Early detection of subclinical anthracycline cardiotoxicity on the basis of QT dispersion.

BACKGROUND: We examined whether dobutamine-stress QT dispersion (QTd) and heart-rate corrected QT dispersion (QTcd) are useful for detecting subclinical anthracycline cardiotoxicity. METHODS: The subjects were 10 control subjects and 37 patients divided into 4 groups according to cumulative anthracycline dose: non-anthracycline group (group N), 7 patients; low anthracycline cumulative dose group (group L), 8 patients (< 200 mg/m²); medium anthracycline cumulative dose group (group M), 16 patients (200 to < 400 mg/m²); and high cumulative group (group H), 6 patients (≥ 400 mg/m²). Standard 12-lead electrocardiograms were recorded. QTd and QTcd were measured and calculated at rest and after administration of dobutamine at 5 or 30 µg/kg/min. We also estimated cardiac function and cardiac reserve function at rest and after administration of dobutamine at a dose of 5 or 30 µg/kg/min. RESULTS: At rest, QTd and QTcd were significantly greater in groups M and H. After administration of dobutamine at 30 µg/kg/min, QTd and QTcd were significantly greater in groups L, M, and H. There was good correlation between QTd and the cumulative anthracycline dose; the correlation formula was y=0.051 x + 42.2 (r = 0.81, p < 0.001). The cumulative anthracycline dose of 152.9 mg/m², calculated from the correlation formula, was the cut-off for detection of electrophysiological cardiac abnormalities. Cardiac performance data at rest and dobutamine stress by echocardiography and pulsed Doppler echocardiography are less sensitive for detecting cardiac abnormalities than are QTd and QTcd. CONCLUSIONS: Dobutamine-stress QTd and QTcd are useful for detecting anthracycline cardiotoxicity and subclinical cardiac abnormality at low cumulative anthracycline doses. We must be aware of the possibility of subclinical myocardial abnormalities in patients with a cumulative anthracycline dose of ≥ 150 mg/m².

Possible synergic effect of angiotensin-I converting enzyme gene insertion/deletion polymorphism and angiotensin-II type-1 receptor 1166A/C gene polymorphism on ischemic heart disease in patients with Kawasaki disease.

ACE I/D and AT1R 1166A/C polymorphisms are considered to comprise individual risk factors for the development of coronary disease. We sought to demonstrate that the ACE I/D and AT1R 1166A/C polymorphisms affect coronary artery stenosis in patients with Kawasaki disease (KD). We examined 147 healthy controls and 281 Japanese children with KD. The patients were further divided into group N (n = 246, no ischemia) and group I (n = 35, severe coronary artery stenosis with myocardial ischemia), and we studied the genotype of ACE I/D and AT1R 1166A/C polymorphisms. We also examined ACE activity in patients with acute KD. We did not detect any prevalent genotypes of the ACE and AT1R polymorphisms between controls and KD patients. However, the prevalence of the D allele in the ACE polymorphism and of the C allele in the AT1R polymorphism tended to be higher in group I than in group N (odds ratios, 2.00 and 2.32, respectively). In addition, the presence of the D and/or C alleles significantly increased the relative risk of developing myocardial ischemia (odds ratio, 2.71; p = 0.038). During the convalescent phase of KD, ACE activity was increased despite significant attenuation during the acute phase. These results suggested that the renin-angiotensin system is associated with the formation of severe coronary artery stenosis and myocardial ischemia.

Estimation of myocardial hemodynamics before and after intervention in children with Kawasaki disease.

OBJECTIVES: We used myocardial fractional flow reserve (FFR(myo)) and coronary flow reserve (CFR) to estimate cut-off values for assessment of the functional severity of coronary stenosis and myocardial ischemia, and we tested the usefulness of coronary blood hemodynamic measurements before and after plain old balloon angioplasty (POBA) and coronary artery bypass graft surgery (CABG). BACKGROUND: Fractional flow reserve and CFR are useful for assessing the functional severity of coronary artery stenosis, coronary microvascular dysfunction, and myocardial ischemia during cardiac catheterization in adults. However, there have been no reports on the use of these measurements in children with Kawasaki disease (KD). METHODS: The study group included 128 patients with 314 coronary branches. The subjects were classified into three groups: normal coronary group, with 206 branches; abnormal coronary artery without ischemia group, with 58 branches; and ischemia group, with 50 branches. RESULTS: In each branch, CFR and FFR(myo) were significantly lower in the ischemia group than in the other groups. Cut-off values for assessing the functional severity of coronary stenosis and CFR were approximately equal to those obtained for adults (CFR: <2.0; FFR(myo): <0.75). We obtained very high sensitivity and specificity for estimating myocardial ischemia using CFR and FFR(myo) (CFR: 94.0% and 98.5%, respectively; FFR(myo): 95.7% and 99.1%, respectively). Both CFR and FFR(myo) were reliable indicators of coronary hemodynamics before and after POBA and CABG. CONCLUSIONS: Together, CFR and FFR(myo) provide a useful index for assessing the functional severity of coronary artery stenosis and myocardial ischemia and estimating the effectiveness of POBA and CABG in children with KD, the same as they do for adults.

Cardiomyocyte regeneration from circulating bone marrow cells in mice.

We investigated the role of circulating bone marrow cells (BMC) in cardiomyocyte regeneration. BMC, isolated from transgenic mice expressing enhanced green fluorescent protein (GFP), were transplanted into lethally irradiated C57BL6 mice. Five weeks after bone marrow transplantation (BMT), flow cytometric analysis for GFP-positive cells confirmed reconstitution of transplanted bone marrow. Bone marrow transplant mice subsequently underwent left coronary artery ligation (myocardial infarction) or sham-operation, and were killed at 1 mo or 3 mo after operation. Infarct size was similar in bone marrow transplant mice at 1 mo (47.1 +/- 5.9%) and at 3 mo (45.3 +/- 7.8%), and echocardiography at 2 and 8 wk revealed decreasing left ventricular function. In infarcted heart, GFP-positive cells that expressed desmin and troponin T-C were identified by confocal microscopy. GFP and troponin T-C double-positive cells were predominantly in the peri-infarcted region (1 mo, 365 +/- 45 cells/50 sections; 3 mo: 458 +/- 100 cells/50 sections; p < 0.05 versus noninfarct, infarct, and sham-operated regions). Furthermore, BMC mobilization and differentiation into cardiomyocytes was found to be complete within 1 mo after myocardial infarction. These results demonstrate that circulating BMC undergo mobilization and differentiation in cardiac cells after myocardial infarction. Future studies are required to determine the molecular signaling mechanisms responsible for this phenomenon.

Genetic diagnosis of Werdnig-Hoffmann disease: a problem for application to prenatal diagnosis.

We report a floppy infant with Werdnig-Hoffmann disease (spinal muscular atrophy: SMA type 1) and Klinefelter syndrome. After genetic counseling with parents, a genetic diagnosis using DNA from the infant's peripheral blood mononuclear cells was performed. The parents' deletion of exons 7 and 8 of the survival motor neuron (smn) gene and exons 4 and 5 of the neuronal apoptosis inhibitory protein (naip) gene were noted in the infant, so he was confirmed to have SMA type 1. The parents wanted to receive a prenatal diagnosis on the next pregnancy. However this genetic test is achieved by confirming that a specific band can not be detected by PCR. Therefore, this method should be applied with great care to prenatal diagnosis using chorionic villi, which may be contaminated with maternal tissue.

Evolution of staged approach for Fontan operation.

BACKGROUND: During the early development of the Fontan operation, a number of physiologic and anatomical limits were proposed as selection criteria, and two criteria, pulmonary vascular resistance and ventricular function, have been important in predicting surgical outcome. The use of the bidirectional cavo pulmonary shunt as a staging procedure performed to control the pulmonary blood flow adequately and reduce ventricular volume over load has resulted in marked improvements in the early and late Fontan procedure results. METHODS AND RESULTS: At our hospital we perform systemic pulmonary shunt or pulmonary artery banding in patients if pulmonary blood flow can not be controlled adequately in the neonatal period and then perform bidirectional cavo pulmonary shunt six months afterwards. During this operation we also performed simultaneous surgical repair for pulmonary artery distortion, anomalies of pulmonary venous connection, restriction of bulboventricular foramen and atrioventricular valve regurgitation. To determine the efficacy of this staged approach in avoiding increases in pulmonary vascular resistance and impaired ventricular function, surgical results were investigated. From February 1995 to May 2001, eighteen patients with cardiac morphology unsuitable for biventricular repair were admitted to our hospital. Twenty-six palliative procedures, were performed including seven pulmonary artery banding, three systemic pulmonary shunt, thirteen bidirectional cavo pulmonary shunt, one original Glenn procedure, four repair of coarctation of the aorta, two total anomalous pulmonary venous connection repair, one mitral valve plasty, and two patients required Damus-Kaye-Stansel procedure to release restrictive bulboventricular foramen. Fifteen patients underwent a modified Fontan operation (total cavopulmonary connection) after these palliative procedures. The operative mortality rate for these palliative procedures was 3.8% (1/26). The operative mortality rate for Fontan operation was 7.1% (1/14). Three patients awaiting the Fontan operation were considered good candidates for a final operation and no patients in this series were considered unsuitable for Fontan completion. CONCLUSION: Our strategy of staged approach for Fontan procedure offers a good prognosis.

Longitudinal evaluation of anthracycline cardiotoxicity by signal-averaged electrocardiography in children with cancer.

BACKGROUND: The aim of the present study was to investigate the detection of anthracycline cardiotoxicity by signal-averaged electrocardiography (SAE) in children with cancer. METHODS: There were 29 patients with a cumulative anthracycline (ATC) dose of 75-600 mg/m2. None of them had congestive heart failure. Patients underwent SAE just before (detection of chronic cardiotoxicity) and just after (detection of acute cardiotoxicity) ATC therapy. Echocardiography and Holter electrocardiography were performed at the same time. The rates of abnormal SAE, echocardiography, and electrocardiogram findings were calculated and compared for every 100 mg/m2 of ATC. RESULTS: The SAE showed a significantly higher detection rate for acute cardiotoxicity was at a cumulative ATC dose of less than 400 mg/m2 when compared with other methods (P < 0.05). The lowest dose at which acute cardiotoxicity was detected by SAE was 117.3 mg/m2. The detection of chronic cardiotoxicity by SAE was significantly higher at a cumulative ATC dose of 100-400 mg/m2 when compared with other methods (P < 0.05), and the lowest value showing toxicity was 373.3 mg/m2. The lowest ATC dose causing chronic cardiotoxicity was significantly lower in patients less than 2-years-old (120.0 +/- 28.3 mg/m2) than in the other age groups (P < 0.05). CONCLUSIONS: Acute and chronic ATC cardiotoxicity were detected by SAE at lower cumulative doses compared with other methods. The technique of SAE was a potentially useful method for detection of cardiotoxicity among those investigated and it provides useful information on subclinical cardiac dysfunction in patients receiving ATC therapy.