Changing concepts of endocardial fibroelastosis.

Endocardial fibroelastosis is not a disease but a reaction of the endocardium. I review the history of the term with emphasis on the gradual understanding of the many causes of this reaction. I include a comprehensive list of diseases or other cardiac stresses that authors have reported in association, and I try to explain the mechanism of the reaction. Although endocardial fibroelastosis is rare today, I issue a warning of a possible epidemic recrudescence of some of the associated diseases. My hope is for nosologic purity, therefore that outworn but surviving concepts will be firmly rejected.

The perspective of ventricular noncompaction as seen by a nonagenarian.

The persistence of so-called spongy myocardium was first reported in humans in the 1960s. Subsequently, a few reports described the condition, utilizing inconsistent facts and terminology. In 1990 the first report appeared using the term "noncompaction", and detailed its clinical implications. Following this report, more descriptions of patients with noncompaction entered the literature. Prior to the availability of high resolution cross-sectional echocardiography, most cases of noncompacted myocardium escaped detection, as few patients underwent angiography. In this essay, I seek to adjudicate and clarify several confusions and controversies in the current literature including the acquired nature of hypertrabeculation, the fate of the so-called sinusoids, the relationship to coronary arteries, and noncompaction as another congenital malformation. The embryonic timing of cessation and reinitiation of compaction is conjectured as an explanation of the varied configurations of noncompaction as seen as a clinical entity. The clinical outcomes of decreased contractility, arrhythmia, and thromboembolism, have been stressed in the current literature, but more study is needed of the gray area between the normal variant and minimal noncompaction. A plea is made for the standardization of methods and terminology.

Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Current information on the epidemiology and outcomes of hypertrophic cardiomyopathy (HCM) in children is limited by disease diversity and small case series. METHODS AND RESULTS: The Pediatric Cardiomyopathy Registry has collected prospective and retrospective data on children diagnosed with HCM since 1990. We identified the various causes of HCM in childhood and determined the relationship between outcomes, cause, and age at presentation. Of 855 patients <18 years of age with HCM, 8.7% (n=74) had inborn errors of metabolism, 9.0% (n=77) had malformation syndromes, 7.5% (n=64) had neuromuscular disorders, and 74.2% (n=634) had idiopathic HCM. Children with HCM associated with inborn errors of metabolism and malformation syndromes have significantly worse survival than the other 2 groups. Patients with idiopathic HCM diagnosed before 1 year of age (n=227) had worse survival from the time of diagnosis than those diagnosed after 1 year of age (n=407). Patients with idiopathic HCM who survived to at least 1 year of age, however, had an annual mortality rate of 1% that was similar regardless of whether they were diagnosed before or after 1 year of age. CONCLUSIONS: In children, HCM is a diverse disorder with outcomes that depend largely on cause and age. Patients presenting before 1 year of age have the broadest spectrum of causes and the poorest outcome. In those children with idiopathic HCM who survive beyond age 1, however, survival is independent of age at diagnosis, with an annual mortality rate (1%) that is much lower than previously reported in children and is not different from has been found in population-based studies in adults.

Incidence, causes, and outcomes of dilated cardiomyopathy in children.

CONTEXT: Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and cause of cardiac transplantation in children. However, the epidemiology and clinical course of DCM in children are not well established. OBJECTIVE: To provide a detailed description of the incidence, causes, outcomes, and related risk factors for DCM in children. DESIGN AND SETTING: Longitudinal study based on a population-based, prospective cohort of children diagnosed as having DCM since January 1, 1996, at 89 pediatric cardiac centers and a retrospectively collected cohort of patients seen primarily at large tertiary care centers in North America and who had diagnoses between January 1, 1990, and December 31, 1995, and were enrolled through February 2003. PARTICIPANTS: A total of 1426 children from the United States and Canada diagnosed as having DCM at younger than 18 years. Primary DCM was determined by strict echocardiographic and/or pathologic criteria. Patients with disease due to endocrine, immunologic, drug toxicity, and other causes were excluded. MAIN OUTCOME MEASURES: Annual incidence per 100,000 children; mortality; cardiac transplantation. RESULTS: The annual incidence of DCM in children younger than 18 years was 0.57 cases per 100,000 per year overall. The annual incidence was higher in boys than in girls (0.66 vs 0.47 cases per 100,000; P<.001), in blacks than in whites (0.98 vs 0.46 cases per 100,000; P<.001), and in infants (<1 year) than in children (4.40 vs 0.34 cases per 100,000; P<.001). The majority of children (66%) had idiopathic disease. The most common known causes were myocarditis (46%) and neuromuscular disease (26%). The 1- and 5-year rates of death or transplantation were 31% and 46%, respectively. Independent risk factors at DCM diagnosis for subsequent death or transplantation were older age, congestive heart failure, lower left ventricular fractional shortening Z score, and cause of DCM (P<.001 for all). CONCLUSIONS: In children, DCM is a diverse disorder with outcomes that depend largely on cause, age, and heart failure status at presentation. Race, sex, and age affect the incidence of disease. Most children do not have a known cause of DCM, which limits the potential for disease-specific therapies.

Factors associated with establishing a causal diagnosis for children with cardiomyopathy.

OBJECTIVE: The goal was to identify the clinical variables associated with establishing a cause of cardiomyopathy in children. METHODS: The Pediatric Cardiomyopathy Registry contains clinical and causal testing information for 916 children who were diagnosed as having cardiomyopathy in North America between 1990 and 1995. Children with a causal diagnosis were compared with those without with respect to several demographic, clinical, and causal testing variables. RESULTS: Cardiomyopathy was 1 of 4 types, hypertrophic (34.2%), dilated (53.8%), restrictive (3.2%), or other or mixed (8.9%). Only one third of cases had a known cause. Children with a known cause for hypertrophic cardiomyopathy were more likely to be female, to be relatively smaller, to present with congestive heart failure, and to have increased left ventricular posterior wall thickness without outflow tract obstruction. For dilated cardiomyopathy, a known cause was associated with older age, lower heart rate, smaller left ventricular dimensions, and greater shortening fraction. Family history of cardiomyopathy predicted a significantly higher rate of causal diagnoses for all cardiomyopathy types, whereas family histories of genetic syndromes and sudden death were also predictive of a cause for hypertrophic and dilated cardiomyopathies. For hypertrophic cardiomyopathy, only blood and urine testing was associated with a causal diagnosis, whereas both viral serologic testing or culture and endomyocardial biopsy were independent predictors of a causal diagnosis in dilated cardiomyopathy. CONCLUSIONS: Certain patient characteristics, family history, echocardiographic findings, laboratory testing, and biopsy were associated significantly with establishing a cause of pediatric cardiomyopathy. Early endomyocardial biopsy should be considered strongly for children with dilated cardiomyopathy, for definitive diagnosis of viral myocarditis. Although not widely used, skeletal muscle biopsy may yield a cause for some patients with hypertrophic cardiomyopathy and for patients suspected of having a mitochondrial disorder.

Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and alpha-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and alpha-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in alpha-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit alpha-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation.

The incidence of pediatric cardiomyopathy in two regions of the United States.

BACKGROUND: Population-based data on the incidence of pediatric cardiomyopathy are rare because of the lack of large, prospective studies. METHODS: Since 1996 the Pediatric Cardiomyopathy Registry sponsored by the National Heart, Lung, and Blood Institute has collected data on all children with newly diagnosed cardiomyopathy in New England and the Central Southwest region (Texas, Oklahoma, and Arkansas) of the United States. We report on all children in these regions who received this diagnosis between 1996 and 1999. RESULTS: We identified 467 cases of cardiomyopathy, for an overall annual incidence of 1.13 per 100,000 children (95 percent confidence interval, 1.03 to 1.23). The incidence was significantly higher among infants younger than 1 year old than among children and adolescents who were 1 to 18 years old (8.34 vs. 0.70 per 100,000, P<0.001). The annual incidence of cardiomyopathy was lower among white children (upper-bound estimate, 1.06 cases per 100,000) than among black children (lower-bound estimate, 1.47 per 100,000; P=0.02) and higher among boys than among girls (1.32 vs. 0.92 per 100,000, P<0.001). The incidence also varied significantly by region: 1.44 cases per 100,000 in New England and 0.98 per 100,000 in the Central Southwest region (P<0.001). When categorized according to type, dilated cardiomyopathy made up 51 percent of the cases, hypertrophic cardiomyopathy 42 percent, and restrictive or other types 3 percent; 4 percent were unspecified. There was no significant difference in the incidence rates according to the year. CONCLUSIONS: The estimated incidence of pediatric cardiomyopathy in two large regions of the United States is 1.13 cases per 100,000 children. Most cases are identified at an early age, and the incidence varies according to sex, region, and racial or ethnic origin.