Impact of gastrointestinal comorbidities in patients with right and left atrial isomerism.

BACKGROUND AND AIM: Heterotaxy syndrome, being right atrial isomerism (RAI) or left atrial isomerism (LAI), often presents with Congenital Heart Disease (CHD). Intestinal abnormalities, including malrotation are common. We assessed the spectrum of gut abnormalities and their impact on medium-term outcome in a cohort of patients with fetal and postnatal diagnoses of heterotaxy syndrome. METHODS: We reviewed the cardiology records of heterotaxy syndrome patients from two centres, regarding the presence of CHD, time for cardiac intervention, presence of gastrointestinal abnormalities, and type/time of surgery. A questionnaire about gastrointestinal status was sent to patients <18 years old. Kaplan-Meier curves were derived for survival data and freedom from intervention. RESULTS: Data were included for 182 patients (49 RAI and 133 LAI) of 247 identified. Questionnaires were sent to 77 families and 47 replied. CHD was present in all RAI and 61.7% of LAI cases. Thirty-eight patients had abdominal surgery (20.9%), similar for RAI and LAI (20.4% versus 21%, p> 0.99): Ladd procedure in 17 (44.7%), non-Ladd in 12 (31.5%), and both procedures in 9 (23.7%). Ten-year freedom from Ladd procedure for all was 86% for the whole cohort (RAI = 87%; LAI = 85%, p = 0.98). Freedom from any gastrointestinal surgery at 10 years was 79% for the whole cohort (RAI = 77%; LAI = 80%, p = 0.54). Ten-year freedom from cardiac surgery was 31% for the whole cohort (RAI = 6%; LAI = 43%, p < 0.0001). CONCLUSIONS: In our cohort, one in five patients required abdominal surgery, mostly in their first year of life, similar for RAI and LAI. Between 1 and 10 years of follow-up, the impact of gastrointestinal abnormalities on outcome was minimal. Medium term survival was related to CHD.

Analysis of outcomes in patients with abnormal laterality undergoing congenital heart surgery.

OBJECTIVE: Laterality anomalies are almost always associated with severe cardiac anomalies. Demographic properties, type of the procedures, associated anomalies, and early and mid-term prognosis of four types of laterality anomalies were analysed. METHODS: A total of 64 consecutive patients with laterality anomalies were enrolled between July 2014 and July 2020. We grouped the patients as situs solitus dextrocardia (SSD) (n = 12; 18.7%); situs inversus (SI) (n = 16; 25%); right atrial isomerism (RAI) (n = 29; 45.3%); and left atrial isomerism (LAI) (n = 7; 10.9%). TAPVC was only present in the RAI group (31%). Incidence of mitral or tricuspid atresia was higher in the SSD group (25%). All the patients were followed up with a mean of 19.06 ± 17.6 (0.1-72) months. RESULTS: Early postoperative mortality was 17 patients, among 107 procedures (15.8%). Twelve patients were in the neonatal period. All ten patients survived after isolated ductal stenting. Fourteen of the deaths were in the RAI group (48.3%). The 3-year survival rates were 85% in LAI, 78.7% in SI, 55.8% in SSD, and 38% in RAI groups. According to the multivariable Cox regression model, mechanical ventilation, kidney injury, RAI, and complex surgery in the neonatal period were independent risk factors for early mortality. CONCLUSION: Laterality anomalies are one of the most challenging patients who commonly had univentricular physiology. The most prevalent anomaly was RAI, and RAI had the worst outcome and survival. Ductal stent is an acceptable first intervention during the neonatal period in suitable patients. Complex procedures may carry a high risk of death in the neonatal period.

Inflammation, Active Fibroplasia, and End-stage Fibrosis in 172 Biliary Atresia Remnants Correlate Poorly With Age at Kasai Portoenterostomy, Visceral Heterotaxy, and Outcome.

Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects <30 days old at KHPE and in those with visceral anomalies. Prevalence of partially preserved epithelium in active fibroplastic biliary atresia lesions at all ages suggests that epithelial regression or injury may not be a primary event or that reepithelialization is already underway at the time of KHPE. We hypothesize that outcome after KHPE results from competition between active fibroplasia and reepithelialization of retained, collapsed but not obliterated lumens. The driver of active fibroplasia is unknown.

Heterotaxy Syndrome and Intestinal Rotation Abnormalities.

BACKGROUND: Infants with heterotaxy syndrome (HS) have abnormal lateralization of organs along the right-left body axis. Intestinal rotation abnormalities (IRAs) are a potential source of morbidity and mortality. For this study, our objective was to prospectively observe a cohort of infants with HS and determine the incidence and natural history of IRA. METHODS: Infants ≤6 months of age with HS were enrolled in this prospective observational study. Exclusion criteria were other congenital abnormalities that necessitated abdominal surgery. HS was defined as any arrangement of organs that was not situs solitus or situs inversus along with associated congenital heart disease. The investigation for IRA was at the discretion of each participating center. RESULTS: Infants were recruited from January 2012 to December 2016. Thirty-eight infants from 7 institutions were included; 22 infants had right isomerism and 16 infants had left isomerism. Twenty-nine infants (76%) were evaluated for IRAs; 21 of 29 evaluations (72%) were abnormal. Eight infants were investigated because of symptoms, and 21 infants were evaluated routinely. The median age at symptom presentation was 46 days (range: 5-171 days). Seven infants had a Ladd procedure; 4 were prophylactic, with 3 as part of a combined procedure, and 3 were emergent. No child suffered acute midgut volvulus over a median follow-up of 1.6 years (range: 0.06-4.93 years). CONCLUSIONS: IRAs are common in infants with HS. Infants with symptoms presented by 6 months of age. There was no failure of expectant management resulting in midgut volvulus during a median follow-up of 1.6 years.

Neonatal Outcomes in Total Anomalous Pulmonary Venous Return: The Role of Prenatal Diagnosis and Pulmonary Venous Obstruction.

The objective of this study is to evaluate neonatal outcomes of total anomalous pulmonary venous return (TAPVR) and identify fetal echocardiography findings associated with preoperative pulmonary venous obstruction (PPVO). This retrospective study evaluated TAPVR cases from 2005 to 2014 for preoperative and postoperative outcomes based on prenatal diagnosis, PPVO, and heterotaxy syndrome. Fetal pulmonary and vertical vein Dopplers were analyzed as predictors of PPVO. Of 137 TAPVR cases, 12% were prenatally diagnosed; 60% had PPVO, and 21% had heterotaxy. Of the prenatally diagnosed patients, 63% also had heterotaxy. TAPVR repair was performed in 135 cases and survival to discharge was 82% (112/137). Heterotaxy was the only independent predictor of mortality on multiple regression analysis [OR 5.5 (CI 1.3-16.7), p = 0.02]. PPVO was associated with preoperative acidosis, need for inhaled nitric oxide, and more emergent surgery, but not postoperative mortality. Fetal vertical vein Doppler peak velocity > 0.74 m/s mmHg predicted PPVO (93% sensitivity; 83% specificity) while pulmonary vein Doppler did not. TAPVR has severe neonatal morbidity and mortality with low prenatal diagnosis rates in the absence of heterotaxy. Patients with obstructed TAPVR had greater preoperative morbidity, but only heterotaxy was independently associated with increased postoperative mortality. Vertical vein velocity helped prenatally identify those at risk of PPVO.

Long-term outcome of patients with right atrial isomerism after common atrioventricular valve plasty.

OBJECTIVES: To review long-term outcomes of patients with right atrial (RA) isomerism who underwent common atrioventricular valve (CAVV) plasty. METHODS: We retrospectively analysed 59 patients with RA isomerism operated on between January 2004 and April 2016. We divided patients into those with CAVV plasty (CAVV plasty (+), 29 patients) and without CAVV plasty (CAVV plasty (-), 30), and we compared the outcome between the groups. We further divided patients into those with CAVV plasty before bidirectional cavopulmonary shunt (BCPS) operation (group before BCPS, 13 patients) or CAVV plasty with or after BCPS (group with or after BCPS, 16), and we compared the outcome between these groups. We reviewed the outcomes of 7 neonatal patients who underwent CAVV plasty. RESULTS: Kaplan-Meier estimated survival rates at 10 years were 70 ± 10% and 69 ± 9% in the CAVV plasty (+) and CAVV plasty (-) groups, respectively ( P = 0.45). Kaplan-Meier estimated survival rates at 10 years were 47 ± 17% and 85 ± 10% in the group before BCPS and group with or after BCPS, respectively ( P = 0.01). Among 7 neonates in the group before BCPS, 4 are alive; Kaplan-Meier estimated survival rates at 1 year and 5 years were 60 ± 20% and 30 ± 24%, respectively. CONCLUSIONS: Patients who underwent CAVV plasty with or after BCPS had good outcomes; the outcome of patients with CAVV plasty was the same as that of those without CAVV plasty. Treatment for patients who require CAVV plasty before BCPS, especially neonates, is challenging.

When the right (Drug) should be left: Prenatal drug exposure and heterotaxy syndrome.

BACKGROUND: Recent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome. METHODS: This case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally. RESULTS: A total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects. CONCLUSION: This study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. Birth Defects Research (Part A) 106:573-579, 2016. © 2016 Wiley Periodicals, Inc.

Screening and Treatment of Intestinal Rotational Abnormalities in Heterotaxy: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess the role of screening and prophylactic surgery for intestinal rotational abnormalities (IRAs) in asymptomatic patients with heterotaxy. STUDY DESIGN: PubMed, Embase, and Cinahl were searched electronically to determine the overall incidence of IRAs in heterotaxy; the detection rate of IRAs associated with screening; the incidence of midgut volvulus in patients without screening; and the incidence of morbidity and mortality after prophylactic and emergency Ladd procedures. Relevant data were computed with a meta-analysis of proportions. Between-study heterogeneity was assessed with the I(2) statistic. RESULTS: From 276 papers identified, 24 studies with a total of 1433 patients with heterotaxy were included for systematic review. No randomized study was identified. True incidence of IRA in heterotaxy could not be ascertained through meta-analysis. In patients who underwent screening, the incidence of IRA was 58%. Acute midgut volvulus occurred in 5.8% of those who did not undergo screening. Postoperative mortality after Ladd procedure mainly was associated with cardiac insufficiency, and overall it was significantly greater in the emergency group compared with the prophylactic group (18% vs 5.6%). The complication rate also was greater in case of emergency vs prophylactic abdominal surgery (27% vs 16%); adhesional small bowel obstruction was the most common complication overall (6%). CONCLUSION: The screen-detected incidences of IRA and acute midgut volvulus were significantly greater in heterotaxy than the normal population. Prophylactic Ladd procedure was associated with less morbidity and mortality compared with emergency surgery. A long-term prospective randomized trial is needed to define the indication for screening and prophylactic treatment of IRA in heterotaxy.

Heterotaxy Syndrome: Proceedings From the 10th International PCICS Meeting.

A session dedicated to heterotaxy syndrome was included in the program of the Tenth International Conference of the Pediatric Cardiac Intensive Care Society in Miami, Florida in December 2014. An invited panel of experts reviewed the anatomic considerations, surgical considerations, noncardiac issues, and long-term outcomes in this challenging group of patients. The presentations, summarized in this article, reflect the current approach to this complex multiorgan syndrome and highlight future areas of clinical interest and research.

The role of screening and prophylactic surgery for malrotation in heterotaxy patients.

PURPOSE: There are no standardized guidelines for screening or management of malrotation in Heterotaxy Syndrome (HS). We sought to review our experience to determine if evidenced based guidelines could be drafted. METHODS: A retrospective chart review was performed at our freestanding children's hospital on all patients under one year of age undergoing a Ladd procedure between 2000 and 2011. In addition, all Heterotaxy patients were reviewed during this period. RESULTS: Twenty-three Heterotaxy patients and seventy-nine Non-Heterotaxy patients underwent a Ladd procedure. Both groups had a high rate of complication. Heterotaxy was associated with significantly higher mortality 30days after Ladd procedure. In our review, we also identified seventy-six HS patients who did not undergo a Ladd procedure. Among these patients, fourteen had normal intestinal anatomy, five had malrotation, and fifty-seven were never evaluated for intestinal malrotation. No patients with intestinal malrotation or unknown intestinal rotation status suffered midgut volvulus. Average follow-up time was 5.1years. CONCLUSIONS: We conclude that prophylactic Ladd procedures in children with Heterotaxy are associated with a high morbidity and mortality. Patients who avoided screening were not exposed to a significant risk of midgut volvulus, and our experience suggests that routine screening of Heterotaxy patients for malrotation should be abandoned.

Heterotaxy syndrome and malrotation: does isomerism influence risk and decision to treat.

PURPOSE: Controversy remains regarding the management of the asymptomatic heterotaxy syndrome (HS) patient with suspected intestinal rotational abnormalities. We evaluated the outcomes for our HS population to identify frequency of malrotation and identify characteristics of children who might benefit from expectant management. METHODS: After IRB approval, a retrospective review of all patients treated for HS at a large tertiary care children's hospital between January 2008 and June 2012 was performed. For the purpose of this paper, malrotation was defined as an operative note that described the presence of Ladd's bands and a narrow mesentery. RESULTS: Thirty-eight patients with HS were identified, including 18 who underwent abdominal exploration. Left atrial isomerisation (LAI) was identified in 13 individuals, and right atrial isomerisation (RAI) was noted in 25. The rate of surgical intervention did not vary between the 2 groups (54%). Malrotation was found in 8 patients: one with LAI and 7 with RAI. This difference in incidence was statistically significant (p=0.04). CONCLUSION: These data suggest that the direction of atrial isomerisation influences the likelihood of true malrotation, where RAI patients are more likely to be malrotated. Given the inherent risk of surgery on this medically fragile patient population, surgeons should consider expectant management for asymptomatic LAI patients.

The incidence and characteristics of supraventricular tachycardia in left atrial isomerism: a high incidence of atrial fibrillation in young patients.

BACKGROUND: In left atrial isomerism (LAI), both atria show left atrial morphology. Although bradyarrhythmias are frequent and highly complex in LAI patients, previous studies have reported a low incidence of supraventricular tachycardia (SVT). METHODS: To evaluate the incidence and characteristics of SVT in LAI, we retrospectively evaluated the clinical characteristics of SVTs in 83 patients with LAI (age at last follow-up, 15.3±10.5 years). RESULTS: There were 27 SVTs in 19 patients (23%), including nine episodes of atrial fibrillation (AF) and eight non-reentrant SVTs. Sixteen of the 19 patients with SVT had histories of atriotomy, but the three patients with AF or non-reentrant tachycardia had no history of atriotomy. The rates of freedom from SVT were 66% and 59% at ages of 20 and 30 years, respectively; the corresponding rates for freedom from AF were 89% and 74%. In multivariate analysis, the predictors of SVT were age (OR, 1.14; 95% CI, 1.06-1.26; p=0.003) and sinus node dysfunction (SND) (OR, 3.88; 95% CI, 1.57-13.34; p=0.01). CONCLUSIONS: In patients with LAI, SVTs are common, and AF and non-reentrant SVTs are the major type of SVTs. The incidence of AF was high in young patients with LAI. The lack of anatomical barriers in the atria that allow the formation of macro-reentrant circuits may account for the higher incidence of AF and non-reentrant SVT than macro-reentrant tachycardia. Moreover, the increasing prevalence of SND with age should contribute to a higher incidence of SVT.

The outcome of patients with right atrial isomerism is poor.

Right-atrial isomerism (RAI) is a heterotaxy syndrome with disturbances of left-right axis development resulting in complex heart malformations and anomalies of the thoracic and abdominal organs. To study the outcome of RAI, all data from patients diagnosed with this syndrome at Helsinki University Hospital between January 1976 and December of 2010 were reviewed. The outcomes were studied for 32 patients (38 % girls). The overall survival was 22 % at a median follow-up time of 13.8 years (range 0.1-33). Extracardiac malformations, mostly asplenic, occurred in 91 % of patients. Cardiac defects included dextrocardia in 44 % and common atrioventricular valve in 100 % of patients. Ventriculoarterial discordance or double-outlet ventricle was seen in 56 and 44 % of patients, respectively. Total anomalous pulmonary venous drainage occurred in 75 % and partially anomalous venous drainage in 13 % of patients. Pulmonary outflow-tract obstruction was identified in 91 % of patients. Cardiac arrhythmias were noted in nine patients (28 %), two of them with atrioventricular block. Cardiovascular surgery was performed in 71 % patients (N = 25), seven patients were inoperable. Biventricular repair was not possible in any of the patients. During long-term follow-up there was no significant difference between the patients with total, normal, or partially anomalous pulmonary venous drainage (P = 0.5). In conclusion, RAI is one of the most severe forms of congenital cardiac diseases. The prognosis remains poor despite modern surgical techniques. When RAI is identified during pregnancy, prenatal counseling, termination, or planning for prompt cardiac treatment after the birth is necessary.

Perioperative atrial tachycardia is associated with increased mortality in infants undergoing cardiac surgery.

OBJECTIVE: Few data are available on the frequency or importance of perioperative atrial tachycardia in infants. We hypothesized that atrial tachycardia in infants undergoing cardiac surgery is not rare and is associated with increased morbidity and mortality. METHODS: From 2007 through 2010, 777 infants (median age, 1.8 months; interquartile range, 0.33-5.73) underwent cardiac surgery. Their medical records were reviewed for atrial tachycardia during the perioperative period. RESULTS: Of the 777 patients, 64 (8.2%) developed atrial tachycardia. The independent risk factors for developing atrial tachycardia included surgical age 6 months or younger (odds ratio, 4.4; 95% confidence interval, 1.1-19.15), use of 3 or more inotropes (odds ratio, 2.9; 95% confidence interval, 1.4-6.2), and heterotaxy syndrome (odds ratio, 2.9; 95% confidence interval, 1.1-7.4). All-cause mortality in the atrial tachycardia group was increased (21.9% vs 7.2%, P<.001) during a median follow-up period of 14.6 months (interquartile range, 6.8-24.6), and atrial tachycardia was independently associated with decreased survival (hazard ratio, 1.9; 95% confidence interval, 1.1-3.8). Infants with perioperative atrial tachycardia had a longer hospital length of stay (32 vs 17 days, P<.001) and duration of inotrope use (10.5 vs 3.0 days, P<.001). A total of 57 patients received antiarrhythmic therapy, with propranolol the most common (n=31). Among the survivors, 48 patients received outpatient antiarrhythmic therapy, which was successfully discontinued in 23 patients at a median duration of 14 months (interquartile range, 5.7-18.6) without recurrence. CONCLUSIONS: Atrial tachycardia is common in infants undergoing cardiac surgery and is independently associated with decreased survival. Among survivors, antiarrhythmic agents successfully controlled atrial tachycardia in most patients with a low recurrence risk after discontinuation.

Risk factor analysis for second-stage palliation of single ventricle anatomy.

BACKGROUND: Single ventricle hearts can be surgically palliated by a series of operations culminating in the Fontan procedure, which establishes a total cavopulmonary connection. The second-stage procedure creates a physiologic connection between the superior vena cava and the pulmonary artery. METHODS: From 1998 to 2010, 557 patients with single ventricle heart disease underwent second-stage surgical palliation. This cohort was retrospectively analyzed to assess patient outcome by a number of anatomic, physiologic, and procedural factors. The analysis excluded patients undergoing hybrid first-stage procedures. RESULTS: The median age at operation was 165 days (range, 59 days to 49 years). The most common anatomic subtypes were hypoplastic left heart syndrome (52%), tricuspid atresia (12%), unbalanced atrioventricular septal defect (10%), double inlet left ventricle (9%), or other (17%). Left ventricular hypoplasia was present in 70%. A hemi-Fontan procedure was done in 89%, and 11% received a bidirectional Glenn. Concomitant atrioventricular valve repair was necessary in 9%. Early mortality was 4.7%, and 5.9% died after discharge but before Fontan. No early or late deaths occurred in patients with tricuspid atresia and double inlet left ventricle. Multivariate analysis demonstrated ventricular dysfunction, atrioventricular valve regurgitation, and unbalanced atrioventricular septal defect were significant adverse risk factors for survival to Fontan. CONCLUSIONS: Second-stage palliation can be performed at low risk for patients with left ventricular dominance, but significant risk remains for patients with left ventricular hypoplasia and unbalanced atrioventricular septal defect. Atrioventricular valve insufficiency is a persistent problem that has not been neutralized by repair strategies.