in all children with cardiomyopathy. Gene identification leads to better individual risk stratification and has the potential to stimulate the development of therapies based on the underlying mutation. The aim of this study is to identify genetic mutations in pediatric cardiomyopathy patients using whole exome sequencing. Hypothesis: Sarcomeric mutations are under-diagnosed causes of all forms of cardiomyopathy in children. Methods: Probands with cardiomyopathy were recruited from 11 institutions. Results of clinical genetic testing prior to enrollment were collected. Whole exome sequencing was performed and mutations were identified in 35 genes currently available on clinical genetic testing panels. Results: The initial 154 probands ...
Background: Maximal interventricular septal wall thickness is a key measurement in patients with ... more Background: Maximal interventricular septal wall thickness is a key measurement in patients with HCM, influencing decision making for ICD placement. Frequent MRIs are often obtained due to perceived inaccuracy of wall thickness with echocardiographic measurements. As children generally have good acoustic windows, we hypothesize that that in children there will be strong correlation between echocardiogram and MRI assessment of myocardial thickness and left ventricular dimensions. Methods: Using a cohort from the Pediatric Cardiomyopathy Biomarkers Study, protocolized echocardiograms and MRIs from 55 children (median age 13.8 yr, range 1-20 yr) were analyzed in a core lab for left ventricular end-diastolic (LVEDV) and end-systolic dimensions (LVESV), LV mass, and maximal interventricular septal wall thickness. Studies were obtained on average within 4 days of each other. Results: 51/55 pairs of echocardiograms and MRIs were analyzed for LVEDV and LVESV. No strong correlation was seen ...
Background: Children with dilated cardiomyopathy (DCM) are at high risk for morbidity and death. ... more Background: Children with dilated cardiomyopathy (DCM) are at high risk for morbidity and death. There are no validated serum biomarkers associated with clinical events. Objective: To evaluate cardiac biomarkers as predictors of clinical endpoints (heart failure, death, or transplant listing, heart transplant). Design / Methods: Patients (<21 years of age at DCM diagnosis) were enrolled at 15 North American pediatric cardiomyopathy centers within one year of diagnosis with collection of serum, echocardiograms and clinical data at enrollment and at intervals for up to 2 years. The main hypothesis was that heart failure, myocyte injury, and inflammatory biomarkers are associated with the primary study endpoint (heart failure, death, or transplant listing, or heart transplant) <90 days of enrollment. Results: Data from 74 subjects were analyzed, median age 2.1 years at enrollment [interquartile range (IQR 0.7-12.8)], 44 (55%) female, and 61 (76%) enrolled within 90 days of diagno...
Background: MRI can assess left ventricular (LV) hypertrophy and LV fibrosis as indicated by late... more Background: MRI can assess left ventricular (LV) hypertrophy and LV fibrosis as indicated by late gadolinium enhancement (LGE). LGE ≥15% of LV mass has been proposed as a threshold for prophylactic...
Introduction: Pediatric cardiomyopathy (CM) is a genetically heterogeneous high-risk condition, w... more Introduction: Pediatric cardiomyopathy (CM) is a genetically heterogeneous high-risk condition, with a large proportion of cases labeled as idiopathic. Hypothesis: A comprehensive sequencing approa...
BACKGROUND Understanding the overall variant burden in pediatric patients with left ventricular n... more BACKGROUND Understanding the overall variant burden in pediatric patients with left ventricular noncompaction (LVNC) has clinical implications. Whole exome sequencing (WES) allows detection of coding variants in both candidate cardiomyopathy genes and those included on commercial panels. Other lines of evidence, including in silico analysis, are necessary to reduce the overwhelming number of variants to those most likely having a phenotypic impact. METHODS Five families, including five pediatric probands with LVNC, 5 other affected, and 10 unaffected family members, had WES performed, followed by bioinformatics filtering and Sanger sequencing. Review of the HGMD, variant classification by ACMG guidelines, and clinical information were used to further refine complex genotypes. RESULTS One nonsense and eleven missense variants were identified. In Family 1, affected siblings carried digenic heterozygous variants: E1350K-MYH7 and A276V-ANKRD1. The proband also carried heterozygous W143X-NRG1. Four affected members of Family 2 carried K184Q-MYH7 while unaffected members did not. In Family 3, homozygous A161T-MYH7 and heterozygous P4935T-OBSCN variants were identified in the proband with the latter being absent in his unaffected brother. In Family 4, proband's father and half-sibling have mild hypertrabeculation and carry T3796I-PLEC. The proband, carrying T3796I-PLEC and V2878A-OBSCN, demonstrated higher trabeculation burden. The proband in Family 5 carried four variants, R3247W-PLEC, C92Y-ERG, T1233M-NCOR2, and E54K-HIST1H4B. Application of ACMG criteria and clinical data revealed that W143X-NRG1, P4935T-OBSCN, and V2878A-OBSCN likely have no phenotypic role. CONCLUSIONS We report nine variants, including novel T3796I-PLEC and biallelic A161T-MYH7, likely contributing to phenotypes ranging from asymptomatic hypertrabeculation to severe LVNC with heart failure.
BackgroundLimited data exist regarding left ventricular remodeling patterns observed in adult sur... more BackgroundLimited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy.MethodsAmong 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8‐14.4 years]; age at evaluation, 35.6 years [IQR, 29.5‐42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed.ResultsOverall, 28.2% of survivors (95% confidence interval [CI], 25.6%‐30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%‐3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%‐1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only ch...
Background: Genetic mutations in the LDB3-encoding the Z-band alternatively spliced PDZ motif-con... more Background: Genetic mutations in the LDB3-encoding the Z-band alternatively spliced PDZ motif-containing protein (ZASP) cause cardiomyopathy associated with arrhythmias and sudden cardiac death (SCD), although the underlying mechanism remains unclear. We have previously identified the common SNP rs34423165 (p.K251R in NM_001080115.1; p.K204R in NM_001080114.1) in a patient with significant family history of QT-prolongation and SCD associated with dilated cardiomyopathy (DCM). We hypothesized that rs34423165 may affect cardiac repolarization and specifically the delayed rectifier K+ channel. Methods and Results: The proband is an 18-year old female presenting with QT-prolongation (QTc = 510 ms) associated with mild LV dilatation. Three of six first relatives were affected, and two of them (father and uncle) died suddenly. The effects of ZASP4-K251R on the delayed rectifier K+ currents were studied using whole-cell mode of patch-clamp techniques. CHO cells expressing Kv7.1 and KCNE1 (IKs), Kv11.1 and KCNE2 ...
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 1996
Viral infections, particularly those caused by cytomegalovirus, are a major cause of postoperativ... more Viral infections, particularly those caused by cytomegalovirus, are a major cause of postoperative morbidity and mortality in heart transplant recipients. These infections have classically been diagnosed by history, physical examination, peripheral viral cultures, and serologic studies. These methods are often time-consuming and lack sensitivity. Positive viral cultures from the heart are rarely obtained, and viral myocarditis and acute cellular rejection are unable to be differentiated histologically. We have therefore used the polymerse chain reaction to diagnose possible viral infection in pediatric heart transplant recipients with findings consistent with acute unexplained rejection. Polymerase chain reaction was used as an aid to diagnose cytomegalovirus infection of cardiac tissue obtained by right ventricular endomyocardial biopsy and follow its long-term course. In addition, polymerase chain reaction was used to diagnose infection of the heart by other viruses in patients wi...
Sudden cardiac death is a significant problem in the United States, with an incidence reported to... more Sudden cardiac death is a significant problem in the United States, with an incidence reported to be greater than 300,000 persons per year (1). Interest in identifying the underlying cause of the death has been focused on cases of unexpected arrhythmogenic death, which is estimated to represent 5% of all sudden deaths (2). In cases in which no structural heart disease can be identified, the long QT syndrome and ventricular preexcitation are most commonly considered as likely causes. Recently, Brugada syndrome (also known by some investigators as idiopathic ventricular fibrillation, IVF), a disease associated with an electrocardiographic (ECG) abnormality of right bundle branch block with ST- elevation in the right precordial leads (V1–V3), has been added to the list of possible causes of sudden death in otherwise healthy, young individuals. The purpose of this chapter is to describe the clinical disorder and the genetics of this disease.
In 1992 a syndrome consisting of syncope episodes and/or sudden death in patients with a structur... more In 1992 a syndrome consisting of syncope episodes and/or sudden death in patients with a structurally normal heart and a characteristic electrocardiogram (ECG) displaying a pattern resembling right bundle branch block with ST segment elevation in leads V1 to V3 was described. The disease is genetically determined with an autosomal dominant pattern of transmission in 50% of the familial cases. Several different mutations have been identified affecting the structure and the function of the sodium channel gene SCN5A. These mutations result in loss of function of the sodium channel. The syndrome appears ubiquitous. The incidence of the disease is difficult to estimate worldwide, but it may cause 4 to 10 sudden deaths per 10,000 inhabitants per year in areas like Thailand and Laos. In these countries, the disease represents the most frequent cause of natural death in young adults. It is estimated that 20 to 50% of sudden deaths in patients with a normal heart result from this syndrome. The disease has been linked to the sudden infant death syndrome and to the sudden unexpected death syndrome by showing that the electrocardiogram and mutations are the same as in Brugada syndrome. The diagnosis is easily made by means of the ECG when it is typical. There exist, however, patients with concealed and intermittent electrocardiographic forms that make the diagnosis difficult. The ECG can be modulated by changes in autonomic balance, body temperature, glucose level, and the administration of drugs like antiarrhythmics, but also neuroleptic and antimalaria drugs.
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Papers by Jeffrey Towbin