Aya Miyazaki

Long QT syndrome with compound mutations is associated with a more severe phenotype: A Japanese multicenter study

BACKGROUND Long QT syndrome (LQTS) can be caused by mutations in the cardiac ion channels. Compound mutations occur at a frequency of 4% to 11% among genotyped LQTS cases. OBJECTIVE The purpose of this study was to determine the clinical characteristics and manner of onset of cardiac events in Japanese patients with LQTS and compound mutations. METHODS Six hundred three genotyped LQTS patients (310 probands and 293 family members) were divided into two groups: those with a single mutation (n = 568) and those with two mutations (n = 35). Clinical phenotypes were compared between the two groups. RESULTS Of 310 genotyped probands, 26 (8.4%) had two mutations in the same or different LQTS-related genes (compound mutations). Among the 603 LQTS patients, compound mutation carriers had significantly longer QTc interval (510 ± 56 ms vs 478± 53 ms, P = .001) and younger age at onset of cardiac events (10 ± 8 years vs 18 ± 16 years, P = .043) than did single mutation carriers. The incidence rate of cardiac events before age 40 years and use of beta-blocker therapy among compound mutation carriers also were different than in single mutation carriers. Subgroup analysis showed more cardiac events in LQTS type 1 (LQT1) and type 2 (LQT2) compound mutations compared to single LQT1 and LQT2 mutations. CONCLUSION Compound mutation carriers are associated with a more severe phenotype than single mutation carriers.

Influence of ventricular morphology on aerobic exercise capacity in patients after the Fontan operation

OBJECTIVES This study investigated the influences of ventricular morphology, hemodynamics and clinical findings on exercise capacity in patients after the Fontan operation. BACKGROUND Determinants of exercise capacity after the Fontan operation remain unclear. METHODS Peak oxygen uptake (PVo2) was determined in 105 patients by exercise test and compared to hemodynamics and clinical findings. Patients were divided into three groups based on ventricular morphology: those with a right ventricle (group RV), a biventricle (group BV) and a left ventricle (group LV). RESULTS Ten patients with atrioventricular valve regurgitation (AVVR) or hypoxia exhibited a low PVo2. After excluding these patients, although PVo2 did not correlate with hemodynamics, except ventricular ejection fraction (p < 0.02), it correlated with age at the Fontan operation and exercise test (p < 0.002). The PVo2 was higher in group LV (63+/-9%) than in groups RV (55+/-9%) and BV (55+/-12%) (p < 0.01), while an inverse correlation between PVo2 and age at operation was demonstrated only in group RV (p < 0.05). Groups RV or BV and age at exercise test were associated with a lower PVo2, whereas group LV was an independent predictor of a higher PVo2 (p < 0.01). During 4.2 years of follow-up, a decrease in peak heart rate was related to a decrease in PVo2 (p < 0.05). The PVo2 decreased in group RV (p < 0.01). CONCLUSIONS In addition to AVVR, hypoxia, and heart rate response, ventricular morphology is related to exercise capacity. Early Fontan operation may be beneficial in terms of exercise capacity, especially in the group RV patients.

Impact of the Evolution of the Fontan Operation on Early and Late Mortality: A Single-Center Experience of 405 Patients Over 3 Decades

BACKGROUND Postoperative mortality has decreased in patients undergoing the Fontan operation, and the determinants of such mortality may also have changed significantly. METHODS We conducted a study intended to focus on clarifying the determinants of mortality in 405 consecutive patients who had undergone a Fontan operation (62 patients after an atriopulmonary connection, 105 after an intra-atrial rerouting, and 238 patients after an extracardiac rerouting) between 1979 and 2010. RESULTS The overall 1-year, 5-year, 10-year, and 15-year rates of survival were 87.1%, 84.6%, 83.4%, and 81.6%, respectively, and the type of procedure as well as heterotaxy syndrome, ventricular ejection fraction, and atrioventricular valve repair at the time of the Fontan operation were independent predictors of overall mortality (p < 0.05 for all). Heterotaxy syndrome and atrioventricular (AV) valve repair were independent predictors of early (less than 6 months postoperative) mortality and the type of procedure was an independent predictor of late (6 or more months postoperative) mortality (p < 0.05 to 0.01). In the era of intra-atrial rerouting, heterotaxy syndrome was the only independent predictor of total, early, and late mortality (p < 0.05 for all), whereas a low ejection fraction, AV valve repair, and repair of a total anomalous pulmonary vein connection, rather than heterotaxy syndrome, were independent predictors of total or early mortality or both (p < 0.05 for all) in the era of extracardiac rerouting. CONCLUSIONS Even in the modern era of extracardiac rerouting in the Fontan operation, a low ventricular ejection fraction, AV valve dysfunction, or a total anomalous pulmonary vein connection remain significant risk factors for mortality in patients with a single-ventricle physiology.

High prevalence of abnormal glucose metabolism in young adult patients with complex congenital heart disease

BACKGROUND Abnormal glucose metabolism (AGM) adversely impacts morbidity and mortality in patients with chronic heart failure. No data on AGM in adult patients with congenital heart disease (ACHD) are available. METHODS To assess the AGM in ACHD and compare the results with their clinical characteristics, we performed a 75-g oral glucose tolerance test to detect AGM, that is, insulin resistance, impaired glucose tolerance, and diabetes mellitus, in 205 consecutive ACHD (24 +/- 8 years), including 16 unrepaired patients, 67 Fontan patients, 122 postbiventricular (BV) patients, and 27 healthy controls (27 +/- 5 years). RESULTS All ACHD groups had a high prevalence of AGM (unrepaired, 43.8%; Fontan, 43.3%; BV, 46.7%; control, 3.7%; P < .001). In the 2 postoperative groups, the Matsuda index was decreased (P < .0001), and greater waist circumference, liver dysfunction, higher plasma renin activity, and diuretic use were associated with AGM. Although male gender was associated with AGM (P < .01), baseline glucose and lipid metabolic variables did not correlate with the 75-g oral glucose tolerance test-induced hyperglycemia (area under the plasma glucose curve [AUC-PG]) in the Fontan patients but did correlate in the BV patients. The AUC-PG correlated inversely with exercise capacity (P < .05) in the 2 postoperative ACHD groups, and the AGM ACHD had a high incidence of future cardiac events (P < .05), especially the Fontan patients with diabetes mellitus (P < .01). CONCLUSIONS Complex ACHD have a high prevalence of AGM, and this newly recognized pathophysiology should be considered in managing long-term survivors of complex ACHD.

Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional Cardiac Sodium Channel

Background—Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy and may contribute to perinatal and neonatal mortality, but the molecular basis of this risk and the relationship to genetic disorders presenting later in life is unclear. We studied the functional and pharmacological properties of a novel de novo cardiac sodium channel gene (SCN5A) mutation associated with an extremely severe perinatal presentation of long-QT syndrome in unrelated probands of different ethnicity. Methods and Results—Two subjects exhibiting severe fetal and perinatal ventricular arrhythmias were screened for SCN5A mutations, and the functional properties of a novel missense mutation (G1631D) were determined by whole-cell patch clamp recording. In vitro electrophysiological studies revealed a profound defect in sodium channel function characterized by ≈10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, and depolarized voltage dependence of activation and inactivation. Single-channel recordings demonstrated increased frequency of late openings, prolonged mean open time, and increased latency to first opening for the mutant. Subjects carrying this mutation responded clinically to the combination of mexiletine with propranolol and survived. Pharmacologically, the mutant exhibited 2-fold greater tonic and use-dependent mexiletine block than wild-type channels. The mutant also exhibited enhanced tonic (2.4-fold) and use-dependent block (≈5-fold) by propranolol, and we observed additive effects of the 2 drugs on the mutant. Conclusions—Our study demonstrates the molecular basis for a malignant perinatal presentation of long-QT syndrome, illustrates novel functional and pharmacological properties of SCN5A-G1631D, which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting.

Haemodynamic characteristics before and after the onset of protein losing enteropathy in patients after the Fontan operation

OBJECTIVES Determinant risk factors for developing protein losing enteropathy (PLE), including haemodynamics, remain unclear in patients after the Fontan operation. METHODS Our purpose was to characterize the serial PLE haemodynamics before and after the onset and to determine the risk factors based on the cardiac catheterization-based analysis. RESULTS Of 354 Fontan survivors who had undergone postoperative cardiac catheterizations, we experienced 26 PLE patients during the follow-up. Non-left ventricular morphology systemic ventricle, functional one-lung pulmonary circulation and an early postoperative high central venous pressure (CVP) were associated with the PLE onset and the high CVP (odds ratio (OR) = 1.19 per 1 mmHg, 95% confidence interval (CI) 1.04-1.37, especially ≥12 mmHg, OR = 3.09, 95% CI 1.25-7.64, P < 0.05 for both) and one-lung pulmonary circulation (OR = 10.0-10.5, P < 0.001) independently predicted the onset. At the time of the PLE onset, a Fontan route stenosis/obstruction, arrhythmias, ventricular dysfunction/heart failure and pulmonary arterio-venous fistulae were demonstrated in 10 (38%), 8 (31%), 4 (15%) and 3 (12%) patients, respectively. When compared with 56 excellent Fontan survivors, the high CVP, ventricular end-diastolic pressure, and pulmonary artery resistance, and the low arterial oxygen saturation, systemic artery pressure, and ventricular ejection fraction characterized the pre-PLE Fontan haemodynamics (P < 0.05-0.0001). However, the following intensive treatments reduced the CVP, systemic artery pressure and cardiac output (P < 0.05-0.01), resulting in haemodynamics no different from those of the excellent survivors, except for the low systemic pressure (P < 0.0001). CONCLUSIONS The pre-PLE haemodynamics was characterized by several impaired haemodynamics, while those after PLE only by a low systemic pressure. A high early postoperative CVP was the only haemodynamic predictor for a new onset of PLE. Strict selective criteria for the operation and strategies to eliminate CVP-raising factors are mandatory to prevent a new onset of PLE.

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.

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.

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.

Abnormal Postexercise Cardiovascular Recovery and Its Determinants in Patients After Right Ventricular Outflow Tract Reconstruction

Background—Abnormal responses of heart rate (HR) and oxygen uptake (&OV0312;o2) during exercise characterize patients after right ventricular outflow tract reconstruction (RVOTR) for congenital heart defects. However, little is known about the postexercise dynamics. Methods and Results—We evaluated postexercise cardiovascular dynamics in 52 patients after closure of an atrioventricular septal defect (group A), 79 patients after RVOTR (group B), and 44 control subjects. HR variability, arterial baroreflex sensitivity (BRS), plasma norepinephrine, and hemodynamics were measured. Although there was no difference between group A and control subjects, declines in HR and &OV0312;o2 after light and peak exercise and in systolic blood pressure (SBP) after peak exercise were delayed in group B. Age, low-frequency component of HR variability, and plasma norepinephrine were independent determinants of early HR decline. Peak SBP and &OV0312;o2 had a great impact on the corresponding recoveries. When the peak values were excluded, body weight, BRS, and right ventricular ejection fraction were independent determinants of early SBP decline. BRS and the pulmonary artery resistance were independent determinants of &OV0312;o2 decline throughout recovery, and age and right systolic ventricular pressure also determined the early &OV0312;o2 decline. BRS and low-frequency component of HR variability were determined independently by the number of surgical procedures. Conclusions—In RVOTR patients, in addition to metabolic and autonomic maturation, surgery-related abnormal cardiac autonomic nervous activity and impaired hemodynamics have a great impact on delayed postexercise cardiovascular recovery.