Electrocardiographic and Clinical Characteristics of Idiopathic Restrictive Cardiomyopathy in Children

Transcription

1 Circ J 2007; 71: Electrocardiographic and Clinical Characteristics of Idiopathic Restrictive Cardiomyopathy in Children Tamaki Hayashi, MD; Etsuko Tsuda, MD; Kenichi Kurosaki, MD; Hatsue Ueda, MD*; Osamu Yamada, MD; Shigeyuki Echigo, MD Background Idiopathic restrictive cardiomyopathy (RCM) is not a single disease and is rare. Methods and Results The clinical features and clinical course of 12 pediatric patients with RCM seen between 1978 and 2005 were retrospectively analyzed. The age at diagnosis ranged from 4 months to 12 years (median 4 years). The age of 7 patients diagnosed because of an abnormal electrocardiogram (ECG) ranged from 4 to 12 years. Three infants less than 2 years old presented with cardiomegaly. Obliquely elevated ST-T segments and the late peak T waves on 12-lead ECG were present in 8 patients (67%). Three patients with ST depression during exercise had no perfusion defects on radioisotope myocardial perfusion imaging. Two patients underwent orthotopic heart transplantation. Of the remaining 10 patients, 7 have died: 4 died suddenly and 3 died of right heart failure. Three patients with a hypertrophic left ventricular wall had a prolonged survival. The probability of survival at 1, 2 and 3 years was 78%, 52% and 26%, respectively. Conclusions Obliquely elevated ST-T segments and the late peak T wave on ECG are characteristic, and reflect the restrictive physiology, which may indicate abnormalities of repolarization of ventricular muscle. The mode of death was either heart failure from pulmonary hypertension or sudden death from presumed ventricular arrhythmia. (Circ J 2007; 71: ) Key Words: Orthotopic heart transplantation; Prolonged QT ST-T abnormalities; Restrictive cardiomyopathy Idiopathic restrictive cardiomyopathy (RCM) in children is rare and its prognosis is poor. 1 3 RCM is not a single disease and its etiology is unknown in most cases. 4 Because of its rarity, there is little information about RCM in children in the literature, and not much is known about its clinical course and outcome in this age group. We therefore reviewed the clinical features, clinical course and outcome of the cases treated at the National Cardiovascular Center. Methods From 1977 to patients with RCM were referred (8 males, 5 females). Their age at diagnosis ranged from 4 months to 12 years (median 4 years) (Table 1). The 13 th patient, who had Noonan syndrome, was lost to follow-up after 4 years, and was excluded from the study. The 3 rd patient s mother had RCM. The 7 th patient had a history of Rendu-Osler-Weber disease in her father and grandfather. RCM was diagnosed by cardiac catheterization. The characteristic hemodynamic feature of RCM is an elevated filling pressure in the left ventricle (LV) associated with normal or nearly normal systolic function. 4 The restrictive physiology is attributed to reduced diastolic ventricular compliance. In this study RCM with hypertrophied LV wall (LVH) was termed restrictive hypertrophied cardiomyopathy, not hypertrophic cardiomyopathy, because of the (Received August 8, 2006; revised manuscript received June 18, 2007; accepted June 26, 2007) Department of Pediatrics, Nara Medical University, Kashihara, *Department of Pathology, National Cardiovascular Center, Suita, Japan Mailing address: Tamaki Hayashi, MD, Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara , Japan. thayashi@naramed-u.ac.jp remarkable restrictive physiology. All 12 patients underwent chest X-ray, 12-lead electrocardiogram (ECG), 2-dimensional echocardiography (2DE) and radioisotope perfusion myocardial imaging at rest. Two patients underwent dipyridamole-loaded myocardial perfusion imaging and 1 had exercise myocardial perfusion imaging. Seven patients performed A Masters-double step test and treadmill test, and 24-h Holter ECG data were obtained for 8 patients. All 12 patients underwent cardiac catheterization, including coronary angiography (CAG), and 3 had repeat cardiac catheterization. Intracardiac pressures were measured and the cardiac index and pulmonary resistance were calculated. Right and left ventricular enddiastolic volumes (RVEDV and LVEDV) were measured by ventriculography, and were expressed as % of normal by body surface area. The right and left ventricular ejection fractions (RVEF and LVEF) were also measured. Endomyocardial biopsies were taken from the right ventricle (RV) of 10 patients. Brain natriuretic peptide (BNP) was measured in 8 patients. The probability of survival time was analyzed by Kaplan-Meier method (survival time is the interval from diagnosis to death). Results Age and Presentation at Diagnosis The presenting features of RCM were as follows: abnormalities of ECG, 7; cardiac murmur, 2; and cardiomegaly, 3. The age of the patients presenting because of an abnormality on ECG ranged from 4 to 12 years (Table 1). Although the presence of an abnormality on ECG was identified before the age of 6 years in the 11 th and 12 th patients, cardiomyopathy was not diagnosed at that time. The 2 patients who were referred because a cardiac murmur was detected were

2 Character of Restrictive Cardiomyopathy of Children 1535 Table 1 Age and Presentation at Diagnosis, and Prognosis Patient no. Age at diagnosis Age at death Survival time Presentation at diagnosis (years) (years) (years) Prognosis LVH Cardiomegaly 2 1 Death (HF) Cardiomegaly 1 Alive 3 1 Cardiomegaly Death (SD) 4 3 Cardiac murmur 5 2 Death after OHT 5 4 Cardiac murmur Death (HF) Abnormalities of ECG 7 2 Death (SD) 7 6 Abnormalities of ECG 8 2 Death (SD) 8 6 Abnormalities of ECG 9 3 Death (SD) 9 8 Abnormalities of ECG 12 3 Death (HF) 10 7 Abnormalities of ECG 3 Alive Abnormalities of ECG 5 Alive after OHT Abnormalities of ECG 4 Alive + LVH, left ventricular hypertrophy; HF, heart failure; SD, sudden death; OHT, orthotopic heart transplantation; ECG, electrocardiogram. Fig 1. (A C) Characteristic ECGs in restrictive cardiomyopathy (patients 2, 4 and 10). Prominent tall and biphasic P waves in the precordial chest leads are seen, with obliquely elevated ST-T segments and notched or biphasic T waves in the precordial leads. The peak of the T waves is late. each 4 years old. Three infants less than 2 years of age presented with cardiomegaly and symptomatic heart failure. Gallop rhythm was detected by auscultation and 2 of the 3 had hepatomegaly. One of the 3 had had been diagnosed as having asthma, because of the cough caused by pulmonary congestion. Chest X-Ray A double shadow because of enlargement of both the left atrium and the pulmonary artery trunk was observed in all 12 patients. The cardiothoracic ratio varied: <50%, 1 patient; 50% and <60%, 8 patients; 60%, 3 patients. Resting ECG All 12 patients had abnormal resting ECGs. Prominent, tall P waves were present in 11, as were biphasic P waves in the precordial chest leads (Fig 1). The criteria for biventricular hypertrophy based on QRS voltage were achieved in 7 patients. All patients had narrow QRS complexes; 10 had ST-T segment abnormalities (Table 2). Obliquely elevated ST-T segments and notched or biphasic T waves in the precordial leads were found in 8 patients (67%), and the peak

3 1536 HAYASHI T et al. Table 2 Abnormalities of the 12-Lead ECG Patient no. QTc (ms) QRS (ms) Pattern of Obliquely elevated Biphasic or hypertrophy ST-T segment notched T wave BVH BVH BVH BVH BVH BVH BVH + + BVH, biventricular hypertrophy. Other abbreviation see in Table 1. Fig 2. (A) Resting 12-lead ECG at the time of diagnosis (patient 11). The QRS voltage indicates biventricular hypertrophy, although the width of the QRS complexes is narrow. (B) 12-lead ECG after Mastersdouble step test (patient 11) shows depression of the ST segments.

4 Character of Restrictive Cardiomyopathy of Children 1537 Table 3 Two-Dimensional Echocardiography Findings Patient no. Bi-atrial LVDd LVEF Mitral flow LV wall thickness enlargement (% of normal) (%) E/A IVS/PW (mm) TR/MR /3 TR sl /7.4 MR sl /6 TR sl /7.3 TR sl, MR sl / NA NA TR sl / NA 3/ / /6 TR sl, MR sl /7 TR sl /13 TR sl, MR sl LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; E/A, E/A velocity ratio; LV, left ventricle; IVS, interventricular septum; PW, posterior wall; TR, tricuspid valve regurgitation; MR, mitral valve regurgitation; sl, slight; NA, not available. Table 4 Hemodynamic Data Patient no. Age (years) Pressure data (mmhg) End-diastolic Mean RV LV PA PC RA CI PVR RVEDV RVEF LVEDV LVEF (L min 1 m 2 ) (U/m 2 )(% of normal) (%) (% of normal) (%) RV, right ventricle; PA, pulmonary artery; PC, pulmonary capillary; RA, right atrium; CI, cardiac index; PVR, pulmonary vascular resistance; RVEDV, right ventricular end-diastolic volume; RVEF, right ventricular ejection fraction; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction. Other abbreviation see in Table 3. of the T waves was late (Figs1A C). The corrected QT interval was prolonged in 8 patients. Three patients followed for more than 3 years had persistent ST-T segment changes. The 11 th patient with moderate LVH had no ST-T segment abnormalities at diagnosis (Fig 2A), but developed ST-T segment depression 4 years later. Although the abnormalities of the ST-T segments resemble the strain pattern of hypertrophic cardiomyopathy, the QRS duration was normal. The ST-T segment depression in the 9 th patient progressed with progression of the right heart failure and pulmonary hypertension. In the 5 th patient, a short run of paroxysmal atrial contractions occurred 1 year after onset of RCM and 14 years later she developed atrial flutter and atrial fibrillation. 24-h Holter ECG, Masters Double-Step Test and Treadmill Test Eight patients underwent 24-h Holter ECG monitoring and 3 had paroxysmal atrial contractions; 1 patient (case no. 5) developed atrial flutter, atrial fibrillation and dysfunction of the sinus node 14 years after the onset. Although 7 patients had ST-T depression during exercise, they had no symptoms of ischemia (Fig 2B). 2DE 2DE revealed bi-atrial enlargement in all 12 patients (Table 3). Left ventricular dimensions ranged from 72% to 135% of normal. The LVEF ranged from 48% to 79%. Moderate LVH was found in the 5 th, 11 th and 12 th patients at diagnosis. The value of the E/A of mitral flow ranged from 1.3 to 3.6. At the time of diagnosis, mitral and tricuspid regurgitation was slight or none in all patients. A large pericardial effusion developed in 2 patients with heart failure during their late course (patients 5, 9), 3 and 15 years after the onset, respectively. The 5 th patient had had a massive pericardial effusion for the past 5 years. The first patient with heart failure had progression of tricuspid regurgitation and ascites in the late follow-up period. Cardiac Catheterization The pressure measurements obtained during cardiac catheterization are shown in Table 4. The mean pulmonary artery pressure ranged from 17 to 49mmHg (median 25mmHg) at diagnosis. The LV ventricular end-diastolic pressure ranged

5 1538 HAYASHI T et al. Radioisotope Myocardial Perfusion Imaging Of the 12 patients 11 did not have perfusion defects on myocardial perfusion imaging at rest. The 12 th patient had a perfusion defect at the apex. Of the 3 patients with ST-T depression during exercise, 2 underwent dipyridamole loaded myocardial perfusion imaging and 1 had exercise myocardial perfusion imaging and none had a perfusion defect. BNP BNP was measured in 8 patients at the time of diagnosis, and was >200 pg/ml in all. BNP increased in 7 patients with progression of cardiomegaly or pulmonary hypertension during follow-up. Medications Diuretics were administered to 11 patients, and aspirin to 1 and warfarin to 2 patients as thrombolytic therapy. Other drugs used included angiotensin-converting enzyme inhibitors for 7; angiotensin II receptor blocker and -blocker for 1 patient each; digoxin for 2, and calcium-channel blocker for 3 patients. Fig 3. Fibrosis of the interstitial tissue in a representative endomyocardium biopsy. (A) Thickening of the endocardium ( 40; Masson trichrome); (B) severe interstitial fibrosis ( 40; Masson trichrome). from 16 to 32 mmhg (median 24 mmhg), and that of the RV from 4 to 27 mmhg (median 11 mmhg). The cardiac index varied from 1.8 to 4.3 L min 1 m 2 (median 2.8L min 1 m 2 ), and pulmonary artery resistance from 1.4 to 12 U/m 2 (median 3.7 U/m 2 ). The RVEDV ranged from 72% to 113% of normal (median 85% of normal), and the RVEF was 39 70% (median 57%). The LVEDV ranged from 51% to 103% of normal (median 86% of normal), and the LVEF was 42 73% (median 61%). CAG was normal in all 12 patients. LV ventricular end-diastolic pressure was increased in all of the 3 patients who underwenta repeat cardiac catheterization. Endomyocardial Histology Fibrosis of the interstitial tissue was present in all 10 biopsy samples and hypertrophy of the myocytes was seen in 8. Structural disarray of varying degrees was found in 5 of the 8 patients with hypertrophy of the endomyocardial myocardium (patients 1, 6, 10, 11, 12). Thickening of the endocardium was present in the 4 th and 12 th patients (Fig3). Prognosis Two patients, aged 4 and 16 years, underwent orthotopic heart transplantation outside Japan. One, patient no. 11, is alive, but the other (patient no. 4) died of acute rejection. Among the remaining 10 patients, 7 have died (Table1). Of the 7 deaths, 6 occurred within 4 years of onset; notably, 2 infants died within 2 years of diagnosis. The probability of survival at 1, 2 and 3 years was 78%, 52% and 26%, respectively. The survival time in patients 5, 11 and 12 with moderate LVH was 19 years, 5 years and 4 years, respectively, and was prolonged compared with the remaining patients without LVH (Table 1). Four of the 7 deaths were sudden: patient no. 3 experienced premonitory symptoms, including pallor and abdominal pain, and died 4 days later; patient no. 6 had had several episodes of chest pain and complained of general malaise and chest pain the day before his death he died suddenly while walking at school; patient no. 8 had had syncope at school 3 years after onset of RCM symptoms and was taken to school by car, but 8 months later, he died suddenly during sleep; his parents had been worried about his pallor for the few days before his death. Three patients died of right heart failure: 1 had massive ascites because of right heart failure with severe tricuspid regurgitation; patient no. 5 had had a massive pericardial effusion with ascites and edema of the lower extremities with a history of cerebral infarction because of atrial fibrillation at the age of 11 years; patient no. 9 has worsening of right heart failure had worsened with rapid progression of pulmonary hypertension. Discussion One of the characteristic ECG abnormalities of RCM is tall, biphasic P waves, indicating bilateral atrial enlargement. 5 In the present series, another common feature was narrow QRS complexes with ST-T segment abnormalities that differed from the strain pattern seen in patients with LVH and enlargement. Although the voltage of the QRS waves in RCM is often high, they are narrow. The T wave is often notched or biphasic, 6 which was also true in our series. Furthermore, most of the ST segments are obliquely elevated and the peak of the T wave is late. These abnormali-

6 Character of Restrictive Cardiomyopathy of Children ties of the ST-T segments on 12-lead ECG are characteristic for RCM, and these typical ST-T segments are especially suspicious for RCM without LVH. Importantly, these abnormalities may result in a prolonged QT interval. The characteristic ST-T segments in idiopathic RCM reflect the restrictive diastolic function and repolarization abnormalities of the ventricular muscle. In the present patients with RCM, death was either sudden or caused by right heart failure; 2 died suddenly during daily activities. A previous report has described ventricular fibrillation inducing torsades de pointes in patients with idiopathic RCM, 7 and, based on the presence of ST-T depression, those authors suggested a relationship between sudden death and acute myocardial infarction in this condition. However, we suspect that sudden death does not necessarily relate to ischemia. In our series, 3 patients had significant ST depression in all leads, except lead I, induced by a Masters-double step test. CAG revealed normal coronary arteries and no perfusion defects were present on either exercise-loaded or dipyridamole-loaded myocardial perfusion imaging. The ST depression in these patients with abnormal ST-T segments at rest is not necessarily related to myocardial ischemia. It is also an ECG characteristic of patients with RCM. We speculate that sudden death in RCM patients is caused by ventricular arrhythmias induced by repolarization abnormalities of the ventricular muscle. In the endomyocardial biopsy specimens from the right ventricle, there was interstitial fibrosis in all 10 patients and it was the only common finding in RCM. The degree of hypertrophy of the myocardium varied, as in previously reported. 8,9 Disarray of the myocardial tissue was found in half of those with hypertrophy of the myocardium. The histological features reflect the fact that there is no single etiology of RCM and the pathologic process is not specific. In our series, 3 patients had hypertrophy of the LV wall and some patients with a hypertrophic ventricular wall and RCM have been previously reported. 1,8 10 In the recent American Heart Association classification, RCM indicates restrictive nonhypertrophied cardiomyopathy, 11 but we believe that there is a second type of RCM in children, namely, restrictive hypertrophied cardiomyopathy. Our 3 patients with restrictive hypertrophied cardiomyopathy had a prolonged survival compared with the patients without LVH (Table 1). Our patients showed 3 presentations. First, cardiomegaly with symptomatic heart failure in infancy; second, cardiac murmur in young children; and third, abnormalities of the ECG detected in school-aged children. RCM is a progressive disease over several years and, especially in infants with cardiomegaly, the clinical course is often rapid. 2 In pediatric RCM, the younger the patient is at the time of disease onset, the shorter the survival time. In the absence of effective treatment to improve the prognosis of children with RCM, orthotopic heart transplantation is currently recommended Determining its timing is difficult, because idiopathic RCM is not a single disease and the clinical course varies. Sudden death can occur in stable patients without severe heart failure. BNP is elevated in the stable condition, and worsens with right heart failure, because of progression of pulmonary hypertension. The progression of the clinical course must be observed carefully, 1539 especially progression of pulmonary hypertension. 12,15 In contrast with adults with RCM, frequent atrial arrhythmias were not detected, except in patient no. 5 who had a long survival. The potential problem of fatal arrhythmia in RCM requires further investigation. Conclusion High-voltage narrow QRS complexes with obliquely elevated ST-T segments and late peak T waves on 12-lead ECG typify suspected RCM. These abnormalities of the ST- T segments and T waves are important findings that indicate abnormal ventricular muscle and may relate to sudden death in these patients. Acknowledgment We thank Professor Peter Olley for his assistance with the language. References 1. Cetta F, O Learry PW, Seward JB, Driscoll DJ. Idiopathic restrictive cardiomyopathy in childhood: Diagnostic features and clinical course. Mayo Clin Proc 1995; 70: Chen S, Balfour IC, Jureidini S. Clinical spectrum of restrictive cardiomyopathy in children. J Heart Lung Transplant 2001; 20: Kushiwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med 1997; 336: Benotti JR, Grossman W, Cohn PF. Clinical profile of restrictive cardiomyopathy. Circulation 1980; 61: Lewis AB. 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