Abstract Most of patients after the Fontan operation can reach their adulthood, however, the management strategy for this complex pathophysiology has not been yet established. In general, elevated ...central venous pressure (CVP) and low cardiac output (CO) due to impaired ventricular preload characterize the Fontan circulation and the ideal hemodynamics could be a combination of a lower CVP with a higher CO. Thus, preserved functional systemic ventricle with low pulmonary artery resistance is thought to be crucial for better long-term outcome. However, on the other hand, because of the unique hemodynamics, these patients have significantly higher incidence of complications, sequelae, and even mortality. The major complications are supraventricular arrhythmias, heart failure, and Fontan-related problems, including protein-losing enteropathy and pulmonary arteriovenous fistulae, both of which are refractory to the treatments, and most of these “Fontan inconveniences” increase as patients age. In addition, one of the recent emerging problems is Fontan-associated liver disease that includes liver cirrhosis and hepatocellular carcinoma. Furthermore, women with Fontan circulation also reach childbearing age and there have been increasing numbers of reports showing a high incidence of pregnancy-associated complications. All these problems may be a part of “Fontan inconveniences” because most of the current Fontan patients are still “young” i.e. in their twenties or thirties and it may be not surprising that more new Fontan-associated pathophysiology emerges as patients age. Recent evidence reminds us of the concept that adult Fontan pathophysiology is not just a cardiovascular disease, rather, a multiorgan disease with many interactions between cardiovascular and non-cardiovascular organs. Therefore, a multidisciplinary approach is mandatory to take care of and anticipate the better long-term outcome.
Background:Fontan-associated liver disease (FALD) is an important late complication involving liver dysfunction, such as liver cirrhosis (LC) and hepatocellular carcinoma (HCC), in patients ...undergoing the Fontan procedure. However, the prevalence, clinical manifestation, and methods of diagnosis of FALD are still not well established.Methods and Results:This study comprised 2 nationwide surveys in Japan. First, the prevalence of LC and/or HCC in patients undergoing the Fontan procedure was determined. Second, clinical manifestations in patients with LC and/or HCC were analyzed, along with data from blood tests, echocardiography, and right heart catheterization. In the 1st survey, of the 2,700 patients who underwent the Fontan procedure, 31 were diagnosed with LC and/or HCC (1.15%), and 5 died due to liver diseases (mortality: 0.19%). In the 2nd survey, data were collected from 17 patients (12 with LC, 2 with HCC, and 3 with LC+HCC. Of these 17 patients, 5 died (mortality: 29.4%). The mean age at diagnosis of LC and HCC was 23 and 31 years, respectively. Computed tomography followed by ultrasound was most frequently used for diagnosis. Blood tests revealed low platelet counts, increased hemoglobin, aspartate aminotransferase, γ-guanosine triphosphate, and total bilirubin levels, and an elevated international normalized ratio of prothrombin time.Conclusions:LC and/or HCC in patients undergoing the Fontan procedure were not rare late complications and were associated with high mortality rates.
Background Elevated central venous pressure (CVP), low cardiac output and mild hypoxia are common early and late after Fontan operation. However, the association of these characteristics with late ...mortality is unclear. We aimed to elucidate the hemodynamic determinants of mortality after Fontan operation. Method We evaluated early (group Early; 0.5 to 5 years postoperatively, n = 387) and late (group Late; ≥15 years postoperatively, n = 161) Fontan hemodynamics that included CVP (mmHg), cardiac index (CI; L/min/m2 ), systemic ventricular end-diastolic volume index (EDVI; ml/m2 ), ejection fraction (EF; %), and arterial blood oxygen saturation (SaO2 ; %). We examined the effect of these variables on 5-year all-cause mortality. Results Mortality was higher in group Late than in group Early (17 vs. 11, P < .0001). In both Groups, higher CVP (hazard ratio HR:1.46 and 1.38, respectively, P < .001–0.0001) and lower SaO2 (HR: 1.12, P < .001 for both) were associated with increased mortality. Greater EDVI (HR per 20: 1.73) and lower EF (HR per 10%: 3.38) were associated with increased mortality only in group Early ( P < .0001 for both). In contrast, only in group Late was higher CI associated with increased mortality (HR: 2.50, 95% confidence interval: 1.30–4.55, P < .01). Seven patients in group Late with both high CVP (≥14) and CI (≥3.0) had the highest mortality (HR: 18.1, 5.55–52.4, P < .0001). Conclusions Elevated CVP and low SaO2 correlate with mortality in both early and late Fontan survivors. EDVI and EF are associated with mortality only in the earlier cohort, whereas interestingly, elevated cardiac output is associated with increased mortality in the later cohort.
Background:Pregnant women with a Fontan circulation have a high risk of obstetric complications, such as preterm delivery and small for gestational age (SGA), which may be affected by low blood flow ...to the placenta and hypoxia. This study investigated placental pathology in a Fontan circulation.Methods and Results:Eighteen pregnancies in 11 women with a Fontan circulation were reviewed. Pregnancy outcomes showed 9 miscarriages and 9 live births, with 4 preterm deliveries. Five neonates were SGA (<5th percentile). Eight placentas from live births in 7 women were available for the study. Five placentas had low weight placenta for gestational age, and 7 grossly showed a chronic subchorionic hematoma. Histological examination revealed all placentas had some form of histological hypoxic lesions: maternal vascular malperfusion in 7, fetal vascular malperfusion in 1, and other hypoxia-related lesions in 8. Quantitative analyses, including immunohistochemistry (CD31, CD68, and hypoxia inducible factor-1α antibodies) and Masson’s trichrome staining, were also performed and compared with 5 control placentas. Capillary density and the area of fibrosis were significantly greater in placentas from women with a Fontan circulation than in control placentas.Conclusions:Placentas in a Fontan circulation were characterized by a high frequency of low placental weight, chronic subchorionic hematoma, and constant histological hypoxic changes, which could reflect altered maternal cardiac conditions and lead to poor pregnancy outcomes.
Background Liver cancer (LC) is a serious late complication after the Fontan operation. However, the incidence, predictors, and prognosis remain unknown. The purpose of our study was to determine ...these clinical characteristics. Methods and Results We assessed liver function in 339 consecutive patients who had undergone the Fontan procedure from 2005 to 2019. LC was histologically diagnosed in 10 patients after a median period of 2.9 years (range: 0.3-13.8; median age: 29.9 years range: 14.4-41.5 years; overall median post-Fontan procedure follow-up: 25.6 years range: 13-32.1 years), and the annual incidence was 0.89%. Over the entire post-Fontan follow-up period, the annual incidences of new-onset LC in the second, third, and fourth decades were 0.14%, 0.43%, and 8.83%, respectively. The patients with LC had longer follow-up periods, higher levels of AFP (α-fetoprotein), and higher values of liver fibrosis indices (
<0.01-0.0001). Moreover, all indices were predictive of new-onset LC (
<0.01-0.0001). The LC treatments were surgical resection (n=3), transarterial chemoembolization (n=3), radiofrequency ablation (n=2), and hospice care (n=2). During a median follow-up of 9.4 months, 4 patients died; the survival rate at 1 year was 60%, and it was better among asymptomatic patients (
<0.01). Conclusions The LC incidence rapidly increased ≥30 years after the Fontan procedure, and liver fibrosis indices and AFP were predictive of new-onset LC. These LC-predictive markers should be monitored closely and mandatorily for early LC detection and better prognosis.
Exercise training is recommended for its possible favorable effects on Fontan pathophysiology. This study aimed to elucidate the impact of pediatric exercise capacity trajectory, which may mimic the ...effect of exercise training, on late adult Fontan pathophysiology.
Since 1990, 97 Fontan patients had consecutively undergone two serial cardiopulmonary exercise tests (CPX1 and CPX2) during childhood (ages 8 ± 2 and 14 ± 2 years) and one during adulthood (CPX3; age 23 ± 5 years). The changes in peak oxygen uptake (PVO2: % of normal value) from CPX1 to CPX2 (1-dPVO2) and from CPX2 to CPX3 (2-dPVO2) were calculated, and then the patients were divided into four subgroups according the 1-dPVO2 and 2-dPVO2.
In their adulthood, when compared with groups with negative 1-dPVO2, the central venous pressure, plasma brain natriuretic peptide level, and renal resistive index were lower, whereas liver synthetic function, body fat-free percentage, and PVO2 were higher in those with positive 1-dPVO2 (p < 0.05–0.0001). However, these favorable associations of 2-d-PVO2 with adult Fontan pathophysiology were not observed, except for the PVO2. After CPX3, 13 unexpected events occurred, and the risk was 76% lower in the groups having positive 1-dPVO2 than in those with negative 1-dPVO2 (hazard ratio, 0.24; 95% confidence interval, 0.09–0.62; p = 0.0035).
A positive exercise capacity trajectory during childhood predicts better adult Fontan pathophysiology, including better prognosis. Thus, prescription of exercise could be a promising strategy in the management of pediatric Fontan patients.
•Pediatric exercise capacity trajectory had impact on adult Fontan physiology.•Post-pediatric exercise capacity trajectory poorly predicts adult Fontan status.•The earlier exercise training starts, the better adult Fontan outcome becomes.
Background:Heart failure (HF) is an important complication in adults with congenital heart disease (CHD), but because only a few studies have focused on acute HF hospitalization in adults with CHD, ...we study aimed to define the clinical characteristics of such patients and examine the differences in acute HF between adults with CHD and acquired heart disease.Methods and Results:We retrospectively evaluated 50 adults with CHD admitted for treatment of acute HF and compared their data with those from Japanese HF registries. Patient mean age was 37±15 years and 58% were male. In total, 86% of the patients had complex forms of CHD and 62% had undergone corrective surgery, including the Fontan procedure; 66% of patients showed right heart hemodynamic abnormality. In-hospital mortality was 4%, which was comparable to the Japanese HF registries. Survival rate was 93% at 1 year and 75% at 3 years, which was similarly poor to the rates of HF secondary to acquired heart disease.Conclusions:We clarified the clinical characteristics of adults with CHD requiring HF hospitalization. Young adults with complex CHD were hospitalized for management of acute right HF. Short-term and mid-term outcomes were similarly poor compared with acute HF secondary to acquired heart disease.
We reviewed the long-term outcome of children with hypertrophic cardiomyopathy (HCM) based on the type.
We reviewed the medical records of 100 patients (male 54 female 46) with HCM at our hospital ...between 1977 and 2015. The survival and cardiac event-free survival rates were calculated by the Kaplan–Meier method.
The age at the time of the diagnosis ranged from 0 to 15 years with a median of 8 years. The number of patients with Noonan syndrome and hypertrophic obstructive cardiomyopathy (HOCM), idiopathic HCM (i-HCM), and secondary HCM (s-HCM) was 13, 13, 65, and 9 respectively. A dilated phase of HCM occurred in 24 patients. Nineteen (79 %) of the 24 patients died of heart failure, and two underwent a heart transplantation. Eight (33 %) of the 24 patients had s-HCM. The median age when a dilated phase occurred was 15 years old, and the median interval from the initial diagnosis to the dilated phase was 8 years. The median time from the diagnosis of a dilated phase to death was 1.6 years. Sudden death and implantable cardioverter defibrillator implantations occurred in 6 and 11 patients at around 15 years old, respectively. The 20-year survival rates were as follows: Noonan syndrome 84 %; HOCM 82 %; i-HCM 71 %; and s-HCM 17 %. Overall, the survival rates at 10, 20, and 30 years were 83 % (95 % confidence interval 73–89), 69 % (58–78), and 63 % (50–74), respectively. The overall cardiac event-free survival rates at 10, 20, and 30 years were 57 % (47–67), 39 % (31–50), and 32 % (21–44), respectively.
The long-term outcome in children with HCM was poor, and the outcome of s-HCM was very poor. The occurrence of a dilated phase worsened the outcome in HCM patients. Sudden death and d-HCM often occurred at around 15 years old.
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•The overall 30-year cardiac event free survival rate was 32 %.•The long-term outcome in children with hypertrophic cardiomyopathy was poor.•The median age when a dilated phase occurred was 15 years old.•Sudden death often occurred at around 15 years old.•The outcome of secondary hypertrophic cardiomyopathy was very poor.
A stiffened, dilated ascending aorta may represent an important predictor of cardiovascular mortality, and has been reported in patients with congenital heart disease, including single ventricle. ...However, the serial conformational changes and determinants of reduced distensibility in ascending aorta have not been clarified.
This retrospective study investigated 115 postoperative Fontan survivors (median age at Fontan: 3.7 years). All patients underwent cardiac catheterization before and 1, 5, 10, and 15 years after the Fontan operation. We measured Z-scores for diameters and stiffness indexes (β) of the ascending aorta and descending aorta from angiograms. We also reviewed the clinical profiles, hemodynamic parameters, and exercise capacities of patients and compared them with results from 47 control subjects.
Fontan survivors displayed significantly larger Z-score and β of the ascending aorta from before to 15 years after surgery than controls, whereas values for the descending aorta were comparable. Z-score for the ascending aorta was decreased, but β was elevated significantly according to the trend test. In multivariable analysis, β of the ascending aorta at 15 years after Fontan operation and its increasing trend were associated with older age at Fontan operation and elevated ventricular end-diastolic pressure. Reduced exercise capacity also correlated with stiffening of the ascending aorta.
Fontan survivors showed progressive stiffening and relatively slow growth of the dilated ascending aorta. Progressive stiffening of the ascending aorta may be coupled to diastolic dysfunction and reduced exercise capacity, suggesting the importance of lifelong management of subclinical Fontan pathophysiology.
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•A stiffened, dilated ascending aorta represents aortopathy in single ventricle.•Ascending aorta grew relatively slowly and its dilation gradually attenuated.•In contrast, stiffness of ascending aorta was elevated in 15-year Fontan survivors.•This stiffening was associated with diastolic dysfunction and exercise intolerance.•Our findings emphasize importance of lifelong management in Fontan survivors.
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