We sought to analyze the prevalence, clinical course, and risk profile of left ventricular systolic dysfunction in adolescents with idiopathic dilated cardiomyopathy. Patients with clinical onset at <13 years (n = 18) or >19 years (n = 14) of age and/or patients followed up for <12 months were excluded. Clinical and biochemical markers were evaluated during 4 ± 3 years of follow-up to determinate predictors of adverse outcome. A composite end point (hospitalization for worsening heart failure, cardiac transplantation, and death) was investigated. The final cohort consisted of 48 patients (median age 17 years) with idiopathic dilated cardiomyopathy. During follow-up, 11 patients required hospitalization for heart failure (21%) and 6 patients entered the transplantation list (4 underwent orthotopic cardiac transplantation, 8%). A Cox multivariate model evidenced N-terminus pro–brain natriuretic peptide (NT–pro-BNP; odds ratio 1, confidence interval 1 to 1.1, p = 0.001), New York Heart Association (NYHA) classes III to IV (odds ratio 2.5, confidence interval 1 to 5.9, p = 0.04), and electrocardiographic atrial enlargement (odd ratios 6.7, confidence interval 1.8 to 25, p = 0.005) as predictors of adverse events (composite end point) at 60 months. The association of NYHA classes III to IV, electrocardiographic atrial enlargement, and NT–pro-BNP value ≥250 pg/ml (are under the curve 0.88) showed 100% sensitivity, 77% specificity, 62% positive predictive value, and 100% negative predictive value. In conclusion, compared to other clinical, echocardiographic, and biochemical parameters, the combination of advanced NYHA class, electrocardiographic atrial enlargement, and NT–pro-BNP ≥250 pg/ml seem to better predict the risk of adverse events in adolescent with long-term systolic dysfunction.
Prevalence and clinical course of progressive left ventricular (LV) dysfunction leading to heart failure have been widely described in children and adults. To date, relatively little information on LV dysfunction developing during adolescence has been reported. In this study, we sought to analyze the risk profile and clinical course of adolescents referred to our cardiomyopathy and heart failure clinic for management of heart failure secondary to idiopathic dilated cardiomyopathy (IDC).
Methods
One hundred sixteen patients were referred to the pediatric heart failure clinic, division of pediatric cardiology, at Monaldi Hospital from January 2001 to February 2007. Overall, 84 (72%) showed LV systolic dysfunction (ejection fraction [EF] ≤45%). Patients with clinical onset of LV systolic dysfunction at <13 years (n = 18) or >19 years (n = 14) of age and/or patients followed up for <12 months were excluded from the study. IDC was defined as an LVEF ≤45% with LV end-diastolic dimension ≥2 SD for an age–body surface area matched population. The diagnosis of myocarditis was suspected (“presumed myocarditis”) according to contemporary presence of a suggestive clinical history (flulike symptoms and/or acute heart failure signs 1 week to 3 weeks before hospital admission); positive inflammatory serologic indexes, such as white blood cell count, C-reactive protein, and/or erythrocyte sedimentation rate; cardiac enzymes such as serum creatine kinase, creatine kinase-MB, and/or cardiac isoform of troponin I; and blood polymerase chain reaction positive for common pathogens. The diagnosis was confirmed by endomyocardial biopsy in 2 patients (“definite myocarditis”). All patients underwent coronary angiography, which excluded an ischemic or congenital cause of the disease. Since 2001, patients referred to the pediatric heart failure clinic, Monaldi Hospital, participated in the same clinical investigation protocol, approved by the ethical committee of our institution, after written informed consent (obtained from the patients or their parent or guardian).
At the time of enrollment and during follow-up, all patients underwent a comprehensive cardiovascular evaluation, including an exhaustive clinical history (family history of sudden death, cardiomyopathy or neuromuscular and inherited disorders, drug abuse), clinical examination, blood collection for biochemical analysis, electrocardiography, echocardiography with color Doppler and tissue Doppler study, 6-minute walking test, cardiopulmonary stress test, 24-hour Holter monitoring with heart rate variability, and analysis of ventricular late potentials. At the time of the first examination, blood samples were collected by venepuncture at rest and placed in tubes containing ethylenediaminetetra-acetic acid. Plasma samples were analyzed for N-terminus pro–brain natriuretic peptide (NT–pro-BNP) and high-sensitivity C-reactive protein using an electrochemiluminescence immunoassay (pro-BNP kit, Roche Diagnostics, Mannheim, Germany) on an Elecsys 2010 analyzer and an IMMAGE automatic immunoassay system (Beckman-Coulter, Brea, California), respectively. Echocardiograms were recorded the same day as the clinical examination to determine New York Heart Association (NYHA) classification. Images were recorded and analyzed off-line by a single investigator, blinded to the clinical status of patients. Three different measurements were repeated for each parameter, and the average was calculated. Two-dimensional measurements were LV end-systolic and end-diastolic internal dimensions, end-diastolic and end-systolic LV volumes, LVEF (percentage), calculated by modified Simpson method, aortic dimension, end-diastolic right ventricular dimension, LV shortening fraction, and maximal wall thickness (as the greatest thickness among the interventricular septum, inferior wall, and lateral wall at different levels). Right ventricular systolic pressure was calculated by tricuspidal regurgitation with continuous-wave Doppler study using the Bernoulli equation. Mitral inflow was analyzed for peak E- and A-wave velocities, acceleration and deceleration times of E-wave velocity, and isovolumetric contraction and relaxation times. Systolic (Sa) and diastolic (Ea and Aa) tissue Doppler (TD) velocities were measured at the mitral lateral, septal, and tricuspid lateral walls in accordance with previously published reports. To study right ventricular function we measured excursions of the tricuspid annular plane by positioning the M-mode cursor on the lateral portion of the tricuspid annulus; this movement reflects the base-to-apex shortening of the right ventricle during systole. A cutoff of ≤14 was considered decreased right ventricular function. LV hypertrophy on electrocardiogram at rest was defined according to criteria of Romhilt and Estes; signs of atrial enlargement, atrioventricular and intraventricular conduction disturbances, q-wave anomalies, and repolarization abnormalities were defined using standard criteria. Analysis of ventricular late potentials was performed by a signal-averaged electrocardiographic technique (Electrocardiographic System Mac 5000, Marquette, Milwaukee, Wisconsin) by the same operator. Heart rate variability by frequency domain analysis allowed identification of 2 major peaks, a low-frequency component (milliseconds) and a high-frequency peak centered on the respiratory frequency (milliseconds), and their ratio. A 6-minute walking distance test was performed to estimate functional exercise capacity. We measured the total distance walked, including fatigue and dyspnea, measured with a modified Borg scale; and heart rate and arterial oxygen saturation by pulse oximetry, as long as feasible. Exercise testing was performed on a cycle ergometer in an upright position (Sensormedics Ergometrics 800 S, Bithoven, the Netherlands) using a ramp protocol of 25 W/min. Cardiovascular response was evaluated by analyzing maximal oxygen uptake, defined as the highest oxygen uptake achieved during exercise. Ventilatory response to exercise was evaluated by analyzing minute ventilation expressed as an absolute value, and ventilatory equivalents for carbon dioxide, measured by plotting ventilatory equivalents against carbon dioxide (abnormal >30).
To assess clinical and echocardiographic changes during follow-up, patients followed at our institution underwent serial cardiovascular evaluations. The following events were evaluated: (1) sudden cardiac death (defined as witnessed sudden death with or without documented ventricular fibrillation, death within 1 hour of new symptoms, or nocturnal death with no previous worsening symptoms); (2) death from congestive cardiac failure (death preceded by progressive signs and symptoms of heart failure or cardiogenic shock); (3) orthotopic cardiac transplantation; (4) hospitalization for worsening of heart failure or new listing for cardiac transplantation; (5) other cardiovascular complications (stroke, thromboembolism); and (6) device implantation (cardioverter defibrillator, permanent pacemaker; implantable recorder) or invasive procedures for significant arrhythmias/syncope. A composite end point (including cardiovascular death, transplantation, and hospitalization for worsening heart failure) was assessed. When risk of adverse events was determined, patients in whom >1 adverse event occurred were treated as though they had only 1 event.
The authors had full access to the data and take full responsibility for the data’s integrity. All authors read the report and agree with its content. SPSS 11.0 (SPSS, Inc., Chicago, Illinois) was used for all analyses. Data are expressed as mean ± SD for normally distributed variables or median (interquartile range) for nonparametric variables. Categorical data are expressed as percentages. Student’s t test or 1-way analysis of variance was used to compare means of continuous variables, and chi-square test was used for comparison of categorical data. Nonparametric data were assessed using the Mann-Whitney U or Kruskal-Wallis test, as appropriate. Correlations were assessed using Pearson correlation coefficient for normally distributed variables and Spearman correlation coefficient for nonparametric data. The relation between significant variables was investigated using a multivariate linear or logistic regression model, whereby clinical variables were selected stepwise to decrease the model to only statistically significant parameters. For survival analysis, start of follow-up was defined as the first cardiovascular evaluation at the pediatric heart failure clinic, Monaldi Hospital. Cox proportional hazards regression was used to determine clinical, biochemical, and echocardiographic predictors of adverse events (composite end point). Sensitivity, specificity, and positive and negative predictive values of significant predictors of adverse cardiac events were measured. Receiver operating characteristic curves were generated to determine the accuracy and optimal threshold of significant variables predicting future adverse cardiovascular events. We compared areas under the receiver operating characteristic curves using the Hanley-McNeil method. To control for the small number of subjects and multiple comparisons, only a p value <0.01 was considered statistically significant. All p values were 2-sided.
Results
The final cohort consisted of 48 patients (41% of overall cohort, 57% of patients with LV systolic dysfunction) who had been diagnosed with LV systolic dysfunction (EF ≤45%) secondary to IDC. Table 1 lists clinical characteristics of the study population. Mean age at the time of cardiovascular evaluation was 17.3 ± 3.5 years (median 17.5, range 13 to 28) and 0.5 ± 0.8 years after symptom onset (median 16.3). Pedigree analysis revealed familial disease in 15 subjects (31%), belonging to 9 different families. Six patients (12.5%) had a family history for sudden cardiac death. Twenty-seven patients were in NYHA class I, 12 patients in NYHA class II, 6 patients in NYHA classes II to III, 2 patients in NYHA class III, and 1 patient in NYHA class IV. Plasma NT–pro-BNP levels were 24 to 2,115 pg/ml (median 167), and plasma high-sensitivity C-reactive protein levels were 0.1 to 5.8 pg/ml (median 1.7). Thirty-five patients had an abnormal standard electrocardiogram (73%). Left atrial enlargement was found in 10 patients (21%). A short PR interval was evident in 3 patients (6%), a first-degree atrioventricular block in 5 patients (10%), and left bundle branch block in 11 patients (23%). Signs of LV hypertrophy were found in 11 patients (23%), q-wave anomalies in 4 patients (8%), ST abnormalities in 12 patients (25%), and T abnormalities in 13 patients (27%). A prolonged QTc interval was found in 6 patients (12.5%). Ventricular late potentials were present in 16 patients (33%). Mean value of low-frequency/high-frequency ratio was 3 ± 2.7 (median 1.9). On 24-hour Holter electrocardiogram, nonsustained ventricular tachycardias were found in 13 patients (27%). Echocardiographic data are presented in Table 1 . The left ventricle was dilated in 40 patients (83%). Segmental wall motion abnormalities were observed in 30 patients (62%). Severe LV dysfunction (EF ≤35%) was revealed in 20 patients (41%). The right ventricle was dilated in 10 patients (21%), and longitudinal right ventricular function was decreased in 4 patients (8%). An abnormal mitral flow pattern was seen in 39 patients (81%), including a pseudo-normal pattern in 10 (21%) and a restrictive pattern in 5 (10%). Septal E/Ea was <8 in 26 patients (54%), 8 to 15 in 16 patients (33%), and >15 in 6 patients (12.5%). Lateral E/Ea was <8 in 36 patients (75%), 8 to 15 in 10 patients (21%), and >15 in 2 patients (4%).
| Median age at diagnosis (years) | 17 (13–19) |
| Median age at study evaluation (years) | 17.5 (13–28) |
| Gender (men) | 35 (73%) |
| Clinical and echocardiographic data | |
| Signs or symptoms of heart failure | 29 (60%) |
| Median NT–pro-BNP value (pg/ml) | 167 (105–2,115) |
| Abnormal electrocardiogram | 35 (73%) |
| Median left ventricular ejection fraction (%) | 38 (30–48) |
| Median left ventricular end-diastolic diameter (mm) | 63 (58–81) |
| Moderate or severe mitral regurgitation | 14 (29%) |
| Median lateral E/Ea | 6.3 (5.3–23.2) |
| Median medial E/Ea | 7.4 (4.7–31.2) |
| Median 6-minute walking distance (m) | 390 (328–520) |
| Median maximal oxygen uptake (ml/kg/min) | 17 (13.3–23.4) |
| Median minute ventilation/carbon dioxide elimination | 25 (22–38) |
| Ventricular arrhythmias | 13 (27%) |
| Medications | |
| Angiotensin-converting enzyme inhibitor | 39 (81%) |
| β blocker | 38 (79%) |
| Loop diuretic | 27 (56%) |
| Digoxin | 23 (48%) |
| Amiodarone | 7 (14%) |
| Follow-up | |
| Implantable cardioverter–defibrillator | 3 (6%) |
| Cardiac resynchronization therapy | 4 (8%) |
| Cardiac hospitalization | 10 (21%) |
| Thromboembolism | 2 (4%) |
| Sudden death | 0 (0%) |
| Transplantation | 4 (8%) |
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