Surgical Outcomes of Patients With Heterotaxy Syndrome　― The Japanese Congenital Cardiovascular Surgery Database ―

Abstract

Background: Cardiac malformations are a major component of heterotaxy syndrome and result in significant mortality and morbidity. This multicenter nationwide Japanese study evaluated mortality and morbidity after initial surgical palliation for patients with heterotaxy syndrome and determined predictors for mortality and morbidity among patients enrolled in the study.

Methods and Results: The Japanese Congenital Cardiovascular Surgery Database (JCCVSD) collects clinical data from 119 domestic institutions specializing in congenital heart disease, covering almost all major congenital heart surgery programs in Japan. Clinical data on preoperative, operative, and postoperative characteristics and survival data within 30 and 90 days were available from the JCCVSD database. Of the 561 patients with heterotaxy syndrome who underwent any of 8 specific initial cardiovascular surgeries, 45 (8.2%) and 75 (13.4%) had died at 30 and 90 days, respectively. Preoperative emergency transport, type of heterotaxy syndrome, low hospital volume, the repair of total anomalous pulmonary vein connection, and the repair of a common atrioventricular valve were identified as significant predictive factors for operative mortality.

Conclusions: Improvements in some medical circumstances, such as fetal diagnosis and the patient transport system, will be needed to improve outcomes for severely ill patients with heterotaxy syndrome. This study describes early outcomes for the largest number of main cardiovascular surgeries to date in infants with heterotaxy syndrome.

Heterotaxy syndrome, a condition in which there is abnormal arrangement of the internal thoraco-abdominal organs across the left-right axis of the body, is characterized by a wide variety of complex cardiac and extracardiac malformations.¹ Cardiac malformations are a major component of heterotaxy syndrome and result in significant mortality and morbidity resulting from arrhythmia and infection.²

In recent decades, there have been improvements in the surgical outcomes of patients with heterotaxy syndrome.^3,4 Outcomes are reportedly better for patients with left isomerism than right isomerism, with the latter group having a high mortality rate after cardiovascular surgery for right isomerism and single ventricle.⁵

The surgical strategy for patients with heterotaxy syndrome (e.g., surgical methods and the timing of the initial surgical intervention) is very important for improving operative mortality. However, treatment strategies for patients with heterotaxy syndrome, including pre- and postoperative management, are not standardized and vary among facilities. Moreover, only a limited number of previous studies have evaluated treatment strategies on a relatively small number of patients in each study.

The aims of this study were to: (1) evaluate mortality and morbidity rates after any of 8 cardiovascular surgeries as the initial palliation for patients with heterotaxy syndrome; and (2) determine predictors of mortality and morbidity in patients enrolled in the present multicenter nationwide Japanese study.

Methods

When applicable, Institutional Review Board (IRB) approval was obtained from each of the study sites on the Committee of the Japanese Cardiovascular Surgery Database (IRB no. CA19-9, 2019). Owing to the retrospective nature of the study, the requirement for individual informed consent was waived.

Data Collection

The Japanese Cardiovascular Surgery Database Organization Committee granted permission to access and analyze the data collected in the Japanese Congenital Cardiovascular Surgery Database (JCCVSD) for this study. The JCCVSD collects clinical data from 119 domestic institutions specializing in congenital heart disease, covering almost all major congenital heart surgery programs in Japan.^6,7 Clinical data on preoperative, operative, and postoperative characteristics, and survival data within 30 and 90 days, were available from the JCCVSD.

Our data collection was as follows. First, from a total of 36,141 files in the JCCVSD for the period 2014–2020, we extracted 3,399 cases registered as heterotaxy syndrome/asplenia syndrome/polysplenia syndrome in the “syndrome” field and/or registered as single ventricle and heterotaxy syndrome in the “diagnosis” field (most patients were registered in both the “syndrome” and “diagnosis” fields). We then filtered the extracted data for patients who underwent initial palliation and selected 1,009 cases. Finally, we chose 561 patients who underwent any of 8 specific cardiovascular surgeries (Figure). The 8 specific cardiovascular surgeries were modified Blalock-Taussig (BT) shunt, central shunt, other types of shunt procedures, pulmonary artery banding (PAB), total anomalous pulmonary vein connection (TAPVC) repair, TAPVC repair plus shunt procedure, bidirectional Glenn (BDG), and bilateral BDG. “Hospital volume” was defined according to the average number of cardiovascular surgeries performed using cardiopulmonary bypass (CPB) per year over the past 5 years. Hospitals were divided into 2 groups based on the number of surgeries per year: ≥50 (n=484) or <50 (n=77).

Figure.

Data collection protocol. BDG, bidirectional Glenn; BT, Blalock-Taussig; JCCVSD, Japanese Congenital Cardiovascular Surgery Database; PAB, pulmonary artery banding; TAPVC, total anomalous pulmonary vein connection.

The primary outcome was mortality at 30 and 90 days after surgery. The JCCVSD obliged medical practitioners to enter life prognosis and complications, including readmission at 90 days after surgery even if the patient was discharged, so that mortality and morbidity data up to 90 days were complete. Secondary outcomes were the absence of postoperative arrhythmia and infection, as morbidities, extracted from the postoperative complication section.

Statistical Analysis

Categorical variables are presented as numbers and percentages. Continuous variables are presented as the median with ranges or as the mean±SD. The significance of differences in demographic and clinical data was evaluated using the unpaired Student’s t-test, Mann-Whitney’s U-test, or Kruskal-Wallis test for continuous variables, and Fisher’s exact test for categorical variables, as applicable. We also conducted multivariable logistic regression with independent variables and a forward-backward stepwise selection method. P<0.05 was considered statistically significant. All statistical analyses were performed using R version 3.6 and later (R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient Demographics

In all, 561 patients met the inclusion criteria and were eligible for analysis (Table 1). There were 282 (50.3%) male patients and 279 (49.7%) female patients. A fetal diagnosis was made for 414 (73.8%) patients. Forty (7.1%) patients were delivered preterm, and 17 (3.3%) were premature babies. Emergency transport was needed for 131 (23.4%) patients. Extracardiac malformations were observed in 71 (12.6%) patients. Ninety-eight (17.5%) patients had polysplenia and 463 (82.5%) did not. The most common fundamental diagnosis was single ventricle, heterotaxy syndrome (n=350; 62.3%), followed by single ventricle with TAPVC (n=46; 8.9%), TAPVC (n=30; 5.3%), and atrioventricular defect (n=24; 4.3%). In all, TAPVC was present in 169 (30.1%) patients. A preoperative cardiac catheter study was performed in 169 (30.1%) patients.

Table 1.

Patient Characteristics (n=561)

Sex: Female/male (n)	279/282
Fetal diagnosis	414 (73.8)
Early delivery	40 (7.1)
Premature baby	17 (3.3)
Emergency transport	131 (23.3)
Main fundamental diagnosis
Single ventricle, heterotaxy syndrome	350 (62.3)
Single ventricle with TAPVC	46 (8.9)
TAPVC	30 (5.3)
AVSD	24 (4.3)
DORV with AVSD	9 (1.6)
Polysplenia	98 (17.5)
Non-polysplenia	463 (82.5)
Extracardiac malformation	71 (12.6)
Presence of TAPVC	169 (30.1)
Hospital volume
No. cardiovascular surgeries <50 per year	77 (13.7)
No. cardiovascular surgeries ≥50 per year	484 (86.3)

Unless indicated otherwise, data are given as n (%). AVSD, atrioventricular septal defect; DORV, double outlet right ventricle; TAPVC, total anomalous pulmonary vein connection.

Operative Characteristics

The median age of patients at the time of any of the 8 cardiovascular surgeries was 34.0 days. Surgical palliation was performed <28 days after birth in 255 (45.5%) patients. The median body weight at the time of the surgeries was 3.3 kg (mean 4.5±5.7 kg). The most common surgery performed was modified BT shunt (n=182; 32.4%), followed by PAB (n=144; 25.7%), TAPVC repair (n=114; 20.3%), BDG (n=51; 9.1%), TAPVC repair plus shunt procedure (n=49; 8.7%), bilateral BDG (n=48; 8.6%), central shunt (n=43;7.7%), and other types of shunt procedures (n=10; 1.8%). As additional palliations, pulmonary artery plasty was performed in 87 (15.5%) patients and common atrioventricular valve plasty (CAVVP) was performed in 42 (7.5%). In aggregate, TAPVC repair was undertaken in 165 (29.4%) patients. CPB was used in 375 (66.8%) patients and the mean duration of CPB was 160.9±95.1 min (median 140 min). During CPB, the aorta was clamped in 231 (41.2%) patients and the mean duration of aortic cross-clamping was 66.8±43.0 min (median 59 min). In addition, circulatory arrest was used in 33 (5.9%) patients.

Mortality and Morbidity

The median length of hospitalization was 30.0 days (mean 52.5±62.1 days). Deaths at 30 and 90 days numbered 45 (8.0%) and 75 (13.4%), respectively. There were 6 deaths after discharge. The main causes of mortality at 30 days were cardiac (n=30), respiratory (n=14), infection (n=5), cerebral (n=3), and other causes (n=2), with 1 patient having more than 1 cause. The main causes of mortality at 90 days were cardiac (n=52), respiratory (n=18), infection (n=6), cerebral (n=3), and other causes (n=9).

Postoperative arrhythmia was observed in 117 (20.9%) patients and infection was seen in 60 (10.7%) patients. Postoperative extracorporeal membrane oxygenation was used in 51 (9.1%) patients. Reinterventions 3 months after the initial palliation were performed in 101 patients, and the most common type of reintervention was cardiovascular surgery (n=87), followed by catheter intervention (n=22), other organ surgery (n=22), and rethoracotomy for bleeding (n=14).

Independent Predictors for Operative Mortality

The results of univariable logistic regression analysis of 90-day mortality and each categorical variable are summarized in Table 2. Emergency transport (P=0.028), type of heterotaxy syndrome (P=0.003), presence of TAPVC (P=0.045), low hospital volume (P=0.016), age at initial palliation (P<0.001), body weight at initial palliation (P<0.001), use of CPB (P=0.004), use of cardiac arrest (P=0.003), TAPVC repair (P<0.001), and additional CAVVP (P<0.001) were identified as independent predictors of 90-day mortality. The results of the multivariable logistic regression analysis for 90-day mortality and each categorical variable are summarized in Table 3. Emergency transport (odds ratio [OR] 2.10; P=0.03), type of heterotaxy syndrome (OR 0.23; P=0.01), low hospital volume (OR: 2.77; P=0.05), TAPVC repair (OR: 4.94; P<0.01), and additional CAVVP (OR:5.54; P<0.01) were identified as significant predictive factors for 90-day mortality.

Table 2.

Univariable Logistic Regression Analysis of Factors Associated With 90-Day Mortality

Factor	Group	No. patients	No. deaths	P value
Sex	Female	279	31	0.118
	Male	282	44
Fetal diagnosis	Yes	414	51	0.220
	No	147	24
Early delivery	Yes	40	7	0.426
	No	521	68
Emergency transport	Yes	131	25	0.028
	No	430	50
Type of heterotaxy	Polysplenia	98	4	0.003
	Non-polysplenia	463	71
Presence of TAPVC	Yes	169	30	0.045
	No	392	45
Hospital volume (cardiac surgeries/year)	≤49	77	17	0.016
	≥50	484	58
Age at initial palliation	≤28 days	255	52	<0.001
	28 days–3 months	161	15
	≥3 months	145	8
BW at initial palliation (kg)	0–2.5	55	13	<0.001
	2.5–3	140	26
	3–3.5	120	23
	3.5–5	122	10
	≥5	124	3
CPB	Yes	375	61	0.004
	No	186	14
Circulatory arrest	Yes	33	10	0.003
	No	528	65
TAPVC repair	Yes	165	46	<0.001
	No	396	29
Additional PA plasty	Yes	87	12	0.899
	No	474	63
Additional CAVV plasty	Yes	42	13	<0.001
	No	519	62

BW, body weight; CAVV, common atrioventricular valve; CPB, cardiopulmonary bypass; PA, pulmonary artery; TAPVC, total anomalous pulmonary vein connection.

Table 3.

Multivariable Logistic Regression Analysis of Factors Associated With 90-Day Mortality

Factor	Group	OR	95% CI	P value
Sex	Female	1.74	0.99–3.06	0.05
	Male	1 (Ref.)
Emergency transport		2.20	1.19–4.07	0.01
Type of heterotaxy	Polysplenia	0.25	0.08–0.75	0.01
	Non-polysplenia	1 (Ref.)
Presence of TAPVC		0.57	0.29–1.10	0.09
Hospital volume (cardiac surgeries/year)	≤49	4.17	1.99–8.76	<0.01
	≥50	1 (Ref.)
BW at the initial palliation (kg)	≤2.5	1 (Ref.)
	2.5–3	0.89	0.38–2.08	0.79
	3–3.5	0.95	0.40–2.26	0.91
	3.5–5	0.45	0.17–1.21	0.11
	≥5	0.08	0.92–0.31	<0.01
TAPVC repair		5.22	2.67–10.18	<0.01
Additional CAVV plasty		5.72	2.27–14.46	<0.01

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 2.

As mentioned above, type of heterotaxy was a significant predictive factor for operative mortality in multivariable analysis; thus, we conducted multivariable logistic regression with independent variables after dividing patients into 2 groups according to the type of heterotaxy. In the polysplenia group, there was no predictive factor for 90-day mortality. Conversely, in non-polysplenia group, emergency transport (OR 2.20; P=0.02), low hospital volume (OR 3.76; P<0.01), TAPVC repair (OR 5.23; P<0.01), and additional CAVVP (OR 5.12; P<0.01) were identified as significant predictive factors for 90-day mortality.

Independent Predictors of Morbidity

Arrhythmia The results of the univariable logistic regression analysis for postoperative arrhythmia and each categorical variable are summarized in Table 4. Emergency transport (P=0.001), presence of TAPVC (P<0.001), use of CPB (P<0.001), use of circulatory arrest (P=0.024), TAPVC repair (P<0.001), and additional CAVVP (P<0.001) were identified as independent predictors of postoperative arrhythmia. The results of the multivariable logistic regression analysis for postoperative arrhythmia are summarized in Table 5. Emergency transport (OR 2.32; P<0.01), the use of CPB (OR 3.75; P<0.001), and additional CAVVP (OR 2.79; P<0.01) were identified as significant predictive factors for postoperative arrhythmia. In addition, age <28 days at operation (OR 2.10, P=0.02; reference: age >3 months) was also an independent predictor for postoperative arrhythmia.

Table 4.

Univariable Logistic Regression Analysis of Factors Associated With Postoperative Arrhythmia

Factor	Group	No. patients	No. with arrhythmia	P value
Sex	Female	279	55	0.508
	Male	282	62
Fetal diagnosis	Yes	414	80	0.134
	No	147	37
Early delivery	Yes	40	10	0.503
	No	521	107
Emergency transport	Yes	131	41	0.001
	No	430	76
Type of heterotaxy	Polysplenia	98	18	0.505
	Non-polysplenia	463	99
Presence of TAPVC	Yes	169	51	<0.001
	No	392	66
Hospital volume (cardiac surgeries/year)	≤49	77	16	0.986
	≥50	484	101
Age at initial palliation	≤28 days	255	64	0.078
	28 days–3 months	161	28
	≥3 months	155	25
BW at initial palliation (kg)	0–2.5	55	11	0.330
	2.5–3	140	36
	3–3.5	120	28
	3.5–5	122	21
	≥5	124	20
CPB	Yes	375	102	<0.001
	No	186	15
Circulatory arrest	Yes	33	12	0.024
	No	528	105
TAPVC repair	Yes	165	58	<0.001
	No	396	59
Additional PA plasty	Yes	87	23	0.163
	No	474	94
Additional CAVV plasty	Yes	42	18	<0.001
	No	519	99

Abbreviations as in Table 2.

Table 5.

Multivariable Logistic Regression Analysis of Factors Associated With Postoperative Arrhythmia

Factor	Group	OR	95% CI	P value
Emergency transport		2.32	1.43–3.77	<0.01
Age at initial palliation	≤28 days	2.10	1.15–3.83	0.02
	28 days–3 months	1.30	0.68–2.46	0.43
	≥3 months	1.00 (Ref.)
CPB	Yes	3.75	1.88–7.47	<0.01
TAPVC repair	Yes	1.62	0.96–2.73	0.07
Additional CAVV plasty	Yes	2.79	1.38–5.65	<0.01

Abbreviations as in Tables 2,3.

Infection The results of the univariable and multivariable logistic regression analysis for postoperative infection and each categorical variable are summarized in Tables 6 and 7, respectively. Age at initial palliation (P=0.026) was an independent predictor of postoperative infection based on univariable analysis. In addition, being aged between 8 days and 3 months at the time of the surgery (OR 0.34, P=0.05; reference: age >3 months) was the only predictive factor in the multivariate analysis for postoperative infection.

Table 6.

Univariable Logistic Regression Analysis of Factors Associated With Postoperative Infection

Factor	Group	No. patients	No. with infection	P value
Sex	Female	279	29	0.819
	Male	282	31
Fetal diagnosis	Yes	414	50	0.076
	No	147	10
Early delivery	Yes	40	4	0.883
	No	521	56
Emergency transport	Yes	131	13	0.744
	No	430	47
Type of heterotaxy	Polysplenia	98	7	0.210
	Non-polysplenia	463	53
Presence of TAPVC	Yes	169	19	0.783
	No	392	41
Hospital volume (cardiac surgeries/year)	≤49	77	6	0.375
	≥50	484	54
Age at initial palliation	≤28 days	255	37	0.026
	28 days–3 months	161	11
	≥3 months	145	12
BW at initial palliation (kg)	0–2.5	55	10	0.073
	2.5–3	140	16
	3–3.5	120	12
	3.5–5	122	16
	≥5	124	6
CPB	Yes	375	38	0.541
	No	186	22
Circulatory arrest	Yes	33	2	0.375
	No	528	58
TAPVC repair	Yes	165	20	0.481
	No	396	40
Additional PA plasty	Yes	87	10	0.793
	No	474	50
Additional CAVV plasty	Yes	42	6	0.434
	No	519	54

Abbreviations as in Table 2.

Table 7.

Multivariable Logistic Regression Analysis of Factors Associated With Postoperative Infection

Factor	Group	OR	95% CI	P value
Fetal diagnosis	Yes	1.82	0.88–3.73	0.10
Type of heterotaxy	Non-polysplenia	1.96	0.85–4.55	0.11
	Polysplenia	1 (Ref.)
Age at initial palliation	≤28 days	1.03	0.31–3.38	0.97
	28 days–3 months	0.34	0.12–1.01	0.05
	≥3 months	1 (Ref.)
BW at initial palliation (kg)	0–2.5	1 (Ref.)
	2.5–3	0.63	0.26–1.52	0.31
	3–3.5	0.63	0.25–1.62	0.34
	3.5–5	1.17	0.39–3.51	0.78
	≥5	0.22	0.04–1.05	0.06
Circulatory arrest	Yes	0.36	0.08–1.58	0.17

Abbreviations as in Tables 2,3.

Discussion

This Japan-wide multicenter study from the JCCVSD provides a detailed analysis of the initial surgical outcomes of patients with heterotaxy syndrome. Deaths at 30 and 90 days after any of the 8 specific initial cardiovascular surgeries performed in 561 patients with heterotaxy syndrome numbered 45 (8.2%) and 75 (13.4%), respectively. In addition, emergency transport, type of heterotaxy syndrome, low hospital volume, TAPVC repair, and additional CAVVP were identified as significant predictive factors for 90-day mortality. To the best of our knowledge, this study describes early outcomes for the largest number of main cardiovascular surgeries reported recently in the literature among infant patients with heterotaxy syndrome.

Study Design

Every file in the JCCVSD was registered on a surgery basis; thus, different kinds of surgeries for patients with heterotaxy syndrome were registered. First, we limited the initial palliations to avoid duplication. In addition, we decided to limit our study to patients undergoing any of the 8 major cardiovascular surgeries that directly affect hemodynamics. This was done so we could focus on the outcomes of cardiovascular surgeries with hemodynamic changes among infants.

Mortality

The surgical outcomes for patients with heterotaxy syndrome have improved recently.^3,4 Anagnostopoulos et al. reported that there were 3 hospital deaths from 45 consecutive patients with heterotaxy syndrome who underwent surgical palliation.³ Chen et al. reported a hospital mortality rate of 4.7% for 42 patients with heterotaxy syndrome whose median age was 6.8 months (range 5 days–22.3 years).⁸ However, the number of patients enrolled in both these studies was relatively small, and the age at the time of surgery also varied because some adolescent patients were included. In the present study, we limited patients to those who underwent an initial palliation and representative cardiovascular surgeries that may affect hemodynamics. In this study, among the 561 selected patients with heterotaxy syndrome, 75 (13.4%) had died by 90 days after any of the 8 designated cardiovascular surgeries. The median and mean lengths of hospitalization were 30.0 and 48.4 days, respectively. From these results, in this group of patients, operative death could be defined as death before 90 days after surgery.

TAPVC Repair

TAPVC repair in patients with heterotaxy syndrome carries a high risk of mortality. Khan et al. reported a discharge mortality of 38% for patients with heterotaxy syndrome who underwent TAPVC repair.⁹ In our study, mortality at 90 days in patients with TAPVC repair was 27.9% (46/165), comparable with previous findings. TAPVC repair was identified as an independent predictor of 90-day mortality. However, the presence of TAPVC itself was not identified as a factor predicting mortality in this study. These results are consistent with our previous study from a single institution.⁵

TAPVC encompasses various subtypes of pulmonary vein connections and presents with different clinical conditions. From these result, TAPVC repair at the initial palliation may be avoided unless TAPVC aggravates hemodynamics, such as pulmonary vein obstruction. However, most patients with TAPVC repair in the present study were thought to have various levels of pulmonary vein obstruction; thus, TAPVC repair could not be delayed.

Hospital Volume

Hospital volume was a predicted risk factor for 30- and 90-day mortality, and the OR of a low-volume center (i.e., mean number of cardiovascular surgeries with CPB <50 per year) for mortality at 90 days was 4.17. Differences in surgical outcomes between high- and low-volume centers are unavoidable. To compensate for this difference, a patient transportation system, including infants with cardiovascular disease, has been established in Japan. However, based on our results, we can speculate that some severely ill patients with heterotaxy syndrome cannot be transported safely. Conversely, fetal diagnosis has recently increased in Japan, which may lead to early diagnosis and a decrease in the transportation of severely ill patients from their place/hospital of birth. In fact, in our study, 414 (73.8%) patients received a fetal diagnosis and we can expect an improvement in mortality from a more aggressive instigation of fetal diagnoses. In a systematic review, Buca et al. reported that approximately one-quarter of fetuses with heterotaxy syndrome died during or after surgery.¹⁰ It may be difficult to save all patients with heterotaxy syndrome, even with an aggressive instigation of fetal diagnoses and improvements in the patient transportation system. However, improvements in such medical systems will be needed for severely ill patients just after birth.

Morbidity

The JCCVSD registers various postoperative complications, as well as preoperative, perioperative, and mortality data. Based on these data, we chose postoperative arrhythmia and postoperative infection as morbidity factors because they are well-known frequent and important postoperative complications. However, each facility has different management strategies to address them.

Heterotaxy syndrome is associated with complex cardiac malformation and abnormal cardiac conduction systems. Patients with right isomerism are reported to have dual sinus nodes and dual atrioventricular nodes, leading to tachycardia; conversely, those with left isomerism are reported not to have normal sinus and atrioventricular nodes, leading to bradycardia.^11,12 However, there are limited reports regarding the prevalence of postoperative arrhythmia in heterotaxy syndrome, especially in infants.

In the present study, emergency transport, additional CAVVP, the use of CPB, and age <28 days at the time of surgery (reference: age >3 months) were identified as independent predictors for postoperative arrhythmia. However, polysplenia and non-polysplenia were not significant predictors. We speculate that the reason for this was that postoperative arrhythmia included various kinds of arrhythmias, including atrial tachycardia and atrioventricular block. The most important result was the high incidence rate of postoperative arrhythmias (117/561; 20.9%). Cardiac involvement was the most frequent cause of mortality, and we speculate that arrhythmia was the most important cardiac cause of death.

Because most patients with heterotaxy syndrome have splenic hypofunction, they are susceptible to bacterial infection.^13,14 Sepsis after cardiovascular surgery is thought to be a crucial risk factor for morbidity and mortality in patients with heterotaxy syndrome.^15,16 However, there are few reports about postoperative infection, especially in infants. In the present study, the incidence of postoperative infection was 10.7% (60/561), and infection was not a major cause of mortality in this group.

Single Ventricle and Heterotaxy Syndrome

Several studies have previously reported poor outcomes in children with heterotaxy syndrome following Glenn or Fontan surgeries.^17,18 Conversely, Marathe et al. recently reported that once the Fontan procedure was successfully completed, heterotaxy syndrome did not appear to be an important risk factor for Fontan failure.¹⁹ We also reported that heterotaxy syndrome was not an independent factor associated with mortality and morbidity in patients after the Fontan procedure.²⁰ Thus, it is important for patients with single ventricle and heterotaxy syndrome to undergo the Fontan procedure and for them to have good hemodynamics after the procedure. Thus, the treatment strategy to ensure good Fontan outcomes, including the content and timing of first-stage palliation, even before birth, must be considered for patients with heterotaxy syndrome. From the results of the present study, hospital volume, fetal diagnosis, and patient transport are important factors for these high-risk groups. A future study investigation Fontan completion in patients with heterotaxy syndrome in Japan is currently being planned.

Study Limitations

This study had some limitations. This retrospective study was conducted using data from the JCCVSD, a national clinical database, in which data entry was completed voluntary. Although we conducted site visits to some hospitals included in the JCCVSD to enhance the reliability of the database, these visits were not sufficient and were hindered by the outbreak of the COVID-19 pandemic. In addition, the database lacks some important information, such as details about heterotaxy syndrome subtypes. However, it is difficult to follow and revise the data.

Conclusions

Based on the results of this multicenter nationwide Japanese study, cardiovascular surgery for infant patients with heterotaxy syndrome remains challenging. Improvements in some medical systems, such as the consolidation of facilities, increasing rates of fetal/remote diagnosis, and improving the patient transport system, will be needed to better the surgical outcomes for severely ill patients with heterotaxy syndrome.

Acknowledgments

The authors thank Editage (www.editage.com) for English language editing a draft of this manuscript.

Sources of Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Disclosures

The authors have no conflicts of interest to disclose. None of the authors has any financial or personal relationship with other people or organizations that could inappropriately influence their work.

IRB Information

IRB approval was obtained when applicable from each of the study sites on the Committee of the Japanese Cardiovascular Surgery Database (IRB no. CA19-9).

Data Availability

The data underlying this article cannot be shared publicly in order that the privacy of the study participants is maintained. After all pertinent regulatory approvals are obtained, deanonymized data will be shared upon reasonable request to the corresponding author.

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