Mid-Term Follow-up of School-Aged Children With Borderline Long QT Interval.

BACKGROUND: There are no definitive diagnostic criteria or follow-up strategies for long QT syndrome (LQTS) in children with a borderline long QT interval (b-LQT).Methods and Results:We retrospectively evaluated the clinical course, genetic testing results, corrected QT interval (QTc), and LQTS score of 59 school-aged children (5-18 years old) with a b-LQT (400≤QTc<500 ms). Syncope, but neither aborted cardiac arrest nor sudden cardiac death, occurred in 2 patients during the follow-up (6±3.4 years) with LQTS scores ≥4.5 points. The genetic testing results were positive in 92%, 57%, and 67% of patients with high, intermediate, and low probabilities of LQTS, respectively. The maximum and mean QTc during the follow-up significantly differed among the categories with a probability of LQTS, but not the minimum QTc. However, the QTc at rest and at the recovery point after exercise stress testing dramatically changed at the last follow-up. Consequently, the probability of LQTS changed in half of the patients. CONCLUSIONS: The LQTS score is a reasonable indicator for evaluating school-aged children with a b-LQT, and patients with a low LQTS score appear to be at low risk for cardiac events. However, the LQTS score can change during follow-up. Therefore, when there is doubt or concern for patients with a b-LQT, it is preferable to continue following them. Guidelines on follow-up strategies are desired for b-LQT.

Interventricular dyssynchrony in a patient with a biventricular physiology and a systemic right ventricle.

We describe of a unique pattern of cardiac dyssynchrony in a patient with a biventricular physiology and systemic right ventricle (RV): the interventricular dyssynchrony due to a contraction delay between the left ventricle and RV. In the present case, the cineangiography and intracardiac electrocardiography of the RV did not reveal intraventricular dyssynchrony of the RV, but revealed interventricular dyssynchrony. In addition, the pressure curves of the ventricles exhibited time phase differences between the two ventricles. The cardiac resynchronization therapy determining the pacing lead positions based on the idea of interventricular dyssynchrony induced reverse cardiac remodeling in this patient with systemic RV dysfunction.

Prominent QTc prolongation in a patient with a rare variant in the cardiac ryanodine receptor gene.

We report the case of a 12-year-old female patient with a history of four syncopal episodes related to exercise over 2 years and who showed prominent QTc prolongation on electrocardiogram; therefore, she was clinically diagnosed with long QT syndrome type-1. However, genetic analysis did not identify any LQT-related genes but showed a rare missense variant in the cardiac ryanodine receptor gene. From the results of drug-loading tests, administration of oral propranolol was initiated; thereafter, she experienced no syncopal episodes. This is a case report demonstrating the "overlapping clinical features" of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia.

Determinants of Aortic Size and Stiffness and the Impact on Exercise Physiology in Patients After the Fontan Operation.

The pathophysiology of congenital heart disease includes aortic dilation and increased stiffness. However, the clinical determinants and significance remain unclear in patients after the Fontan operation.Size and stiffness index (SI) of the ascending and descending aorta (aAO and dAO, respectively) were assessed using angiography in 130 consecutive Fontan patients and 30 age-matched controls. Compared with controls, Fontan patients showed a dilated aAO and smaller dAO (P < 0.0001) with greater SI (3.2 ± 0.7 versus 2.2 ± 0.3 for aAO and 2.7 ± 0.6 versus 2.2 ± 0.3 for dAO, P < 0.0001 for both). aAO was stiffer than dAO (P < 0.0001) and the greater aAO size was independently determined by the presence of pulmonary atresia, older age at Fontan operation, and low arterial oxygen saturation (P < 0.05-0.01). High plasma levels of brain natriuretic peptide (BNP) and glucose were independently associated with aAO SI (P < 0.05-0.01) and the SI ratio of aAO to dAO SI, whereas body mass index, plasma levels of highsensitivity C-reactive protein, and dAO size were independently associated with dAO SI (P < 0.05-0.01). A greater aAO and aAO/dAO ratio predicted an impaired exercise blood pressure response (P < 0.0001). Furthermore, in addition to age at Fontan operation and BNP level, the aAO SI independently predicted a lower peak oxygen uptake (P < 0.05).Fontan patients have a stiffer dilated aAO with rapidly tapering smaller dAO that predicts exercise pathophysiology. In addition to intrinsic aortic structural abnormalities, heart failure severities as well as traditional cardiovascular risk factors are also involved in the aortic structural and functional abnormalities.

Cardiopulmonary variables during exercise predict pregnancy outcome in women with congenital heart disease.

BACKGROUND: Maternal New York Heart Association (NYHA) class is associated with pregnancy outcome in women with congenital heart disease (WCHD), but objective predictive criteria of exercise capacity have not been established. METHODS AND RESULTS: A total of 33 WCHD (age, 28 ± 5 years; NYHA class, 1.3 ± 0.6) who had undergone cardiopulmonary exercise testing (CPX) 1.8 ± 2.2 years before their delivery were retrospectively identified. Maternal, cardiac, and neonatal events occurred in 8 (24%), 12 (36%), and 14 (42%), respectively. All CPX parameters correlated with neonatal birth weight (P<0.05-0.001). Exercise time, peak heart rate (HR), peak systolic blood pressure, and peak oxygen uptake (VO(2)) were associated with cardiac events (P<0.05-0.01), and exercise time and peak VO(2) were also associated with neonatal events (P<0.05). Exercise time, peak HR, and peak VO(2) were associated with at least 1 of the 3 events (P<0.05-0.01). Receiver operating characteristic analysis showed that peak HR <150 beats/min and/or peak VO(2) <22.0 ml · kg(-1) · min(-1), peak VO(2) <26.2 ml · kg(-1) · min(-1), and peak HR <150 beats/min and/or peak VO(2) <25.3 ml · kg(-1) · min(-1) predicted a high probability of maternal cardiac, neonatal, and maternal cardiac and/or neonatal event, respectively. CONCLUSIONS: CPX parameters predict pregnancy outcome and peak HR ≥ 150 beats/min and/or peak VO(2) ≥ 25 ml · kg(-1) · min(-1) may be reference value(s) for a safer pregnancy outcome in WCHD.

Changes in cerebral oxygen saturation and blood flow during hypoxic gas ventilation therapy in HLHS and CoA/IAA complex with markedly increased pulmonary blood flow.

BACKGROUND: Hypoxic gas ventilation therapy has recently been performed to prevent post-birth increased pulmonary blood flow in cases of congenital heart diseases with increased pulmonary blood flow. However, how the oxygen supply to the tissues changes during breathing a hypoxic gas mixture, remains unknown. The changes in cerebral oxygen saturation and blood supply during hypoxic gas ventilation therapy using a nitrogen gas mixture were studied. METHODS AND RESULTS: Cerebral regional oxygen saturation (cerebral rSO(2)) was measured by near-infrared spectroscopy, and changes in middle cerebral artery (MCA) blood flow and an index of vascular resistance (RI) were assessed in 8 consecutive patients having congenital heart diseases with increased pulmonary blood flow. In all patients, urinary volume increased significantly, and the respiratory rate showed a clear decrease. Percutaneous oxygen saturation showed no significant change. The average of cerebral rSO(2) was 67.3% before hypoxic gas ventilation, but increased to 69.4%, 69.1%, and 70.7% within 1, 12, and 24 h after initiation of treatment, respectively. MCA blood flow significantly increased in the diastolic phase, and RI significantly improved from 0.80 to 0.68 within 12 h after initiation of therapy. CONCLUSIONS: These results indicate that hypoxic gas ventilation therapy does not decrease cerebral oxygen saturation, but safely improves the cerebral blood supply in cases of congenital heart diseases with increased pulmonary blood flow.

Left ventricular reverse remodeling with infantile dilated cardiomyopathy and pitfalls of carvedilol therapy.

BACKGROUND: The left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (DCM) and the treatment with carvedilol in infants with severe heart failure remain poorly understood. METHODS: We reviewed the medical records of 5 infants around 12 months old referred to our hospital with severe heart failure due to DCM. Increased left ventricular fractional shortening (LVFS) by more than 10% and the percent of normal of left ventricular end-diastolic dimension (%LVDd) less than 120% were defined as LVRR in this study. RESULTS: DCM onset ranged from 8 to 16 months. Initial treatment of their acute heart failure was successful in all 5 but 4 patients relapsed despite the usual dose of carvedilol (induction 0.02-maintenance 0.4mg/kg/day), and developed worsening heart failure. Brain natriuretic peptide (BNP) levels which increased again after the acute treatment had fallen subsequent to discontinuing or decreasing carvedilol. Over 24 months, LVFS had increased from 11±2% (mean±SD) to 34±5% (p<0.05), and %LVDd decreased from 149±27% to 108±11% (p<0.05). CONCLUSIONS: LVRR was found at 2 years after the onset of DCM. Usual dose induction of carvedilol therapy can sometimes worsen heart failure after successful initial conventional treatment for the acute heart failure in DCM. Close control of carvedilol treatment may determine the prognosis of infantile DCM around 12 months old. It is prudent to increase low-dose carvedilol slowly corresponding with the BNP level.

Heart failure with preserved right ventricular ejection fraction in postoperative adults with congenital heart disease: A subtype of severe right ventricular pathophysiology.

BACKGROUND: Right ventricle (RV) may determine heart failure (HF) severity in adults with congenital heart disease (ACHD). However, the association of RV properties with clinical profiles remains unclear. PURPOSE: To clarify the associations of RV properties with biomarkers, exercise capacity, and unscheduled hospitalization (USH) in postoperative ACHD patients. METHODS AND RESULTS: We evaluated determinants of RV end-diastolic volume (EDVI, ml/m(2)) and pressure (EDP, mmHg) in 260 patients who were divided into 4 groups, i.e., those with RVEDVI<100 and EDP≥10 (A, n=49, 19%), those with RVEDVI≥100 with EDP≥10 (B, n=22), those with RVEDVI<100 and EDP<10 (C, n=134), and those with RVEDVI≥100 and EDP<10 (D, n=55). EDVI, EDP, and ejection fraction (EF, %) of the RV were independently associated with the corresponding value of the left ventricle (LV) (p<0.0001 for all). Group A had a RV-EF of 53±8 and was defined HF with preserved RV-EF (RV-HFpEF). Younger age, lower platelet count, and elevated plasma γ-glutamyltransferase independently predicted the RV-HFpEF. When the presence of pulmonary hypertension and LV-HFpEF was included in the analysis, these two factors independently predicted the presence of RV-HFpEF (p<0.05-0.001). On multivariate analysis, older age, number of surgeries, cardiac index, and RV systolic pressure independently determined peak oxygen uptake (PVO2, p<0.05) and RV outflow reconstruction independently predicted USH. The RV-HFpEF group showed the lowest PVO2 and highest incidence of USH among the 4 groups (p<0.05). CONCLUSIONS: Impaired RV characteristics, especially RV-HFpEF, with liver dysfunction and lower platelet count predicted lower exercise capacity with a poorer prognosis in postoperative ACHD patients.

Prognostic value of exercise variables in 335 patients after the Fontan operation: a 23-year single-center experience of cardiopulmonary exercise testing.

BACKGROUND: The prognostic value of cardiopulmonary exercise testing (CPX) for mortality risk remains controversial in Fontan patients. PURPOSE: Our goal of the present study was to clarify the prognostic value of major CPX variables and the factors determining exercise capacity in a large cohort of Fontan patients. METHODS: Since 1990, heart rate (HR), oxygen uptake (VO2 ), and ventilatory equivalent for carbon dioxide production (VE/VCO2 ) at peak exercise were determined in 335 Fontan patients (18 ± 5 years old), and the CPX variables were compared with the clinical profile and events. RESULTS: When compared with 209 controls, peak HR (148 ± 24 bpm), VO2 (27 ± 7 mL/kg/minute, [61 ± 15%]), and VE/VCO2 (40 ± 8 [117 ± 24%]) were markedly impaired in the Fontan patients (P < .0001). During a follow-up of 3.1 ± 2.7 years, 62 Fontan pathophysiological-associated events requiring unscheduled hospitalization (USH) occurred, and 24 patients died. All the CPX variables predicted the USH and mortality (P < .001-.0001). On multivariate analysis, in addition to use of diuretics (P = .0007) and low cardiac index (P = .0426), peak VO2 independently predicted the USH (hazard ratio: 0.95 per %, 95% confidence interval: 0.91-0.99, P = .014), while for mortality, multivariate analysis revealed that, in addition to heterotaxy syndrome (P = .0128) and year at first Fontan operation (P = .0532), peak VO2 independently predicted mortality (hazard ratio: 0.88 per %, 95% confidence interval: 0.76-0.98, P = .0217). CONCLUSION: Fontan patients exhibit markedly impaired CPX variables, and all the major variables, especially peak VO2 , predicted the risk of both morbidity and mortality.

Hyperuricemia reflects global Fontan pathophysiology and associates with morbidity and mortality in patients after the Fontan operation.

BACKGROUND: Serum uric acid (UA, mg/dl) levels associate with the pathophysiology and prognosis in patients with chronic heart failure. PURPOSE: To clarify the clinical significance of hyperuricemia (HUA, UA>7.0) in Fontan patients. METHODS AND RESULTS: We prospectively measured UA in 197 child and 102 adult Fontan patients and compared the results with the clinical variables, including hemodynamics, exercise capacity, and plasma levels of norepinephrine (NE) and brain natriuretic peptide, and unscheduled hospitalization (USH), including all-cause mortality. The mean UA was 5.8 ± 1.7 and 66 patients (22%, 34% in the adults) showed HUA. HUA was associated with lower peak oxygen uptake only in adults (r = -0.35, p < 0.0001). In children the use of diuretics, central venous pressure, liver enzymes, NE, and plasma creatinine (Cr) independently associated with UA. Of those, in addition to hypoxia, the use of diuretics and Cr independently predicted HUA (p < 0.05-0.001). In adults, hypoxia, plasma levels of sodium and Cr independently determined UA. Of those, hypoxia and hyponatremia independently predicted HUA (p < 0.05-0.001). During a follow-up of 49 ± 27 months, 67 USH, including 17 deaths, occurred. In all patients, on univariate analysis, HUA predicted mortality (hazard ratio: 3.2, 95% confidence interval: 1.2-8.6, p = 0.0193). HUA predicted USH in all, adult and child Fontan patients (p<0.05-0.0001), however, these prognostic values, including for mortality, were not independent in the multivariate analyses. CONCLUSIONS: UA reflects global postoperative Fontan pathophysiology, including the prognosis, with some differences between child and adult patients. However, the prognostic value of HUA may be limited in multivariate models in this particular cohort.

Prevalence and predictors of haemostatic complications in 412 Fontan patients: their relation to anticoagulation and haemodynamics.

OBJECTIVES: Our aim in the present study was to determine the prevalence of haemostatic events in our Fontan patients, to identify predictive factors and to determine their association with haemodynamics and anticoagulant therapy. METHODS: We retrospectively evaluated 424 Fontan patients and examined correlations between postoperative haemodynamics and anticoagulant regimens with haemostatic events. RESULTS: After exclusion of 12 patients with a mechanical valve at the time of Fontan operation, our 412 patients were sub-divided into 21 groups based on the therapeutic duration of warfarin and antiplatelet agent therapy. During the early 5- to 10-year postoperative period, patients receiving warfarin showed higher central venous pressure and lower arterial oxygen saturation (Sat) (P < 0.05-0.001). During a mean follow-up of 11.2 years, 29 (7.0%) haemostatic events occurred. With regard to haemorrhagic events, haemoptysis was most common (n = 13, 45%), followed by cerebral bleeds in 3 (10%). Of thrombo-embolic events, thrombosis in the Fontan pathway was the most common (n = 7, 24%), followed by cerebral infarction in 3. Early haemorrhagic events were associated with late Fontan operation and use of preoperative renin-angiotensin system blockers, while late events were related to heterotaxy syndrome, male gender and low Sat (P < 0.05-0.01). A low Sat was the only predictor of early postoperative thrombo-embolic events (P = 0.0192). Among the three subgroup analyses of fixed anticoagulant regimens, the most frequent haemorrhagic events were associated with long-term use of warfarin (P = 0.0033). None of the anticoagulant regimens that included warfarin and/or antiplatelet agents were independently associated with haemostatic events throughout the follow-up. CONCLUSIONS: Anticoagulant regimens in Fontan patients varied widely with a significant trend for warfarin use in patients with impaired haemodynamics. Low arterial oxygenation may predict haemostatic events. The relatively high prevalence of haemorrhagic complications indicates the need for individualized anticoagulant administration throughout the follow-up.

Comparison of prognostic variables in children and adults with Fontan circulation.

BACKGROUND: Non-cardiac complications, such as hepato-renal and metabolic problems, are emerging late after the Fontan operation due to its unique hemodynamics. Consequently, associations between clinical variables and postoperative outcome may change during the prolonged postoperative course. METHODS AND RESULTS: To determine if child and adult Fontan patients differ in the impact of cardiac and non-cardiac variables on clinical outcome, we prospectively evaluated associations between hemodynamics, neurohumoral factors, exercise variables, hepato-renal function and metabolic variables and unscheduled hospitalization, including death in 167 consecutive child and 116 adult Fontan patients. When compared with child patients, the adult patients showed higher rates of medications, lower cardiac index, higher values of natriuretic peptides, greater renal dysfunction, more cholestatic livers, and more impaired responses to exercise (p<0.05-0.0001). During the follow-up of 3.7 ± 2.1 years, 64 clinical events (37 in adults), including 13 deaths, occurred. A high CVP and low arterial oxygen satutration strongly predicted the child events (p<0.001), whereas these prognostic parameters were marginal in the adults. Instead, renal dysfunction and metabolic abnormality predicted adult events (p<0.05). Neurohumoral activation, low albumin, hyponatremia, and impaired exercise variables equally predicted clinical events in child and adult Fontan patients. CONCLUSIONS: Distinctive differences in predictive value of clinical variables exist between child and adult Fontan patients. In addition to cardiac issues, we should consider non-cardiac determinents of clinical outcome to maximize our efforts to improve prognosis for adult Fontan survivors.

Low fasting plasma glucose level predicts morbidity and mortality in symptomatic adults with congenital heart disease.

BACKGROUND: Adults with complex congenital heart disease (ACHD) have a high prevalence of abnormal glucose regulation (AGR: impaired glucose tolerance and diabetes mellitus). However, the impact of AGR on the prognosis remains unclear. PURPOSE: Our purpose was to clarify the prognostic value of AGR in ACHD. METHODS AND RESULTS: We performed a 75 g oral glucose tolerance test in 438 consecutive patients with ACHD (age 26 ± 8 years), including 38 unrepaired, 148 Fontan, 252 biventricular, and 27 healthy subjects and investigated associations between AGR and clinical events that required hospitalization or caused deaths from all-causes. When compared with the healthy group, fasting blood glucose level (FPG, mg/dl) was lower in the unrepaired and Fontan subjects (p<0.05-0.01) and the prevalence of low FPG (≤ 80 mg/dl) was also higher in the unrepaired (58%), Fontan (47%), and biventricular group (33%) than in the healthy control (11%) (p<0.0001). Postprandial hyperglycemia (area under the curve of glucose: PG-AUC) was higher in all ACHD groups (p<0.0001 for all). New York Heart Association class and lower FPG independently predicted the hospitalization (FPG ≤ 84 mg/dl) and mortality (FPG ≤ 80 mg/dl) (p<0.05-0.0001), while the PG-AUC was not an independent predictor. When compared with the asymptomatic ACHD, symptomatic ACHD with lower FPG had high hazard ratios of 2.2 (95% confidence interval [CI]: 1.3-3.8, p<0.002) and 3.3 (95% CI: 1.2-11.9, p<0.03) for the hospitalizations and all-cause mortality, respectively. CONCLUSIONS: Low FPG is not uncommon in ACHD and the low FPG predicts the morbidity and all-cause mortality in symptomatic ACHD.

Impact of central venous pressure on cardiorenal interactions in adult patients with congenital heart disease after biventricular repair.

BACKGROUND: Cardiorenal interactions adversely impact the prognosis in heart failure patients an effect which crucially involves increased central venous pressure (CVP). However, it is unclear whether the same pathophysiology operates in adults with congenital heart disease (CHD). PURPOSE: The present study was designed to assess cardiorenal interactions in adults with CHD after biventricular repair. METHODS AND RESULTS: We measured the kidney length (KL, cm/m) and renal resistive index (RI) in 77 consecutive patients and 30 controls. We also measured hemodynamics, plasma B-type natriuretic peptide level, 24-hour creatinine clearance, and peak oxygen uptake in each patient. The CVP correlated with the KL (r = 0.44, P <.001) and the RI was greater in the patients (P <.0001). The high RI was independently determined by the CVP, aortic pressure, and cardiac index (P <.05-.001), and correlated with the 24-hour creatinine clearance (r = -0.30, P <.05). The RI correlated closely with the neurohumoral activations and peak oxygen uptake (|r| = 0.45-0.50, P <.0001), and the patients with a traditional criteria of high RI (≥0.70) had a higher incidence of cardiovascular events that required unscheduled hospitalization (hazard ratio = 2.78, 95% confidence interval 1.26-6.10, P <.05). Multivariate Cox model with the cutoff values of KL ≥68 cm/m and RI ≥0.74 revealed that a greater KL (hazard ratio = 4.03, 95% confidence interval 1.46-11.1, P <.01) as well as B-type natriuretic peptide (P <.001) independently predicted the events. CONCLUSIONS: Hemodynamics, especially a high CVP, independently predicted the enlarged kidney and abnormal intrarenal flow dynamics that are closely associated with heart failure severity and cardiovascular events in adults with CHD after biventricular repair.