Genetic mutation analysis in Japanese patients with non-syndromic congenital heart disease.

Congenital heart disease (CHD) is the most common birth defect occurring in humans and some transcriptional factors have been identified as causative. However, additional mutation analysis of these genes is necessary to develop effective diagnostic and medical treatment methods. We conducted sequence analysis of the coding regions of NKX2.5, GATA4, TBX1, TBX5, TBX20, CFC1 and ZIC3 in 111 Japanese patients with non-syndromic CHD and 9 of their relatives. All patient samples were also analyzed by multiplex ligation-dependent probe amplification using probes involved in chromosome deletion related to CHD. Five novel variations of TBX5, GATA4 and TBX20 were detected in 6 of the patients, whereas none were found in 200 controls. The TBX5 variation p.Pro108Thr, located in the T-box domain, was identified in a patient with tricuspid atresia, an exon-intron boundary variation of GATA4 (IVS4+5G>A) was detected in a Tetralogy of Fallot patient and an 8p23 microdeletion was detected in one patient with atrioventricular septal defect and psychomotor delay. A total of seven non-synonymous polymorphisms were found in the patients and controls. Accumulation of novel variations of genes involving the cardiac development may be required for better understanding of CHD.

Risk factors for in-hospital mortality during infective endocarditis in patients with congenital heart disease.

Despite developments in preventative and medical therapy, infective endocarditis (IE) carries a high rate of mortality. Risk factors for mortality are unknown in pediatric and adult patients with congenital heart disease (CHD). We determined the risk factors for in-hospital mortality in pediatric and adult patients with CHD. A retrospective observational cohort study was conducted from January 1997 to December 2001 in Japan. Of the 239 patients for whom complete data were available, 216 patients with CHD were identified. Outcomes were alive or deceased. The proposed modified Duke's criteria identified 137 patients, aged 1 month to 62 years with a median of 12 years, with IE. In-hospital mortality was 10%. Four risk factors were independently associated with mortality by stepwise logistic regression analysis: (1) vegetation size > or =20 mm (odds ratio 40.6, 95% confidence interval 2.42 to 681); (2) age <1 year (odds ratio 19.5, 95% confidence interval 1.74 to 219); (3) presence of heart failure (odds ratio 7.16, 95% confidence ratio 1.34 to 38.4); and (4) Staphylococcus aureus as a causative organism (odds ratio 5.68, 95% confidence interval 1.16 to 27.9). Surgical intervention emerged as a predictive factor for lower in-hospital mortality (odds ratio 0.045, 95% confidence interval 0.003 to 0.70) by stepwise logistic regression analysis. In conclusion, surgical intervention, which decreases the risk of in-hospital mortality, should always be considered.

Myocardial scintigraphy after pacemaker implantation for congenital complete atrioventricular block.

Patients with isolated congenital complete atrioventricular block (CCAVB) occasionally develop dilated cardiomyopathy (DCM), despite early pacemaker implantation. However, the etiology of the DCM and its relationship to permanent ventricular pacing are not fully understood. Twenty-five patients with CCAVB underwent (99m) technetium (Tc) myocardial perfusion scintigraphy. Five patients were studied before and after pacing, providing a total of 30 image sets, which were divided into three groups; group 1: CCAVB before pacemaker implantation (PMI) (n = 11); group 2: CCAVB after PMI who did not subsequently develop DCM (n = 13); group 3: CCAVB after PMI who subsequently developed DCM (n = 6). Perfusion defects on single-photon-emission computed tomography (SPECT) were identified in group 1, 0 of 11 patients; group 2, 85% of patients; and group 3, 100% of patients. In groups 2 and 3, in patients with right ventricular pacing, the perfusion defects were mainly in the septum or between the apex and septum. On 20 segments' polar maps, the distribution of %uptake showed a similar pattern in groups 2 and 3, the degree of decreased %uptake and the number of segments with decreased %uptake being more severe in group 3. "Artificial" left bundle branch block (LBBB) pattern myocardial contraction induced by right ventricular pacing decreased myocardial perfusion around the apex and septum. Some patients with CCAVB will develop left ventricular dysfunction caused by artificial LBBB-induced interventricular asynchrony.

Heart rate dynamics during and after exercise in postoperative congenital heart disease patients. Their relation to cardiac autonomic nervous activity and intrinsic sinus node dysfunction.

BACKGROUND: Abnormal exercise-related heart rate (HR) dynamics, that is, blunted exercise HR response, lower peak HR, and delayed HR recovery after exercise, are associated with high morbidity and mortality in adults with acquired and congenital heart disease (CHD). However, the precise mechanisms underlying the abnormal HR dynamics remain unclear. OBJECTIVES: The purpose of this study is to evaluate the precise contribution of cardiac autonomic nervous activity (CANA) and sinus node function on exercise-related HR dynamics in postoperative patients with CHD. METHODS: We analyzed our previous data in 53 postoperative patients with CHD who had undergone pharmacologic evaluation, including intrinsic HR, and compared the results with HR dynamics. RESULTS: Intrinsic HR (84% +/- 11%) was lower than the expected value and independently correlated with resting HR (P < .05). Univariate analysis demonstrated that all CANA indices significantly correlated with most HR dynamic parameters. On multivariate analysis, basal parasympathetic nervous activity significantly influenced all HR dynamics (P < .05-.0001), except for peak HR, whereas postsynaptic beta sensitivity of the sinus node significantly influenced all HR dynamics (P < .05-.001), except for early HR recovery. Resting plasma norepinephrine significantly correlated with all HR dynamics (P < .05-.001), except for resting HR. CONCLUSIONS: Lower resting and peak HRs are independently associated with intrinsic sinus node dysfunction and abnormal sympathetic CANA, respectively. A blunted HR increase and delayed early HR recovery are independently associated with impaired sympathetic and parasympathetic CANAs with the greater influence on a blunted exercise HR increase.

Long-term patency of internal thoracic artery grafts for coronary artery stenosis due to Kawasaki disease: comparison of early with recent results in small children.

BACKGROUND: The results of coronary artery bypass grafting using the internal thoracic artery (ITA) had been reported less satisfactory in patients < 12 years old with coronary artery lesions caused by Kawasaki disease. METHODS: Since 1983, 67 patients have undergone this operation in our hospital; their age at operation ranged from 1 to 59 years (median 11 years), and the total number of ITA grafts was 95. The interval from operation to latest graft patency as confirmed by angiogram or echocardiogram ranged from 4 months to 23 years (median 8 years). For analysis of graft patency rates, patients were divided into 4 groups based on year of coronary artery bypass grafting and age when grafted. The groups based on year were from 1983 to 1993 (early) and from 1994 to 2006 (later), whereas the age groups were age at operation < 12 years and age at operation > or = 12 years. From 1999, percutaneous transluminal balloon angioplasty was performed for postoperative anastomotic stenosis. RESULTS: Percutaneous transluminal balloon angioplasty for anastomotic stenosis in ITA graft was performed in 6 patients. When the age at operation was < 12 years, the 10-year patency rate in the later period was 94.4% (n = 18), significantly > the 70.0% (n = 30) seen in the earlier period (P < .05). CONCLUSION: Recent results of ITA grafts in patients < 12 years old have improved through the application of appropriate indications and percutaneous transluminal balloon angioplasty for anastomotic stenosis. Once good flow in the ITA 1 year after surgery is confirmed, graft patency will persist > 20 years.

Comparison of late post-operative cardiopulmonary responses in the Fontan versus ventricular septation for double-inlet left ventricular repair.

Ventricular septation (VS) and the Fontan procedure are alternatives for definitive repair in patients with double-inlet left ventricle; although VS is theoretically preferable, the current preference in practice is the Fontan procedure. However, the long-term outcomes of both procedures remain unclear. To address this issue, cardiopulmonary responses during exercise were measured in patients with double-inlet left ventricle, and the impact of the type of procedure performed, Fontan or VS, on long-term exercise capacity and late postoperative clinical profiles was assessed. Fourteen post-Fontan patients (mean age 17+/-6 years) and 13 VS patients (mean age 19+/-4 years) underwent exercise testing. Of the 13 VS patients, 5 required atrioventricular valve replacement (AVVR), and 7 required pacemaker implantation. Although no difference in peak oxygen uptake was found between the VS and Fontan patients, peak oxygen uptake was higher in VS patients without AVVR (30+/-8 ml/kg/min) than in VS patients with AVVR (19+/-1 ml/kg/min) and Fontan patients (22+/-6 ml/kg/min) (p<0.01). There was no significant difference in peak oxygen uptake between the VS patients with and without pacemaker implantation (p=0.09). The clinical profiles of the VS and Fontan patients were similar in terms of medication and freedom from tachyarrhythmias or reoperations during the follow-up period. In conclusion, the data suggest that VS without AVVR provides excellent future exercise capacity in selected patients with double-inlet left ventricle.

Possible role of adrenomedullin in the regulation of Fontan circulation: mature form of plasma adrenomedullin is extracted in the lung in patients with Fontan procedure.

OBJECTIVE: We investigated the pathophysiological significance of molecular forms of adrenomedullin (AM) in patients after the Fontan procedure. METHODS: Plasma concentrations of mature AM (AM-m), an active form, glycine-extended AM (AM-Gly), an inactive form, and total AM (AM-T: AM-m+AM-Gly) were measured by specific immunoradiometric assay in the femoral vein, pulmonary artery and femoral artery of 29 consecutive patients after the Fontan procedure. The eleven patients who had history of Kawasaki disease and have normal coronary and hemodynamics served as control. RESULTS: Patients who underwent Fontan procedure had significantly higher venous concentrations of AM-T, AM-Gly, and AM-m than age-matched normal controls (AM-T, 12.0+/-3.3 vs. 9.6+/-2.0; AM-Gly, 10.4+/-3.0 vs. 8.5+/-1.6; AM-m, 1.6+/-0.7 vs. 1.0+/-0.6 pmol/l, each p<0.05). In patients with Fontan procedure, there were no differences in plasma AM-T, AM-Gly or AM-m levels between the femoral vein and pulmonary artery, however, there was a significant step-down in the AM-m levels, but not in plasma AM-T or AM-Gly levels, between the pulmonary artery and femoral artery (1.3+/-0.6 to 1.0+/-0.6, p<0.05). The venous concentrations of AM-m correlated negatively with systemic blood flow (cardiac output) (r=-0.46, p<0.05). CONCLUSIONS: Results suggest that in Fontan circulation plasma AM-m is increased in parallel with those of AM-T and AM-Gly and that AM-m is extracted in the lung. Extracted AM-m may be involved in the regulation of pulmonary arterial tonus, although further studies are necessary to elucidate the exact role of AM in Fontan circulation.

Change in plasma volume during peak exercise in patients with cyanotic congenital heart disease after definitive operation.

OBJECTIVES: To evaluate changes in plasma volume (deltaPV) during exercise in patients with single ventricular physiology with cyanosis; post-Fontan patients; and in patients after right ventricular outflow tract reconstruction (RVOTR). BACKGROUND: Compensatory mechanisms which regulate body fluid volumes operate in heart failure patients to maintain blood pressure. A better understanding of this pathophysiological process, especially during exercise, should help manage and follow such patients. METHODS: Twenty-six CHD patients (14+/-4 years), including 5 cyanotic patients, 12 after the Fontan operation, 9 after RVOTR, and 13 controls (14+/-5 years), performed a treadmill exercise test. DeltaPV from rest to peak was calculated and compared with changes in cardiovascular responses, plasma total protein (TP), norepinephrine (NE), osmolality (Osm), and blood lactate concentration (La). RESULTS: DeltaPV was smaller in CHD patients than in controls (Cyanotic: -5.9%, Fontan: -10.0%, RVOTR: -11.4%, CONTROLS: -14.5%, p<0.001). In all subjects, peak heart rate, systolic blood pressure and oxygen uptake correlated inversely with deltaPV (p<0.05 to 0.005). DeltaPV correlated inversely with changes in TP, NE, and La (p<0.005 for all), but not with the change in Osm. In CHD patients, the deltaPV correlated only with the NE increase (p<0.01). CONCLUSIONS: DeltaPV is smaller in CHD patients than in controls, especially in cyanotic patients. The smaller increases in cardiovascular responses during exercise and La are associated with the small deltaPV. These mechanisms may help to maintain cardiac output and increased sympathetic nervous activity may be beneficial to ensure sufficient perfusion pressure against deltaPV during exercise.

Effects of postural change on oxygen saturation and respiration in patients after the Fontan operation: platypnea and orthodeoxia.

The aim of this study was to assess whether platypnea and orthodeoxia occur in Fontan patients. We divided 14 Fontan patients into 2 groups: 8 patients who had pulmonary arteriovenous fistulas and/or intra-atrial shunts (group A) and 6 patients who had neither pulmonary arteriovenous fistulas nor intra-atrial shunts (group B). They were compared with 9 controls (group C). Arterial oxygen saturation, minute ventilation per body weight and ventilatory equivalent for carbon dioxide were measured in the supine and then sitting positions. In group A, 1 patient had platypnea and 3 patients had orthodeoxia (changes in the saturation from the supine position to the sitting position were -4% to -7%) accompanied with slight hyperpnea, and all 4 patients had both pulmonary arteriovenous fistulas and intra-atrial shunts. Contrary, patients in group B had neither platypnea nor orthodeoxia. The saturation was significantly lower and the minute ventilation was significantly higher in the sitting position than in the supine position in group A (p < 0.05). The other groups showed no significant difference in the saturation or the minute ventilation between the 2 positions. All groups showed the ventilatory equivalent was significantly higher in the sitting position than in the supine position (p < 0.05 to 0.01). We demonstrated platypnea and orthodeoxia in Fontan patients with pulmonary arteriovenous fistulas and intra-atrial shunts. We believe platypnea and orthodeoxia should be regard as a complication in Fontan patients with pulmonary arteriovenous fistulas and/or intra-atrial shunts.

Risk factors for arrhythmia and late death in patients with right ventricle to pulmonary artery conduit repair--Japanese multicenter study.

BACKGROUND: Arrhythmia and late cardiac deaths are thought to be major complications in patients after right ventricle (RV) to pulmonary artery (PA) conduit repair, although the incidence and predictors of these complications remain unknown. The aim of this study was to clarify the incidence and risk factors for arrhythmia and late deaths in patients with the RV to PA conduit repair through a Japanese multicenter study. METHODS: Three hundred fifty-one hospital survivors who underwent the RV to PA conduit repair before 1995 were studied. RESULTS: Survival rate after repair was 92% at 10 years, 88% at 20 and 25 years, respectively. Late death was observed in 30 (8.5%) including 4 patients with sudden death (SD). Higher right ventricular pressure (p = 0.02), larger cardio-thoracic ratio after repair (p = 0.02) and higher incidence of brady- or tachy-arrhythmia and SD (9/30) were associated with late death. Six (1.7%) patients developed ventricular tachycardia or ventricular fibrillation (VT/Vf). There were 22 patients who had 23 new-onset supraventricular tachy-arrhythmia (SVT). Right ventricular hypertension (p = 0.04) was associated with VT/Vf or SD. Male sex (p < 0.01), absence of previously aorto-pulmonary shunt (p < 0.05), older age at repair (p < 0.01) or longer length of follow-up (p < 0.01) were associated with SVT. CONCLUSION: Arrhythmia and late sudden death are relatively common late after the RV to PA conduit repair. Our data support recent surgical strategies of earlier primary operation and timely reoperation for progressive right ventricular outflow stenosis that may reduce the incidence of late arrhythmias and SD.