Decreased Proteasomal Function Exacerbates Endoplasmic Reticulum Stress-Induced Chronic Inflammation in Obese Adipose Tissue.

Low-grade chronic inflammation contributes to both aging and the pathogenesis of age-related diseases. White adipose tissue (WAT) in obese individuals exhibits chronic inflammation, which is associated with obesity-related disorders. Aging exacerbates obesity-related inflammation in WAT; however, the molecular mechanisms underlying chronic inflammation and its exacerbation by aging remain unclear. Age-related decline in activity of the proteasome, a multisubunit proteolytic complex, has been implicated in age-related diseases. This study employed a mouse model with decreased proteasomal function that exhibits age-related phenotypes to investigate the impact of adipocyte senescence on WAT inflammation. Transgenic mice expressing proteasomal subunit ß5t with weak chymotrypsin-like activity experience reduced lifespan and develop age-related phenotypes. Mice fed with a high-fat diet and experiencing proteasomal dysfunction exhibited increased WAT inflammation, increased infiltration of proinflammatory M1-like macrophages, and increased proinflammatory adipocytokine-like monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and tumor necrosis factor-α, which are all associated with activation of endoplasmic reticulum (ER) stress-related pathways. Impaired proteasomal activity also activated ER stress-related molecules and induced expression of proinflammatory adipocytokines in adipocyte-like cells differentiated from 3T3-L1 cells. Collectively, the results suggesed that impaired proteasomal activity increases ER stress and that subsequent inflammatory pathways play pivotal roles in WAT inflammation. Because proteasomal function declines with age, age-related proteasome impairment may be involved in obesity-related inflammation among elderly individuals.

Decreased proteasome function increases oxidative stress in the early stage of pressure ulcer development.

The aging process in the elderly results in heightened skin fragility associated with various disorders, including pressure ulcers (PUs). Despite the high incidence of PUs in the elderly population, there is a limited body of research specifically examining the impact of aging on the development of pressure ulcers. Therefore, investigating age-related physiological abnormalities is essential to elucidate the pathogenesis of PUs. Ischemia-reperfusion (I/R) injury and the subsequent oxidative stress caused by reactive oxygen species (ROS) play essential roles in the early stage of PUs. In this study, we used a mouse model of proteasomal dysfunction with an age-related phenotype to examine the role of proteasome activity in cutaneous I/R injury in vivo. Decreased proteasome function did not affect the expression of inflammatory cytokines and adhesion molecules in the I/R area in transgenic mice; however, proteasome inhibition increased oxidative stress that was not attenuated by activation of the oxidative stress response mediated by NF-E2-related factor 2 (Nrf2). In dermal fibroblasts (FCs) subjected to hypoxia-reoxygenation (H/R), proteasome inhibition induced oxidative stress and ROS production, and Nrf2 activation did not adequately upregulate antioxidant enzyme expression, possibly leading to antioxidant/oxidant imbalance. The free radical scavenger edaravone had protective effects against I/R injury in vivo and decreased oxidative stress in FCs treated with a proteasome inhibitor and subjected to H/R in vitro. The results suggest that the age-related decline in proteasome activity promotes cutaneous I/R injury-induced oxidative stress, and free radical scavengers may exert protective effects by preventing oxidative stress in the early stage of PUs.

Iroquois homeobox 3 regulates odontoblast proliferation and differentiation mediated by Wnt5a expression.

Iroquois homeobox (Irx) genes are TALE-class homeobox genes that are evolutionarily conserved across species and have multiple critical cellular functions in fundamental tissue development processes. Previous studies have shown that Irxs genes are expressed during tooth development. However, the precise roles of genes in teeth remain unclear. Here, we demonstrated for the first time that Irx3 is an essential molecule for the proliferation and differentiation of odontoblasts. Using cDNA synthesized from postnatal day 1 (P1) tooth germs, we examined the expression of all Irx genes (Irx1-Irx6) by RT-PCR and found that all genes except Irx4 were expressed in the tooth tissue. Irx1-Irx3 a were expressed in the dental epithelial cell line M3H1 cells, while Irx3 and Irx5 were expressed in the dental mesenchymal cell line mDP cells. Only Irx3 was expressed in both undifferentiated cell lines. Immunostaining also revealed the presence of IRX3 in the dental epithelial cells and mesenchymal condensation. Inhibition of endogenous Irx3 by siRNA blocks the proliferation and differentiation of mDP cells. Wnt3a, Wnt5a, and Bmp4 are factors involved in odontoblast differentiation and were highly expressed in mDP cells by quantitative PCR analysis. Interestingly, the expression of Wnt5a (but not Wnt3a or Bmp4) was suppressed by Irx3 siRNA. These results suggest that Irx3 plays an essential role in part through the regulation of Wnt5a expression during odontoblast proliferation and differentiation.

Control of Heart Rate in Infant and Child Tachyarrhythmia With Reduced Cardiac Function Using Landiolol (HEARTFUL)　- Results of a Prospective, Multicenter, Uncontrolled Clinical Study.

BACKGROUND: The prospective Control of HEART rate in inFant and child tachyarrhythmia with reduced cardiac function Using Landiolol (HEARTFUL) study investigated the effectiveness and safety of landiolol, a short-acting ß1 selective blocker, in children.Methods and Results: Twenty-five inpatients aged ≥3 months to <15 years who developed supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, and inappropriate sinus tachycardia) were treated with landiolol. The primary endpoint, the percent of patients with a reduction in heart rate ≥20% from the initial rate of tachycardia, or termination of tachycardia at 2 h after starting landiolol, was achieved in 12/25 patients (48.0%; 95% CI 28.4-67.6), which exceeded the predetermined threshold (38.0%). At 2 h after starting landiolol administration, heart rate had decreased by ≥20% in 45.8% (11/24) and recovery to sinus rhythm was achieved in 40.0% (6/15) of the patients. Adverse reactions (ARs) occurred in 24.0% (6/25) of patients, and the study was discontinued in 4.0% (1/25) of the patients; however, none of these ARs were considered serious. The most common AR was hypotension (20.0% [5/25] of patients). CONCLUSIONS: The HEARTFUL study has demonstrated the efficacy of landiolol, by reducing heart rate or terminating tachycardia, in pediatric patients with supraventricular tachyarrhythmias. Although serious ARs and concerns were not identified in this study, physicians should be always cautious of circulatory collapse due to hypotension.

Successful Pacemaker Setting Using Treadmill Exercise Test in a Child with Fontan Circulation.

The usefulness of a treadmill exercise test for determining optimal pacemaker settings remains unknown. An 8-year-old boy with Fontan circulation and a dual-chamber pacemaker for a rate-dependent advanced atrioventricular block suffered from dullness and poor school attendance. Although the pacemaker log showed an atrial tachycardia/fibrillation episode, treadmill exercise testing revealed sinus tachycardia, which converted to a 2:1 atrioventricular block. The pacemaker setting was optimized, with improvement in the patient's condition.Treadmill exercise testing helps optimize dual-chamber pacemaker settings in children with complex congenital heart disease involved in energy-consuming physical activities and having a wide working range in sinus rate.

Relationship between the Amount of Menstrual Flow and Cardiac Status in Women with Fontan Circulation.

A high prevalence of heavy menstrual bleeding (HMB) has been reported in women with Fontan circulation. Cyanosis has been reported to contribute to HMB, and menstruation has been suggested to affect cardiac status in women with congenital heart disease. This study aimed to evaluate the relationship between the amount of menstrual flow and cardiac status in women with Fontan circulation.Twenty women who had undergone the Fontan procedure were prospectively investigated and the amount of their menstrual flow was evaluated using a questionnaire. Participants were divided into two groups-small and large menstrual bleeding groups-and their clinical data, including the results of hematological tests and echocardiographic findings, were evaluated.One (5%) woman showed primary amenorrhea. Eight of the remaining 19 (42%) women were included in the large menstrual bleeding group. Women with large menstrual bleeding showed a significantly higher hematocrit level (47.1% [36.2%-50.3%] versus 42.1% [35.3%-44.9%], P = 0.006) and longer QRS duration (106 [92-172] ms versus 88 [78-140] ms, P = 0.008), as well as a lower fractional area change (37.4% [35.6%-47.2%] versus 47.0% [38.2%-55.7%], P = 0.010) and global longitudinal strain (-10.5% [-14.9% to -6.6%] versus -13.9% [-20.5% to -7.8%], P = 0.041) of the dominant ventricle on echocardiography, than women with small bleeding.Erythrocytosis, longer QRS duration, and reduced ventricular function were related to increased menstrual bleeding in women with Fontan circulation. These functions may be interrelated with the amount of menstrual flow in such women.

The Ventricular Hypokinesis at the Apical Pacing Site due to the Early Shortening and Rebound Stretch in a Case with Fontan Procedure.

The left ventricular (LV) apex is recommended as the first choice for positioning the epicardial pacing. We encountered a patient with congenital heart disease (CHD) showing hypokinesis of the LV apical pacing site after implantation of a pacemaker with epicardial leads. This phenomenon was revealed by the early shortening and systolic rebound stretch of the same lesion on two-dimensional speckle tracking echocardiography, which developed in the intraventricular dyssynchrony between the LV apex and base. Cardiac resynchronization therapy provided an excellent result around the hypokinetic lesion. It is wise to arrange detailed evaluations in each patient with complicated CHD, aiming at a successful treatment to enable ventricular synchronicity.

Electrocardiographic features of arrhythmogenic right ventricular cardiomyopathy in school-aged children.

It can be difficult to distinguish children with early-stage arrhythmogenic right ventricular cardiomyopathy (ARVC) from those with benign premature ventricular contraction (PVC). We retrospectively evaluated six school-aged children with ARVC and compared with those of 20 with benign PVC. The median age at initial presentation was 11.4 and 10.2 years in ARVC and benign PVC, respectively. None of the ARVC patients fulfilled the diagnostic criteria of ARVC at initial presentation. At ARVC diagnosis, the treadmill exercise test and Holter monitoring showed provoked PVC during exercise and pleomorphic PVC in all ARVC cases, respectively. During the observation period, terminal activation duration (TAD) was prolonged in all ARVC patients. In addition, ΔTAD (5.5 [3-10] ms) were significantly longer than those with benign PVC (p < 0.001). A new notched S-wave in V1 appeared in four (67%) ARVC patients, who had myocardial abnormalities in the right ventricle, and in zero benign PVC. Our electrocardiographic findings, such as provoked PVC during exercise, pleomorphic PVC, prolonged TAD, and a new notched S-wave in V1 could contribute to the early detection of ARVC in school-aged children.

2021 PACES expert consensus statement on the indications and management of cardiovascular implantable electronic devices in pediatric patients.

In view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consensus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology (ACC), and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate CIED follow-up in pediatric patients.

2021 PACES expert consensus statement on the indications and management of cardiovascular implantable electronic devices in pediatric patients: Executive summary.

Guidelines for the implantation of cardiac implantable electronic devices (CIEDs) have evolved since publication of the initial ACC/AHA pacemaker guidelines in 1984 [1]. CIEDs have evolved to include novel forms of cardiac pacing, the development of implantable cardioverter defibrillators (ICDs) and the introduction of devices for long term monitoring of heart rhythm and other physiologic parameters. In view of the increasing complexity of both devices and patients, practice guidelines, by necessity, have become increasingly specific. In 2018, the ACC/AHA/HRS published Guidelines on the Evaluation and Management of Patients with Bradycardia and Cardiac Conduction Delay [2], which were specific recommendations for patients >18 years of age. This age-specific threshold was established in view of the differing indications for CIEDs in young patients as well as size-specific technology factors. Therefore, the following document was developed to update and further delineate indications for the use and management of CIEDs in pediatric patients, defined as ≤21 years of age, with recognition that there is often overlap in the care of patents between 18 and 21 years of age. This document is an abbreviated expert consensus statement (ECS) intended to focus primarily on the indications for CIEDs in the setting of specific disease/diagnostic categories. This document will also provide guidance regarding the management of lead systems and follow-up evaluation for pediatric patients with CIEDs. The recommendations are presented in an abbreviated modular format, with each section including the complete table of recommendations along with a brief synopsis of supportive text and select references to provide some context for the recommendations. This document is not intended to provide an exhaustive discussion of the basis for each of the recommendations, which are further addressed in the comprehensive PACES-CIED document [3], with further data easily accessible in electronic searches or textbooks.

2021 PACES expert consensus statement on the indications and management of cardiovascular implantable electronic devices in pediatric patients.

In view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consensus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology (ACC), and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate CIED follow-up in pediatric patients.

CRT in a congenital heart disease patient with interventricular dyssynchrony due to an RV conduction delay.

We encountered a unique pattern of cardiac dyssynchrony in a patient with complex congenital heart disease (heterotaxy syndrome) with a biventricular physiology and systemic left ventricle (LV). On speckle tracking echocardiography, dyssynchrony was not detected within the LV, but was noted in an interventricular fashion between the LV and right ventricle (RV). An electrophysiologic study revealed a conduction delay in the subpulmonary RV. Cardiac resynchronization therapy provided reverse cardiac remodeling and an excellent result in our patient by placing the pacing leads around the dyssynchronous lesion.

Evaluating the response to cardiac resynchronization therapy performed with a new ventricular morphology-based strategy for congenital heart disease.

BACKGROUND: In cardiac resynchronization therapy (CRT) for patients with congenital heart disease (CHD) and a ventricular morphology other than a systemic left ventricle (LV), we previously proposed pacing sites that are different from those used for a systemic LV. The leads should be placed laterally on opposite sides of both ventricles in patients with short-axis dyssynchrony and a single ventricular physiology with two ventricles, whereas they should be placed at the farthest sites along the longitudinal direction in the right ventricle (RV) in patients with long-axis dyssynchrony of the RV. Moreover, in patients with interventricular dyssynchrony and a biventricular physiology with a systemic RV, they should be placed at sites that both ventricles can contract simultaneously. We retrospectively investigated 27 consecutive procedures in 24 patients with CHD who underwent CRT to evaluate the effectiveness of a new ventricular morphology-based CRT strategy. The responder rate was 63% (17/27). The reasons for a non-response to CRT in 10 cases were as follows: non-optimal lead positions during CRT, 4; no systemic ventricular conduction delay or heart failure symptoms before the CRT, 5; short follow-up periods after the CRT, 2; and an extremely dilated systemic RV, 1. The responder rate became 88% (14/16), after excluding the procedures without a ventricular conduction delay or heart failure symptoms and those with non-optimal lead positions. This new strategy for CRT can provide favorable results for CHD patients with a systemic ventricular conduction delay and heart failure.

Extremely short setting of optimal sensed atrioventricular interval in patients after Fontan procedure with implanted dual-chamber pacemaker.

BACKGROUND: Atrioventricular interval optimisation is important in patients with dual-chamber pacing, especially with heart failure. In patients with CHD, especially in those with Fontan circulation, the systemic atrial contraction is supposed to be more important than in patients without structural heart disease. METHODS: We retrospectively evaluated two patients after Fontan procedure with dual-chamber pacemaker with a unique setting of optimal sensed atrioventricular interval. RESULTS: The optimal sensed atrioventricular interval determined by echocardiogram was extremely short sensed atrioventricular interval at 25 and 30 ms in both cases; however, the actual P wave and ventricular pacing interval showed 180 and 140 ms, respectively. In both cases, the atrial epicardial leads were implanted on the opposite site of the origin of their own atrial rhythm. The time differences between sensed atrioventricular interval and actual P wave and ventricular pacing interval occurred because of the site of the epicardial atrial pacing leads and the intra-atrial conduction delay. CONCLUSION: We need to consider the origin of the atrial rhythm, the site of the epicardial atrial lead, and the atrial conduction delay by using electrocardiogram and X-ray when we set the optimal sensed atrioventricular interval in complicated CHD.

Vaccine adjuvant ARNAX promotes mucosal IgA production in influenza HA vaccination.

Adjuvant stimulates pattern-recognition receptors (PRRs) expressed by dendritic cells, which causes immune-enhancing of T lymphocytes. Adjuvant also induces innate immune response in whole-body cells via PRRs to evoke cytokinemia. A cytokine-mediated immune response is important for the systemic protection of a host from microbial infections. Using an influenza subcomponent vaccine in a mouse model, we intranasally administered a TLR3-specific adjuvant ARNAX + HA split vaccine to mice. ARNAX efficiently induced mucosal IgA and systemic IgG production by nasal drop. Moreover, ARNAX + HA simultaneously induced CD8 and CD4 T cell activation. We have previously shown that ARNAX does not induce harmful systemic cytokine production. Thus, our findings indicate that the ARNAX + HA vaccine is a harmless prophylactic vaccine for flu that induces HA-specific T cell activation and IgA/IgG production. These results suggested that ARNAX + antigen enhanced the immune response without inducing inflammatory toxicity for vaccination against infectious diseases.

Clinical Characteristics of Adult Patients With Congenital Heart Disease Hospitalized for Acute Heart Failure.

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.

Recognizability of heterologous co-chaperones with Streptococcus intermedius DnaK and Escherichia coli DnaK.

Streptococcus intermedius DnaK complements the temperature-sensitive phenotype of an Escherichia coli dnaK null mutant only when co-chaperones DnaJ and GrpE are co-expressed. Therefore, whether S. intermedius DnaK and E. coli DnaK can recognize heterologous co-chaperones in vitro was examined. Addition of heterologous GrpE to DnaK and DnaJ partially stimulated adenosine triphosphatase (ATPase) activity, and almost completely stimulated luciferase refolding activity. Addition of heterologous DnaJ to GrpE and DnaK also stimulated ATPase activity; however, significant luciferase refolding activity was not observed. Moreover, E. coli DnaJ had a negative effect on the luciferase refolding activity of the S. intermedius DnaK chaperone system. In E. coli chaperone mutants, with the exception of E. coli DnaJ, stronger expression of the heterologous co-chaperones partially or almost completely complemented the temperature-sensitive-phenotype. These results indicate that all heterologous co-chaperones can at least partially recognize DnaK of a distantly related species. A region of the ATPase domain that is present in the DnaK of gram-negative bacteria is absent from the DnaK of gram-positive bacteria. This region is believed to be important for recognition of co-chaperones from gram-negative bacteria. However, insertion of this segment into S. intermedius DnaK failed to increase its ability to recognize E. coli co-chaperones, implying that this region is unnecessary or insufficient for the recognition of E. coli co-chaperones. Thus, our data suggest that a basic structural similarity is conserved among the components of the S. intermedius and E. coli DnaK chaperone systems, allowing weak associations between heterologous components.

Comparison of Clinical Profiles in Patients with Protein-Losing Enteropathy With and Without Fontan Circulation.

Protein-losing enteropathy (PLE) is a life-threatening complication in patients following the Fontan operation. However, PLE also develops in some patients with congenital heart disease (CHD) after biventricular repair (BVR). This study compared clinical profiles of PLE patients following the Fontan operation with those after BVR. We retrospectively reviewed clinical charts of postoperative CHD patients with PLE. The study population comprised 42 PLE patients (14BVR, 28Fontan). Postoperative follow-up period until onset was significantly shorter in the Fontan group than in the BVR group (14 ± 2 vs. 8 ± 1 years, p = 0.02), while there was no difference in PLE onset age between groups. Furthermore, there were no differences in prevalence of clinically relevant arrhythmias, cardiac output, or central venous pressure between the two groups at PLE onset. Percentage of structural lesions (valve regurgitation and/or stenotic lesions) responsible for development of PLE and ventricular end-diastolic pressure were higher in the BVR group than in the Fontan group (93 vs. 50%, p < 0.01), (13.4 ± 6.3 vs. 7.5 ± 4.1, p < 0.0001). Catheter intervention was applied in 2Fontan and 6BVR patients, while surgical intervention was required in 8BVR and 7Fontan patients. Of these, catheter intervention was effective in 2 (25%, 1Fontan, 1BVR) and surgical intervention was effective in 4 (26.7%, 1Fontan, 3BVR). Only one patient (5.3%) improved without intervention. Complete PLE remission rate was higher in the BVR group than in the Fontan group (38 vs. 7%, p = 0.02). During follow-up, death of 2 BVR and 8 Fontan patients occurred. There were no group differences in 5- to 10-year survival rates after PLE onset (81 vs. 81%, BVR, 81 vs. 66%, Fontan). Although BVR patients may have greater chance of PLE remission when compared with those exhibiting Fontan pathophysiology, mortality in PLE-CHD patients was significantly high regardless of postoperative hemodynamics.

Hemodynamic determinants of mortality after Fontan operation.

BACKGROUND: Elevated central venous pressure (CVP), low cardiac output, and mild hypoxia are common early and late after Fontan operations. 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; 0.5-5years postoperatively, n=387) and late (group late; ≥15years postoperatively, n=161) Fontan hemodynamics that included CVP (mm Hg), cardiac index (CI; L/min per m2), systemic ventricular end-diastolic volume index (mL/m2), ejection fraction (EF; %), and arterial blood oxygen saturation (%). 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-.0001) and lower arterial blood oxygen saturation (HR 1.12, P<.001 for both) were associated with increased mortality. Greater end-diastolic volume index (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% CI 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 arterial blood oxygen saturation correlate with mortality in both early and late Fontan survivors. End-diastolic volume index 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.