Abstract
BACKGROUND:
The long-term impact of ventricular dominance on Fontan outcomes is controversial. We examined this in a 25-year cohort.
METHODS:
Patients from October 1998 to February 2022 were reviewed. Primary outcomes were transplant-free survival and Fontan failure (death, transplantation, takedown, protein-losing enteropathy, or plastic bronchitis). Secondary outcomes included hospital and intensive care length of stay. Kaplan-Meier methodology compared outcomes by ventricular dominance. Multiphase parametric risk hazard analysis identified risk factors for primary outcomes.
RESULTS:
There were 195 patients (104 right ventricular dominant). Baseline characteristics were comparable. Perioperative survival was similar (right ventricular dominant 98%, non-right ventricular dominant 100%, p=0.51). The proportion of patients experiencing death or transplantation was 8.7% and Fontan failure was 11.8% during a median follow-up of 4.5 [0.3 – 9.8] years. Right ventricular dominant patients had reduced transplant-free survival (10-year estimates: 80% (95% CI 70–91%) vs. 92% (83–100%), p=.04) and freedom from Fontan failure (73% (62–86%) vs. 92% (83–100%), p=.04). Multiphase hazard modeling resolved 2 risk phases. The early phase spanned from surgery to approximately 6 months after. The late phase spanned from approximately 6 months after surgery onwards. In multivariable analysis, right ventricular dominance was an independent risk factor for death or transplantation (parameter estimate 1.3±0.6, p=0.04) and Fontan failure (1.1±0.5, p=0.04) during the second phase, with no significant first phase risk factors.
CONCLUSIONS:
Right ventricular dominance was associated with long-term complications after Fontan, including mortality, transplantation, and Fontan failure. This cohort may benefit from heightened surveillance in a multi-disciplinary Fontan clinic after the perioperative period.
Despite long-term survival in Fontan patients increasing in recent years, morbidity and mortality remain significant.[1, 2] Late adverse events associated with single ventricle (SV) Fontan circulation are common.[3, 4] These include arrhythmias, thromboembolisms, liver disease, effusions, renal dysfunction, and reinterventions such as pacemaker placement or Fontan revision.[5–7] Fontan failure has been defined to include death, heart transplantation, placement of ventricular assist devices, takedown, protein losing enteropathy, and plastic bronchitis.[5, 8, 9] It is reported that over 70% of patients experience late adverse events and that nearly half experience Fontan failure within 25 years.[8, 10]
Patients with right ventricular dominant lesions may experience these adverse events more often than their non-right ventricular dominant counterparts. This is because the right ventricle and tricuspid valve develop to support pulmonary circulation and are thought to be inferior in the long-term maintenance of systemic circulation. Prior work has shown that right ventricular dominance imparts worse outcomes for SV patients in the neonatal period, however, the impact of right ventricular dominance on patients who survive to Fontan is a topic of ongoing investigation.[8, 11–14] Additionally, preoperative factors which may be predictive of survival have not been fully identified.[15, 16] This controversy may be due to a lack of long-term follow-up. A better understanding of the impact of ventricular dominance on Fontan outcomes will allow us to improve counseling for the families of children with congenital heart disease and design surveillance pathways for patients at higher risk of long-term complications.
The objective of this retrospective institutional study was to examine the impact of ventricular morphology on perioperative survival, freedom from Fontan failure, and transplant-free survival in Fontan patients. We hypothesized that right ventricular dominance would be associated with comparable perioperative survival, but lower transplant-free survival and decreased freedom from Fontan failure.
PATIENTS AND METHODS
Patients
All patients undergoing the Fontan operation at our institution between October 1998 and February 2022 were identified using an institutional database of SV patients cross-referenced with institutional data submitted to the Society of Thoracic Surgeons Congenital Heart Surgery database. Patients were excluded if they underwent the atriopulmonary connection Fontan technique due to limited sample size, or if the Fontan procedure at our institution was a revision. Follow-up was complete as of February 2022 and the median length of follow-up was 4.5 [0.3 – 9.8] years. Patients lost to follow-up were censored at the date of the last known alive. This study was approved by the Institutional Review Board and the need for individual patient consent was waived given the retrospective design.
Clinical and operative data
Demographic features, preoperative characteristics, operative variables, and postoperative outcomes were obtained for all patients by reviewing the electronic medical record. Demographic and preoperative data collected included sex, age at Fontan, weight at Fontan, prematurity at birth (gestational age <37 weeks), presence of a genetic syndrome, underlying cardiac diagnosis, initial cardiac surgical palliation, pre-Fontan O2 saturation, and pre-Fontan cardiac catheterization data (mean pulmonary artery pressure (mPAP), end diastolic pressure (EDP), and trans-pulmonary gradient (TPG)). Operative data included surgical technique, intentional creation of a fenestration, presence of a concomitant procedure, cross-clamp use, and cardiopulmonary bypass time. Outcomes included chest tube duration, intensive care unit length of stay, hospital length of stay, perioperative survival (30 days after Fontan/survival to hospital discharge), transplant-free survival, and freedom from Fontan failure (death, transplantation, Fontan takedown, protein losing enteropathy (PLE) or plastic bronchitis).
Statistical analysis
Baseline characteristics were summarized and compared using descriptive statistics. The normality of all continuous variables was assessed using the Shapiro-Wilkes test. Kaplan-Meier methodology assessed transplant-free survival and freedom from Fontan failure. Patients experiencing multiple end points were censored at the first occurrence. Log-rank testing compared survival curves. Median imputation was used to account for missing data and a threshold of p<0.05 was utilized for statistical significance.
Multi-phase parametric risk hazard analysis was performed to identify factors associated with the survival outcomes.[17] Parametric models were built based on the Kaplan-Meier curves. This modeling technique was chosen because the proportional hazards assumption was not valid throughout the analysis period. Candidate covariates, determined a priori based on a literature review of risk factors for morbidity and mortality following Fontan, included ventricular dominance, cardiopulmonary bypass time, pre-operative mPAP, age at Fontan, concomitant procedures at the time of Fontan, type of Fontan, and era (pre- and post-2011).[8, 18–20] Bootstrapping with aggregation, or sampling with replacement (n=300), guided the variable selection.[21] The final model was constructed using forward stepwise selection, with p<0.1 for entry and p<0.05 for retention. Analyses were performed using R software (version 4.1.0, R Foundation for Statistical Computing, Vienna Austria) and SAS version 9.4 (SAS Institute Inc., Cary, NC).
RESULTS
Baseline and Operative Characteristics
A total of 215 SV patients underwent Fontan at our institution between October 1998 and February 2022. Of these, 2 were excluded as they underwent atriopulmonary connections and 18 were excluded as their interventions at our institution represented revisions of a prior Fontan at a different center. Thus, a total of 195 patients underwent primary Fontan palliation using the ECC (182) or LT (13) approach during the study (Figure 1).
Figure 1:
Consort flow diagram. ECC=Extra-cardiac conduit, LT=Lateral tunnel, HLHS=Hypoplastic left heart syndrome, TA=Tricuspid atresia, UAVC=Unbalanced atrioventricular canal, DORV=Double outlet right ventricle, DILV=Double inlet left ventricle, PA=Pulmonary atresia, TGA=Transposition of the great arteries
Of these, 104 (53%) were right ventricular dominant patients and 91 (47%) were non-right ventricular dominant patients. There were 108 (55%) male patients. There were 23 (12%) patients born premature and 12 (6%) with an underlying genetic syndrome (Supplemental Table 1). The median age at Fontan for the entire cohort was 38 months (33 – 46). The median weight at Fontan was 13.5 kg (12.2 – 15.1). Among patients with right ventricular dominance, 65 (63%) had an underlying diagnosis of HLHS. Among all patients, 81 (42%) underwent the Norwood operation as their first stage palliation. Baseline characteristics including age and weight at intervention, prematurity at birth, presence of a genetic syndrome, pre-Fontan hemodynamics, surgical technique, use of fenestration and presence of a concomitant procedure (Supplemental Table 2) did not differ between the ventricular dominance groups. CPB time [125 minutes (91 – 150), 118 minutes (96 – 151), p=0.79] and cross clamp use [35%, 27%, p=0.87] were not statistically different (Table 1). Additional data regarding the concomitant procedures and genetic syndromes present in this cohort is available in Supplementary Table 1 and Supplementary Table 2 respectively.
Table 1:
Baseline characteristics
| Non-Right Ventricular Dominant N=91 (47%) | Right Ventricular Domant N=104 (53%) | Total N=195 | P-value* | |
|---|---|---|---|---|
| Patient demographics | ||||
| Male sex | 45 (49%) | 63 (61%) | 108 (55%) | 0.12 |
| Age at Fontan (months) | 38 [33 – 44] | 38 [33 – 47] | 38 [33 – 46] | 0.97 |
| Premature, <37 weeks | 11 (12%) | 12 (12%) | 23 (12%) | 0.99 |
| Genetic Syndrome | 5 (5%) | 7 (7%) | 12 (6%) | 0.72 |
| Weight, kg | 13.8 [12.6 – 15.9] | 13.5 [12.1 – 15] | 13.5 [12.2 – 15.1] | 0.25 |
| Underlying diagnosis | <0.001 | |||
| HLHS | 0 (0%) | 65 (63%) | 65 (33%) | |
| TA | 31 (34%) | 0 (0%) | 31 (16%) | |
| UAVC | 10 (11%) | 21 (20%) | 31 (16%) | |
| DORV | 7 (8%) | 17 (16%) | 24 (12%) | |
| DILV | 18 (20%) | 0 (0%) | 18 (9%) | |
| PA/IVS | 24 (26%) | 0 (0%) | 24 (12%) | |
| TGA | 1 (1%) | 1 (1%) | 2 (1%) | |
| First stage palliation | <0.001 | |||
| Norwood | 11 (12%) | 70 (67%) | 81 (42%) | |
| BTT Shunt | 47 (52%) | 13 (13%) | 60 (31%) | |
| PA Banding | 13 (14%) | 12 (12%) | 25 (13%) | |
| Other | 15 (17%) | 8 (8%) | 23 (12%) | |
| Pre-Fontan hemodynamics | ||||
| O2 Sat (%) | 83 [80 – 86] | 83 [80 – 86] | 83 [80 – 86] | 0.47 |
| mPAP (mmHg) | 11 [9 – 12] | 11 [9 – 13] | 11 [9 – 13] | 0.99 |
| EDP (mmHg) | 6 [5 – 8] | 7 [6 – 8] | 7 [5 – 8] | 0.66 |
| TPG (mmHg) | 5 [4 – 6] | 4 [3.5 – 5.5] | 5 [3.5 – 6] | 0.07 |
| Operative characteristics | ||||
| ECC | 86 (95%) | 96 (92%) | 182 (93%) | 0.54 |
| LT | 5 (5%) | 8 (8%) | 13 (7%) | |
| Fenestration | 48 (53%) | 70 (67%) | 118 (61%) | 0.04 |
| Concomitant procedure | 42 (46%) | 42 (40%) | 84 (43%) | 0.42 |
| CPB time (minutes) | 118 [96 – 151] | 125 [91 – 150] | 122 [94 – 150] | 0.79 |
| Cross clamp use | 25 (27%) | 36 (35%) | 61 (31%) | 0.87 |
IQR= Interquartile range, ECC=Extra-cardiac conduit, LT=Lateral tunnel, HLHS=Hypoplastic left heart syndrome, TA=Tricuspid atresia, UAVC=Unbalanced atrioventricular canal, DORV=Double outlet right ventricle, DILV=Double inlet left ventricle, PA/IVS=Pulmonary atresia with intact ventricular septum, TGA=Transposition of the great arteries, BTT=Blalock-Thomas-Taussig, PA=Pulmonary artery, EDG=End diastolic pressure, TPG=Transpulmonary gradient, CPB=Cardiopulmonary bypass
Perioperative Outcomes
Patients with right ventricular dominant lesions had longer chest tube requirements [7 days (5 – 16), 6 days (4 – 7.5), p<0.001], longer intensive care unit stays [4 days (2 – 9), 3 days (2 – 5), p=0.02], longer hospital stays [10 days (8 – 23), 9 days (7 – 12), p<0.001], and comparable perioperative survival [98%, 100%, p=0.51] (Table 2).
Table 2:
Perioperative outcomes and Fontan failure events
| Non-Right Ventricular Dominant (N=91) | Right Ventricular Dominant (N=104) | Total (N=195) | P-value* | |
|---|---|---|---|---|
| Perioperative outcomes | ||||
| Chest tube duration (days) | 6 [4 – 7.5] | 7 [5 – 16] | 6 [5 – 9] | <0.001 |
| Intensive care unit stay (days) | 3 [2 – 5] | 4 [2 – 9] | 3 [2 – 7] | 0.02 |
| Hospital length of stay (days) | 9 [7 – 12] | 10 [8 – 23] | 9 [8 – 16] | <0.001 |
| Perioperative survival | 91 (100%) | 102 (98%) | 193 (99%) | 0.51 |
| Fontan failure events | ||||
| Death | 2 (2%) | 10 (10%) | 12 (6%) | |
| Transplant | 2 (2%) | 3 (3%) | 5 (3%) | |
| Fontan Takedown | 0 (0%) | 1 (1%) | 1 (1%) | |
| Protein losing enteropathy | 4 (4%) | 2 (2%) | 6 (3%) | |
| Plastic bronchitis | 2 (2%) | 3 (3%) | 5 (3%) |
Categorical variables were compared using the chi-square test and continuous variables were compared using the Kruskal-Wallis test.
Long-Term Follow-Up
During a median follow-up of 4.5 [0.28 – 9.8] years, the proportion of death or transplantation was 8.7% and Fontan failure was 11.8%. Forty-eight (25%) patients were considered lost to follow-up as they had not reached a study end point and had no records available for review within 24 months of the study end date. Kaplan-Meier analysis demonstrated reduced transplant-free survival (10-year estimates: 80% (95% CI 70–91%) vs.92% (83–100%), p=.04) and freedom from Fontan failure (10-year estimates: 73% (62–86%) vs. 92% (83–100%), p=.04) for patients with right ventricular dominant lesions (Figure 2). Twenty-three patients met the study end points of death, transplantation, or Fontan failure, with four of those patients experiencing multiple, sequential end state events (Table 2). Parametric survival functions demonstrating each phase of risk along with relative contributions of each individual hazard phase to the overall hazard for both outcomes are demonstrated in Supplemental Figures 1 and 2.
Figure 2:
(A) Freedom from Fontan failure and (B) Transplant-free survival stratified by right ventricular dominance (RVD) and non-RVD.
The parametric model resolved two distinct phases of risk for both outcomes. No factors were associated with the first phase of risk for either outcome, which included the first 5.4 months following Fontan for Fontan failure and the first 7.1 months following Fontan for death or transplantation (Figure 3). For death or transplantation, there were 17 events, with 5 in the 1st phase and 12 in the 2nd. For Fontan failure, there were 23 events, with 6 in the 1st phase and 17 in the 2nd. Longer cardiopulmonary bypass time and right ventricular dominance were significantly associated with the second phase of risk for both transplant-free survival and freedom from Fontan failure (Table 3).
Figure 3:
(A) Hazard for Fontan failure after Fontan and (B) Hazard for death/transplantation after Fontan, demonstrating two discrete risk phases - first prior to and then after the initial ~6 months following repair.
Table 3:
Factors associated with the second phase of risk
| Parameter Estimate ± Standard Error | P-value | Reliability* | |
|---|---|---|---|
| Transplant-free survival | |||
| Longer CPB time (Min) | 0.02 ± 0.005 | 0.0006 | 81% |
| RV dominance | 1.3 ± 0.6 | 0.04 | 45% |
| Freedom from Fontan Failure | |||
| Longer CPB time (Min) | 0.02 ± 0.004 | < 0.0001 | 96% |
| RV dominance | 1.1 ± 0.5 | 0.04 | 46% |
Reliability is defined as the number of samples in which the variable was present during bootstrapping
COMMENT
Principal findings
The impact of ventricular morphology on Fontan outcomes remains a topic of investigation. In a single-institutional study spanning 25 years, we show that right ventricular dominance is associated with excellent perioperative survival but lower rates of transplant-free survival and freedom from Fontan failure. The increased incidence of adverse events is concentrated to a risk phase beginning 6 months after Fontan. There was no increased risk in the 6 months immediately after Fontan.
Right ventricular dominance is an independent risk factor for adverse outcomes following Fontan
The impact of right ventricular dominance on SV patients followed from birth is established, but there has been limited investigation into the impact of right ventricular dominance on patients after Fontan. Studies to date have been constrained by small sample size, limited follow-up, and varied study design.[20, 22–24] The strength of our study is the length of cohort follow-up and granularity of patient data.
Our findings are similar to those of d’Udekem and colleagues who found worse long-term outcomes for Fontan patients with an underlying diagnosis of HLHS in the Australia/New Zealand Fontan cohort.[8] Notably, our study population of right ventricular dominant patients consisted of 63% HLHS, whereas the Australia/New Zealand right ventricular dominant cohort was 28% HLHS. The high proportion of HLHS patients in our cohort may help explain the pronounced difference in outcomes between our patient groups, as HLHS represents the most severe form of right ventricular dominant single ventricle heart lesions. Yong and Giannico reached similar conclusions when they demonstrated that HLHS and TAPVR are associated with worse long-term outcomes in Fontan patients, though neither commented on the outcomes of right ventricular dominant patients with other underlying diagnoses.[23, 24] Similar to our study, West and colleagues demonstrated that right ventricular dominance was associated with decreased freedom from Fontan failure in a 12 year cohort of 140 ECC Fontan patients. [20] Pollack and colleagues showed right ventricular dominance was associated with worse perioperative cardiac function after Fontan, but the study was truncated at hospital discharge and included fewer than 100 patients.[22] Sharma showed that severe complications such as PLE and plastic bronchitis preferentially affected right ventricular dominant patients in their retrospective analysis of 1500 patients.[25] Another study, comparing the outcomes of patients with single and two-ventricle Fontan circulation concluded that single ventricle patients fared no worse than their two-ventricle counterparts, though this study did not explore any potential impact of ventricular dominance on the single-ventricle population.[26]
Our finding that right ventricular dominance continues to carry risk in SV patients progressing to Fontan palliation is consistent with emerging literature on the topic of Fontan outcomes in right ventricular dominant patients and may suggest a benefit to heightened postoperative monitoring and surveillance in these patients. We are unaware of guidelines suggesting differential surveillance based on ventricular dominance. This is highlighted by the 2019 American Heart Association statement on Fontan circulation. Despite representing the most comprehensive document of its kind, it makes no distinction between surveillance pathways for patients based on ventricular dominance. [27, 28] We assert that the emerging data regarding the impact of ventricular dominance on Fontan outcomes suggests a role for unique surveillance pathways between right ventricular and non-right ventricular dominant patients.
The finding that these patients achieve similar rates of perioperative survival, and that long-term outcomes can be resolved into two phases of risk, supports the conclusion that heightened vigilance in the years after surgical convalescence would be most beneficial. There are likely several reasons for this finding but we hypothesize two main factors. First, the cumulative insult of increased surgical complexity with attendant morbidity and complications in the neonatal period leads to persistent physiologic inefficiency that creates a sub-optimal Fontan substrate in right ventricular dominant patients. Our finding that increased CPB time is also associated with increased late complications supports this hypothesis, as the increased CPB time generally reflects increased complexity associated with cumulative morbidity. Second, independent of these cumulative hits and operative complexity, we assert that the developmental structure of a right ventricular dominant heart results in decreased ventricular and valvular performance in the years following Fontan palliation, owing to its development for pulmonary rather than systemic circulation.
Given the diverse multisystem complications that Fontan patients experience, we and others believe it is best for surveillance to take place in a multidisciplinary Fontan clinic. The benefits of such integrated approaches to managing complex disease states are well established in other domains but remain an emerging area of interest for patients with SV heart defects.[29, 30] Existing evidence and expert guidance suggest that such clinics should provide access to experts in cardiology, nephrology, hepatology, gastroenterology, urology, neurology, psychiatry, and surgery.[31, 32]
Another important consideration is that the population of patients with Fontan physiology continues to age as long-term outcomes improve. This raises questions about ongoing quality of life, neurodevelopment, functional limitations, mental health, and the potential for yet unidentified complications of the operation. Thus, as the cohort advances into adulthood, it is important that adult specialists be prepared to manage the sequela of Fontan circulation in an in an interdisciplinary setting.[27, 33] Attention should be given to both traditional quantitative measures of organ function and patient reported outcome measures which have the potential to capture additional information about patient wellness.[34, 35] The development of such multidisciplinary longitudinal clinics may result in a prospective, data driven, unified approach to patient management.
Limitations
As a retrospective review, the management of our patient cohort was neither standardized nor randomized. Additionally, while congenital heart defects are the most common spectrum of birth defects, they remain rare. Thus, despite representing one of the most comprehensive and long-term studies on the relationship between ventricular morphology and Fontan outcomes, the sample size of our cohort limits our power and left us unable to comment on the extent to which the risk associated with ventricular dominance was influenced by underlying cardiac diagnosis. Additionally, due to the extended study period, baseline echocardiography was not available for all patients, precluding an analysis of baseline ventricular function and atrioventricular valve regurgitation as independent predictors of poor outcomes.
Further, the majority of events (failure, death, or transplantation) were concentrated in the second phase. Given the low number of events in the first phase, the possibility remains that RV dominance is associated with our outcomes of interest during the first phase, but that our study lacked the statistical power to detect this.
Finally, a low overall event rate makes conclusions about individual complications difficult. This has been addressed by using a composite complication outcome, Fontan failure. As an institutional review, our outcomes are limited in their generalizability since they represent the care received by the team at our tertiary referral center.
Conclusions
In this single-institution study, right ventricular dominance was associated with long-term complications following Fontan palliation, including mortality, transplantation, and Fontan failure. These data suggest that Fontan patients with right ventricular dominant morphology should be targeted for heightened surveillance and monitoring after the perioperative period, preferably in a multi-disciplinary Fontan clinic. This will be an increasingly important topic of study as the population of patients with Fontan circulation continues to age and enters long-term surveillance.
Supplementary Material
ABBREVIATIONS
- CPB
Cardiopulmonary bypass
- ECC
Extra cardiac conduit
- EDP
End diastolic pressure
- EHR
Electronic health record
- HLHS
Hypoplastic left heart syndrome
- IQR
Interquartile range
- LT
Lateral tunnel
- MPAP
Mean pulmonary arterial pressure
- STS
Society of Thoracic Surgeons
- SV
Single ventricle
- TPG
Transpulmonary gradient
Footnotes
Conflicts of Interest and Funding Disclosure:
None
Meeting Presentation:
Accepted for Oral presentation at the 69th Annual Southern Thoracic Surgical Association
First Scientific Session
Fort Lauderdale, Florida
November 9th – 12th, 2022
Disclosures: None
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