Heterotaxy syndrome, also known as isomerism, encompasses a heterogeneous group of laterality disorders involving thoracoabdominal visceral organs. It is frequently associated with complex cardiac defects and anomalies in venous return. Although rare, comprising 2-3% of all congenital heart diseases (CHDs), these conditions often necessitate heart transplantation due to the anatomical complexity that hinders successful univentricular palliations or reparations. Previous studies and blog entries have highlighted these patients as a high-risk group for cardiac surgery, with poorer morbidity and mortality outcomes compared to other CHDs. However, data specifically on transplantation are scarce.
The article under review analyzed outcomes of heart transplantation in children with heterotaxy syndrome using cross-referenced data from the United Network for Organ Sharing (UNOS) and the Pediatric Health Information System (PHIS) registries. It included patients under 18 years of age who underwent heart transplantation between 2016 and 2019, excluding those with genetic anomalies. The cohort was divided into three groups: heterotaxy, other CHDs, and cardiomyopathies. Data were collected on demographics, clinical variables (such as dialysis, mechanical ventilation, ECMO, or ventricular assistance), waiting list and ischemia times, and post-transplant outcomes (mortality, hospital stay duration, primary graft dysfunction, stroke, rejection, pacemaker or dialysis requirements). Non-parametric methods were used for univariate analysis, while Kaplan-Meier survival curves and log-rank tests evaluated survival. A Cox regression model was developed for the heterotaxy group, incorporating previously identified risk factors for worse post-transplant survival.
A total of 1,122 patients were analyzed: 143 in the heterotaxy group, 428 in the other CHDs group, and 551 in the cardiomyopathy group. The baseline characteristics of the heterotaxy and other CHDs groups were similar, with both groups having younger and lighter patients compared to the cardiomyopathy group. Patients with heterotaxy and other CHDs required more inotropic support and mechanical ventilation but were less likely to receive ventricular assist devices at the time of transplantation. ECMO use was low and comparable across all groups. The waiting list duration was longer for the heterotaxy group (91 days vs. 63 days for other CHDs vs. 56 days for cardiomyopathies; p < .001). Ischemia time was comparable between the heterotaxy and other CHD groups and longer than for cardiomyopathies (3.8 h vs. 3.4 h; p < .001). Operative mortality was 1% for cardiomyopathies and 4% for the other two groups (p < .001). There were no significant differences in other post-transplant complications. Hospital stays were shorter in the cardiomyopathy group (57 days vs. 99 days for other CHDs vs. 89 days for heterotaxy; p < .001). Rejection rates during hospitalization were similar across groups; however, at one year post-transplant, rejection rates were higher for heterotaxy (22% vs. 19% for other CHDs vs. 13% for cardiomyopathies; p < .001). Five-year survival was highest in the cardiomyopathy group (87%), followed by other CHDs (78%) and heterotaxy (69%), primarily due to lower early mortality in the cardiomyopathy group. A more pronounced survival decline was observed in the heterotaxy group around the three-year mark, although this difference did not reach statistical significance. No risk factors significantly affecting survival were identified in the multivariable analysis for the heterotaxy group.
COMMENTARY:
As previously noted, cardiac surgery in patients with heterotaxy syndrome carries higher morbidity and mortality compared to other CHDs. Despite the expectation that similar factors might adversely impact transplantation outcomes (e.g., venous return anomalies, prior univentricular palliations necessitating complex vascular reconstructions, challenging re-sternotomies, and extracardiac conditions like primary ciliary dyskinesia, immunodeficiency, and gastrointestinal anomalies), this study found no significant differences in procedural mortality, ischemia times, hospital stays, or postoperative complications between heterotaxy and other CHD groups. The authors attribute this to improved case selection for the transplantation waiting list, the more recent cohort analyzed, and greater surgical experience. Consistent with previous findings, global mortality remained higher for CHD patients (with and without heterotaxy) compared to cardiomyopathy patients, who exhibited better pre-transplant clinical stability due to higher rates of ventricular assistance.
The greater heterogeneity of heterotaxy patients presents challenges for study and classification. Improved coding systems, such as ICD-10, have enabled better identification, but the limited follow-up period (three years) restricts long-term outcome evaluation. Additionally, the lack of differentiation between subgroups (e.g., left vs. right atrial isomerism or biventricular vs. univentricular defects) limits the granularity of the data. The absence of pre-transplant evolution metrics, such as waiting list mortality, introduces potential survival bias.
The slightly elevated one-year rejection rate in the heterotaxy group could reflect heightened sensitization from prior surgeries. However, data on pre-transplant procedural history and anti-HLA antibodies were insufficient. Similarly, immune suppression adjustments for infection risks in heterotaxy-associated immunodeficiencies were not addressed, highlighting areas for further research.
Despite its limitations, this study provides valuable insights into an under-researched population. The findings suggest that transplantation outcomes for children with heterotaxy are comparable to other CHDs, supporting their inclusion in transplant lists before clinical deterioration compromises prognosis. Future research should aim to confirm these findings and explore the specific characteristics of this group in greater depth.
REFERENCE:
Alsoufi B, Kozik D, Lambert AN, Deshpande S, Sparks JD, Trivedi J. Outcomes of heart transplants in children with heterotaxy syndrome. Eur J Cardiothorac Surg. 2024 Jun 3;65(6):ezae204. doi: 10.1093/ejcts/ezae204.
