Susan W. Denfield

Clinical Characterization of Left Ventricular Noncompaction in Children A Relatively Common Form of Cardiomyopathy

Background—Left ventricular noncompaction (LVNC) is a reportedly uncommon genetic disorder of endocardial morphogenesis with a reportedly high mortality rate. The purpose of this study was to identify the clinical characteristics of children with LVNC. Methods and Results—We retrospectively reviewed 36 children with LVNC evaluated at Texas Children’s Hospital (TCH) from January 1997 to December 2002. Five children had associated cardiac lesions. There were 16 girls and 20 boys. The median age at presentation was 90 days (range, 1 day to 17 years). The median duration of follow-up was 3.2 years (range, 0.5 to 12 years). Twenty-seven patients (75%) had ECG abnormalities, most commonly biventricular hypertrophy (10 patients, 28%). Both ventricles were involved in 8 patients (22%) and only the left ventricle in 28 patients (78%). Left ventricular systolic function was depressed in 30 patients (83%), with a median ejection fraction of 30% (range, 15% to 66%) at diagnosis. Nine patients presenting in the first year of life with depressed left ventricular contractility had a transient recovery of function; however, ejection fraction deteriorated later in life, at a median interval of 6.3years (range, 3 to 12 years). Two patients had an “undulating” phenotype from dilated to hypertrophic cardiomyopathy. Two patients (6%) were identified with an underlying G4.5 gene mutation. Five patients (14%) died during the study. Conclusions—LVNC does not have an invariably fatal course when diagnosed in the neonatal period. A significant number of patients have transient recovery of function followed by later deterioration, which may account for many patients presenting as adults, some manifesting an “undulating” phenotype.

Characterization of Left Ventricular Diastolic Function by Tissue Doppler Imaging and Clinical Status in Children With Hypertrophic Cardiomyopathy

Background—Conventional transmitral Doppler indices are unreliable in assessing clinical status in patients with hypertrophic cardiomyopathy (HCM) because they are affected by loading conditions. This study sought to determine whether tissue Doppler velocities are predictive of adverse clinical outcomes including death, cardiac arrest, ventricular tachycardia (VT), significant cardiac symptoms, and exercise capacity in children with HCM. Methods and Results—We studied 80 consecutive children (median age 12 years, median follow-up 26 months) evaluated at 1 hospital from January 1999 to August 2003 compared with 80 age- and gender-matched controls. Patients underwent echocardiography, ambulatory Holter monitoring, and upright exercise testing. Children with HCM had significantly decreased early diastolic tissue Doppler velocities at the lateral mitral (13.2 versus 19.3 cm/s), tricuspid (13.3 versus 16.3 cm/s), and septal (9.4 versus 13.5 cm/s) annuli compared with controls (P <0.001 for each comparison). By forward stepwise regression analysis, early transmitral left ventricular filling velocity (E)/septal Ea ratio predicted death, cardiac arrest, or VT (r =0.610, R2 =0.37, P <0.001). Peak oxygen consumption (&OV0312;O2) was most predictive of children who developed symptoms (r =0.427, R2 =0.182, P <0.001). Peak &OV0312;O2 correlated inversely with E/Ea septal ratio (r =−0.740, P <0.01). Conclusions—Transmitral E/septal Ea ratio predicts children with HCM who are at risk of adverse clinical outcomes including death, cardiac arrest, VT, and significant cardiac symptoms. Peak &OV0312;O2 correlated with peak exercise capacity in HCM patients.

Association of Parvovirus B19 Genome in Children With Myocarditis and Cardiac Allograft Rejection Diagnosis Using the Polymerase Chain Reaction

BACKGROUND Inflammatory diseases of the heart, including myocarditis and cardiac transplant rejection, are important causes of morbidity and mortality in children. Although viral infection may be suspected in either of these clinical conditions, the definitive etiology is often difficult to ascertain. Furthermore, the histology is identical for both disorders. Coxsackievirus has long been considered the most common cause of viral myocarditis; however, we previously demonstrated by polymerase chain reaction (PCR) analysis that many different, and sometimes unexpected, viruses may be responsible for myocarditis and cardiac rejection. In this study, we describe the association of parvovirus genome identified through PCR analysis of cardiac tissue in the clinical setting of myocarditis and cardiac allograft rejection. METHODS AND RESULTS Myocardial tissue from endomyocardial biopsy, explant, or autopsy was analyzed for parvovirus B19 using primers designed to amplify a 699-base pair PCR product from the VP1 gene region. Samples tested included those obtained from patients with suspected myocarditis (n=360) or transplant rejection (n=200) or control subjects (n=250). Parvoviral genome was identified through PCR in 9 patients (3 myocarditis; 6 transplant) and no control patients. Of the 3 patients with myocarditis, 1 presented with cardiac arrest leading to death, 1 developed dilated cardiomyopathy, and the other gradually improved. Four of the 6 transplant patients had evidence of significant rejection on the basis of endomyocardial biopsy histology. All transplant patients survived the infection. CONCLUSIONS Parvovirus is associated with myocarditis in a small percentage of children and may be a potential contributor to cardiac transplant rejection. PCR may provide a rapid and sensitive method of diagnosis.

B-Type Natriuretic Peptide Predicts Adverse Cardiovascular Events in Pediatric Outpatients With Chronic Left Ventricular Systolic Dysfunction

Background— Plasma B-type natriuretic peptide (BNP) levels are elevated in adults with heart failure and correlate with functional classification and prognosis. The range and predictive power of BNP concentrations in children with chronic heart failure, however, are not known. Methods and Results— Whole blood BNP concentrations were measured in 53 consecutive patients with chronic left ventricular (LV) systolic dysfunction (biventricular hearts, ejection fraction <50%, >3 months since diagnosis). Children who had been hospitalized within 3 months before potential enrollment and those <2 months or >21 years of age were excluded. BNP concentrations were measured with the Triage assay (Biosite Diagnostics, Inc, San Diego, Calif). Echocardiographers and clinicians were blinded to BNP levels. An adverse cardiovascular event was defined as cardiac death, cardiac-related hospitalization, or listing for cardiac transplantation. The median age of patients with LV dysfunction was 9.3 years (interquartile range [IQR], 2.7 to 15.1 years). BNP levels were elevated in children with LV dysfunction compared with healthy controls (median, 78 pg/mL [IQR, 22 to 551 pg/mL] versus median, 7 pg/mL [IQR, 5 to 11 pg/mL]; P<0.0001). Whole blood BNP concentrations were increased in patients who had a 90-day adverse cardiovascular event compared with those who did not (median, 735 pg/mL [IQR, 685 to 1510 pg/mL] versus median, 37 pg/mL [IQR, 14 to 92 pg/mL]; P<0.001). Patients with a BNP concentration ≥300 pg/mL were at increased risk of death, hospitalization, or listing for cardiac transplantation (adjusted hazard ratio, 63.6; P<0.0001). Conclusions— BNP concentrations are elevated in children with chronic LV systolic dysfunction and predict the 90-day composite end point of death, hospitalization, or listing for cardiac transplantation.

Sudden Death and Cardiovascular Collapse in Children With Restrictive Cardiomyopathy

BACKGROUND Restrictive cardiomyopathy (RCM) is rare in children, and the prognosis is poor. In the present study, we evaluated all pediatric patients with RCM who were at our institution during a 31-year period to determine the clinical outcome and cause of death. Those who sustained sudden, unanticipated cardiac arrests were evaluated for risk factors that are predictive of sudden death. METHODS AND RESULTS Eighteen consecutive patients were reviewed. Presentation, clinical course, laboratory data, and histopathological evidence of ischemia were compared between patients with and without sudden death events. The results demonstrated that patients who were at risk for sudden death were girls with chest pain, syncope, or both at presentation and without congestive heart failure. Although not statistically significant for sudden death, Holter monitor evidence of ischemia predicted death within months. Histopathological evidence of acute or chronic ischemia was found in the majority of patients, with acute ischemia more common among those who sustained sudden death events. CONCLUSIONS All children with RCM are at risk for ischemia-related complications and death, and some are at risk of sudden death. In the present study, patients at risk of sudden death appeared well and had no evidence of ongoing heart failure but often had signs or symptoms of ischemia characterized by chest pain, syncope, or both. ECGs and Holter monitors may be useful screening tools. The use of beta-blockade, the placement of an implantable cardioverter-defibrillator, and preferential status 1A or B listing for cardiac transplantation are proposed for pediatric patients with RCM and evidence of ongoing ischemia.

Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children

Background—Some patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy also present with skeletal myopathy and Wolff-Parkinson-White (WPW) syndrome; mutations in the gene encoding the lysosome-associated protein-2 (LAMP-2) have been identified in these patients, suggesting that some of these patients have Danon disease. In this study we investigated the frequency of LAMP2 mutations in an unselected pediatric HCM population. Methods and Results—LAMP2 was amplified from genomic DNA isolated from peripheral lymphocytes of 50 patients diagnosed with HCM and analyzed by direct DNA sequencing. In 2 of the 50 probands (4%), nonsense mutations were identified. In 1 family the proband initially presented with HCM as a teenager, which progressed to dilated cardiomyopathy (DCM) and heart failure. Skeletal myopathy and WPW were also noted. The teenage sister of the proband is a carrier of the same LAMP2 mutation and has HCM without skeletal myopathy or WPW. The other proband presented with HCM, WPW, and skeletal myopathy as a teenager, whereas his carrier mother developed DCM during her 40s. Skeletal and cardiac muscle sections revealed the absence of LAMP-2 on immunohistochemical staining. Conclusions—LAMP2 mutations may account for a significant proportion of cases of HCM in children, especially when skeletal myopathy and/or WPW is present, suggesting that Danon disease is an underrecognized entity in the pediatric cardiology community.

Echocardiographic predictors of adverse clinical events in children with dilated cardiomyopathy: a prospective clinical study

Objectives: To compare tissue Doppler (TD) velocities between patients with dilated cardiomyopathy (DCM) and normal controls and to determine whether TD velocities, Tei index, right ventricular fractional area change, and left ventricular ejection fraction (LVEF) predict adverse clinical outcomes in children with DCM. Methods: Prospective evaluation of children with DCM. Results: 54 children with DCM and 54 age and sex matched control group participants were studied. Mitral inflow velocities were similar for both groups except for decreased mitral deceleration time in patients with DCM. Systolic and diastolic TD velocities at the mitral annulus (septal and lateral sides) and tricuspid annulus were significantly reduced in children with DCM compared with controls (p < 0.001 for each). By multivariate analysis, after adjustment for Tei index and right ventricular fractional area change, decreased LVEF and tricuspid velocity during early diastole (Ea) were predictors of the primary end point (PEP), a composite end point consisting of need for hospitalisation or the outcome transplantation or death. Tricuspid Ea velocity < 8.5 cm/s had 87% specificity and 60% sensitivity for reaching the PEP. LVEF < 30% had 68% specificity and 74% sensitivity for the PEP. Combined LVEF < 30% and tricuspid Ea < 11.5 cm/s had 100% specificity and 44% sensitivity for the PEP. Conclusions: Children with DCM have significantly lower TD velocities than normal controls. In such cases, lower LVEF (< 30%) is more sensitive but less specific than lower tricuspid Ea velocities (< 8.5 cm/s) in predicting which patients are at risk of hospitalisation, transplantation, or death.

Mortality and Sudden Death in Pediatric Left Ventricular Noncompaction in a Tertiary Referral Center

Background— Left ventricular noncompaction is a cardiomyopathy characterized by excessive trabeculation of the left ventricle, progressive myocardial dysfunction, and early mortality. Left ventricular noncompaction has a heterogeneous clinical presentation that includes arrhythmia and sudden cardiac death. Methods and Results— We retrospectively reviewed all children diagnosed with left ventricular noncompaction at Texas Children’s Hospital from January 1990 to January 2009. Patients with congenital cardiac lesions were excluded. Two hundred forty-two children were diagnosed with isolated left ventricular noncompaction over the study period. Thirty-one (12.8%) died, and 13 (5.4%) were received a transplant. One hundred fifty (62%) presented with or developed cardiac dysfunction. The presence of cardiac dysfunction was strongly associated with mortality (hazard ratio, 11; P<0.001). ECG abnormalities were present in 87%, with ventricular hypertrophy and repolarization abnormalities occurring most commonly. Repolarization abnormalities were associated with increased mortality (hazard ratio, 2.1; P=0.02). Eighty children (33.1%) had an arrhythmia, and those with arrhythmias had increased mortality (hazard ratio, 2.8; P=0.002). Forty-two (17.4%) had ventricular tachycardia, with 5 presenting with resuscitated sudden cardiac death. In total, there were 15 cases of sudden cardiac death in the cohort (6.2%). Nearly all patients with sudden death (14 of 15) had abnormal cardiac dimensions or cardiac dysfunction. No patient with normal cardiac dimensions and function without preceding arrhythmias died. Conclusions— Left ventricular noncompaction has a high mortality rate and is strongly associated with arrhythmias in children. Preceding cardiac dysfunction or ventricular arrhythmias are associated with increased mortality. Children with normal cardiac dimensions and normal function are at low risk for sudden death.

Worsening renal function in children hospitalized with decompensated heart failure: Evidence for a pediatric cardiorenal syndrome?*

Objectives: The purpose of this study was to determine the incidence of renal insufficiency in children hospitalized with acute decompensated heart failure and whether worsening renal function is associated with adverse cardiovascular outcome. Design: Prospective observational cohort study. Setting: Single-center childrens hospital. Patients: All pediatric patients from birth to age 21 yrs admitted to our institution with acute decompensated heart failure from October 2003 to October 2005. Interventions: None. Measurements and Main Results: Acute decompensated heart failure was defined as new-onset or acute exacerbation of heart failure signs or symptoms requiring hospitalization and inpatient treatment. We required that heart failure be attributable to ventricular dysfunction only. Worsening renal function was defined as an increase in serum creatinine by ≥0.3 mg/dL during hospitalization. Sixty-three patients (35 male, 28 female) comprised 73 patient hospitalizations. Median age at admission was 10 yrs (range 0.1–20.3 yrs). Median serum creatinine at admission was 0.6 mg/dL (range 0.2–3.5 mg/dL), and median creatinine clearance was 103 mL/min/1.73 m2 (range 22–431 mL/min/1.73 m2). Serum creatinine increased during 60 of 73 (82%) patient hospitalizations (median increase 0.2 mg/dL, range 0.1–2.7 mg/dL), and worsening renal function occurred in 35 of 73 (48%) patient hospitalizations. Clinical variables associated with worsening renal function included admission serum creatinine (p = .009) and blood urea nitrogen (p = .04) and, during hospitalization, continuous infusions of dopamine (p = .028) or nesiritide (p = .007). Worsening renal function was independently associated with the combined end point of in-hospital death or need for mechanical circulatory support (adjusted odds ratio 10.2; 95% confidence interval 1.7–61.2, p = .011). Worsening renal function was also associated with longer observed length of stay (33 ± 30 days vs. 18 ± 25 days, p < .03). Conclusions: These data suggest that an important cardiorenal interaction occurs in children hospitalized for acute decompensated heart failure. Renal function commonly worsens in such patients and is associated with prolonged hospitalization and in-hospital death or the need for mechanical circulatory assistance.

New Mutations in the KVLQT1 Potassium Channel That Cause Long-QT Syndrome

BACKGROUND Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQT2), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A). METHODS AND RESULTS After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. CONCLUSIONS We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of-function mechanism or a dominant-negative mechanism.