Invasive Hemodynamics in Asymptomatic Adult Fontan Patients and According to Different Clinical Phenotypes

Abstract

Background. The correlation between hemodynamics and clinical phenotypes/symptoms in adults post Fontan procedure has not been well studied. Moreover, the “expected” hemodynamics in those who are asymptomatic remain unclear. Methods. This retrospective cohort included 155 adult patients post Fontan undergoing right and left cardiac catheterization between December 1999 and November 2017. Patients were categorized according to the primary indication for cardiac catheterization/clinical status, ie, fluid overload, atrial arrhythmia, exercise intolerance, abnormal liver imaging (in the absence of other indications), or asymptomatic. Underlying hemodynamics and survival were compared. Results. Primary indications for cardiac catheterization were atrial arrhythmias in 49, fluid overload in 44, exercise intolerance in 37, and abnormal liver imaging in 13 patients; 12 patients were asymptomatic. The fluid overload and abnormal liver imaging groups had the highest median Fontan pressures, at 17 mm Hg (interquartile range [IQR], 14-21.8) and 17 mm Hg (IQR, 12.5-17), respectively. Among asymptomatic patients, median pulmonary artery wedge pressure was 8 mm Hg (IQR, 6-11.8) and median Fontan pressure was 13 mm Hg (IQR, 12-14.5). There was no difference in the prevalence of abnormalities of the Fontan circuit or ≥ moderate valvular regurgitation among groups. During a median follow-up of 5.3 years (IQR, 1.4-9.4), there were 48 deaths. Survival was the lowest in patients presenting with fluid overload (5-year survival, 55.6%); there were no deaths among asymptomatic patients. Conclusion. Asymptomatic adult Fontan patients typically have ventricular filling pressures <10 mm Hg and Fontan pressures <15 mm Hg and demonstrate excellent prognosis. Indication for catheterization predicted survival among our adult Fontan patients; the worst prognosis was noted among those presenting with fluid overload.

J INVASIVE CARDIOL 2022;34(5):E374-E379. Epub 2022 March 18.

Key words: cardiac catheterization, Fontan, hemodynamics

The long-term complications of the Fontan palliation, such as atrial arrhythmias, protein-losing enteropathy, and ventricular systolic and diastolic dysfunction, have been extensively reported.¹ Additionally, increasing emphasis has been placed on risks of developing Fontan-related liver disease, including hepatocellular carcinoma.^2,3 As the number of patients post Fontan palliation increases, it is expected that the prevalence of Fontan-related comorbidities will increase, especially among adults. The prognostic implications of pre- and post-Fontan hemodynamic abnormalities (particularly increased central venous pressure) have been well studied.^4,5 More recently, hemodynamic profiles have been proposed to aid prognostication and perhaps management of these patients.^6,7 Fewer investigators, however, have focused on the correlation between hemodynamics and clinical phenotypes/symptoms in this population. In addition, the “expected” normal hemodynamics in asymptomatic adult patient post Fontan remain elusive.

Structural abnormalities of the Fontan system, such as residual aortic coarctation/recoarctation and Fontan obstruction, tend not to be well tolerated in patients with single ventricle, as they add burden to the delicate balance posed by the Fontan physiology. As recommended by the guidelines, patients presenting with Fontan-related comorbidities typically undergo extensive evaluation (frequently including cardiac catheterization) in an attempt to delineate potential, but more importantly, reversible culprits.⁸ Despite the routine use of comprehensive multimodality search for structural abnormalities in failing/symptomatic adult Fontan patients, the prevalence of these abnormalities, specifically according to clinical presentation, has not been well described.

The aims of the present study were: (1) to characterize the underlying hemodynamics in adult Fontan patients according to their clinical phenotype/indications for invasive hemodynamic assessment; (2) to characterize the long-term prognosis in adult Fontan patients according to their clinical phenotype/indications for invasive hemodynamic assessment; and (3) to assess the prevalence of abnormalities of the Fontan circuit in these patients.

Methods

This retrospective cohort included 155 adult Fontan patients (age ≥18 years) undergoing right and left cardiac catheterization at Mayo Clinic in Rochester, Minnesota between December 1999 and November 2017. Only patients authorizing the use of their records for medical research were included. The institutional review board approved the study.

Medical records were individually reviewed by one of the coauthors (WRM). Patients were then categorized according to the primary indication for cardiac catheterization and clinical status at the time of the procedure: fluid overload (ascites, leg edema, anasarca, and/or pulmonary congestion); atrial arrhythmia (new-onset or refractory atrial arrhythmias); exercise intolerance (fatigue, exertional dyspnea); abnormal liver imaging (cross-sectional imaging or ultrasound consistent with cirrhosis or hepatic congestion/marked hepatomegaly in the absence of the above-mentioned indications); or asymptomatic. If multiple indications were present, the predominant one according to the clinical notes was chosen; when ascites was present, patients were arbitrarily classified as fluid overload.

Cardiac catheterization reports were manually reviewed; pressure measurements represent an average of 6-8 consecutive beats according to the heart rate. Pulmonary and systemic flow were calculated by Fick method and used for the calculation of pulmonary vascular resistance index and cardiac index, respectively. Abnormalities of the Fontan circuit were defined as residual intracardiac shunt, obstruction of the Fontan anastomosis/conduit, pulmonary artery hypoplasia/stenosis, extrinsic pulmonary vein compression, and/or aortic coarctation/recoarctation requiring surgical or percutaneous intervention. In 3 patients, significant structural abnormalities were present, but no intervention was pursued because of prohibitive surgical risk and unavailability of satisfactory percutaneous interventions (2 of whom were referred for transplant evaluation).

As previously reported, cirrhosis was defined as 1 of following: cirrhotic appearance of the liver by ultrasound, computerized tomography, or magnetic resonance; liver stiffness >5 kPA on magnetic resonance elastography; evidence of portosystemic collateral circulation; or stage 4 hepatic fibrosis on biopsy.⁹Protein-losing enteropathy was defined as the coexistence of hypoalbuminemia and increased fecal alpha-1 antitrypsin levels. Ventricular ejection fraction and degree of valvular regurgitation were assessed by transthoracic echocardiography. Survival was ascertained using the Mayo Clinic registration database and Accurint, an institutionally approved location service.

Statistical analysis. Nominal variables are presented as count with percentage. Continuous variables are presented as median with interquartile range (IQR, 25th-75th percentile). Comparisons between multiple groups were performed using Kruskal-Wallis and Fisher exact tests for continuous and nominal variables, respectively. Survival curves were constructed by Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards regression analysis was used to assess the prognostic value of each variable. Variables included in the univariable analysis were chosen a priori based on previously published data or based on their clinical importance.^4,5 A P-value <.05 was considered statistically significant. Analyses were performed with JMP software, version 10.0 (SAS Institute, Inc).

Results

The primary indications for cardiac catheterization were atrial arrhythmias in 49, fluid overload in 44, exercise intolerance in 37, and abnormal liver imaging in 13 patients. Twelve patients were asymptomatic at the time of invasive assessment and referred for cardiac catheterization due to cyanosis/hypoxemia in 5, as part of intracoronary stem cell delivery in 3, at the time of coronary angiography in 2, due to valvular disease in 1, and during consideration of Fontan conversion in 1 patient.

Underlying congenital lesions were tricuspid atresia in 57 (38%), double-inlet left ventricle in 42 (27%), pulmonary atresia with intact ventricular septum in 16 (10%), hypoplastic left heart syndrome in 6 (4%), and other in 34 patients (22%). Types of Fontan connection were atriopulmonary in 91 (59%), lateral tunnel in 30 (19%), extracardiac in 21 (14%), intra-atrial conduit in 12 (8%), and other in 1 patient (<1%).

Demographic and clinical data according to indications for invasive assessments are presented in Table 1, while comparisons between asymptomatic patients vs others are shown in Supplemental Table S1. Asymptomatic patients were younger and more commonly had right ventricular morphology and non-atriopulmonary Fontan connections than patients in other groups; ventricular ejection fraction and Fontan pressures were also lower among asymptomatic patients. As expected, the prevalence of atriopulmonary Fontan connection was the highest among patients referred for catheterization due to atrial arrhythmias and protein-losing enteropathy was most prevalent among those with fluid overload. Of note, none of asymptomatic patients had atrial arrhythmia at the time of the procedure.

Invasive hemodynamics and structural abnormalities of the Fontan system. The fluid overload and abnormal liver imaging groups had the highest median Fontan pressures, at 17 mm Hg (IQR, 14-21.8) and 17 mm Hg (IQR, 12.5-17). Median arterial oxygen saturation levels were higher in the arrhythmia and abnormal liver imaging groups. Median cardiac index was the lowest in the arrhythmia group and this group also showed a much higher systemic vascular resistance compared with others.

Structural abnormalities of the Fontan circuit were present in 23.9% of patients and ≥ moderate valvular regurgitation was present in 18.1%; 38.7% of patients had either an abnormal Fontan circuit or significant valvular regurgitation. Details regarding structural abnormalities and valvular disorders are presented in Supplemental Table S2. The prevalence of structural abnormalities of the Fontan circuit according to phenotype was as follows: 6 patients (46%) in the abnormal liver imaging group, 10 patients (27%) in the exercise intolerance group, 10 patients (22.7%) in the fluid overload group, and 1 patient (8%) in the asymptomatic group. The prevalence of ≥ moderate valvular regurgitation according to phenotype was 9 patients (24.3%) in the exercise intolerance group, 2 patients (16.7%) in the asymptomatic group, 8 patients (16.3%) in the arrhythmia group, 7 patients (15.9%) in the fluid overload group, and 2 patients (15.3%) in the abnormal liver imaging group. The prevalence of Fontan anastomosis/conduit obstruction was higher in the abnormal liver imaging group (P<.01); there were no differences in the prevalence of abnormalities of the Fontan system (P=.26) or ≥ moderate valvular regurgitation (P=.87) among groups.

Survival. During a median follow-up of 5.3 years (IQR, 1.4-9.4), there were 48 deaths. There were 14 cardiovascular and 11 non-cardiovascular deaths, including 6 deaths related to liver disease. Cause of death was unknown in 22 patients (46.8%). Overall survival according to phenotype is presented in Figure 1. Of note, there were no deaths among asymptomatic patients. Survival was the lowest in patients presenting with fluid overload, with 5-year survival rate at 55.6% compared with 89.5% for the atrial arrhythmia group, 80.1% for the exercise intolerance group, and 81% for the abnormal liver imaging group. Among symptomatic patients, those in the atrial arrhythmia group had better long-term survival than others (P<.001); no differences were seen when the exercise intolerance and abnormal liver groups were individually compared with the remainder of the cohort.

In the multivariate model (Table 2), fluid overload phenotype (hazard ratio [HR] 2.3; 95% confidence interval [CI], 1.1-5.1), heterotaxy (HR, 3.0; 95% CI, 1.2-7.5), and creatinine clearance <60 mL/m²•min (HR, 2.5; 95% CI, 1.1-6.0) were independently associated with mortality. There was no association between the presence of abnormalities of the Fontan circuit or the presence of ≥ moderate valvular regurgitation and long-term mortality.

Discussion

To the best of our knowledge, this is the first attempt to try to correlate invasive hemodynamics and clinical phenotypes in adult Fontan patients. Several important observations can be derived from our results: (1) despite the high prevalence of right ventricular morphology and systolic dysfunction among asymptomatic patients, ventricular filling pressures were still typically <10 mm Hg and Fontan pressures <15 mm Hg in this group and their prognosis was excellent; (2) long-term survival of patients presenting with fluid overload was poor, whereas a good prognosis was noted among those undergoing evaluation for atrial arrhythmias; (3) the prevalence of abnormalities of the Fontan circuit approached 25% for the entire cohort; (4) patients referred for catheterization due to abnormal liver imaging who were otherwise asymptomatic demonstrated Fontan pressure >15 mm Hg in >50% and an abnormal Fontan pathway in >40%.

As the Fontan physiology is intrinsically abnormal when compared with a 2-ventricle circulation, the definition of “normal” Fontan hemodynamics poses an obvious challenge. This complexity is deepened by the fact that underlying hemodynamics might differ according to the type of Fontan connection. Although invasive hemodynamic markers of worse prognosis have been described in patients post Fontan, well-accepted cut-offs for “normal” values are still lacking. Perhaps even more elusive are the “expected” hemodynamics in adults who have been subjected to Fontan physiology but yet remain asymptomatic. Ohuchi et al reported a central venous pressure of 10.1 ± 1.8 mm Hg, ventricular end-diastolic pressure of 6.8 ± 1.6 mm Hg, and cardiac index of 2.6 ± 0.6 L/min•m² in 18 long-term survivors undergoing periodic cardiac catheterization who were free of Fontan-related complications and had ventricular ejection fraction ≥40%.¹⁰ Our findings are similar to those reported by Ohuchi et al, despite the inherent biases of our study population, as routine cardiac catheterization is not performed at our institution. The median ventricular end-diastolic and pulmonary artery wedge pressures were in the single digits in our asymptomatic group, with 83% of asymptomatic patients demonstrating a Fontan pressure of ≤15 mm Hg. Median values for filling pressures, Fontan pressures, and cardiac indexes for our asymptomatic patients were similar to those reported by Hebson et al among their asymptomatic pediatric Fontan patients undergoing routine cardiac catheterization.¹¹ Thus, our findings suggest that even in older Fontan patients, “normal” resting hemodynamics should not differ significantly from those of “good Fontan” pediatric patients.

Interestingly, despite being symptomatic, overall hemodynamics were not significantly abnormal in most patients presenting with atrial arrhythmias. Moreover, obstruction of Fontan system was present in only one-fifth of these patients. These observations would suggest that in a large proportion of patients (particularly those with atriopulmonary Fontan connections), arrhythmias are a consequence of an intrinsic arrhythmogenic milieu of the Fontan system (ie, severe dilation of the right atrium, surgical scars/incisions) rather than driven by unfavorable hemodynamics. Therefore, these patients should probably not be seen in a similar fashion to other patients with “Fontan failure,” which is further supported by their more favorable long-term prognosis (5-year and 10-year survival rates of 89% and 83%, respectively) compared with other groups of symptomatic patients in our cohort.

In contrast, the prognosis of patients in the fluid overload group was poor. The deleterious long-term effects of elevated venous pressure in Fontan patients have been well outlined in the literature.^4,5,12 Therefore, it is not surprising that patients in our cohort presenting with fluid overload had the worst prognosis. The poor outcomes in this group should not be overlooked as we noted a 5-year survival close to 50%. These findings indicate that fluid overload patients need to be followed closely and should perhaps be considered for advanced heart failure/transplant evaluation early in the course, especially when initial therapies are not successful.

It should be noted that a significant number of patients referred for catheterization solely due to abnormal liver imaging were found to have either elevated Fontan pressures or obstruction of the Fontan pathway (46% of patients underwent either surgical or percutaneous interventions for narrowing of the Fontan connection/conduit, and a Fontan pressure >15 mm Hg was present in 57% of those without Fontan obstruction). Some have proposed that the degree of fibrosis on liver biopsy neither predicts clinical outcomes nor is it significantly associated with underlying hemodynamic findings.^13,14 Despite the increase in awareness regarding Fontan liver disease and the risk of hepatocellular carcinoma, the pathology and long-term impact of Fontan-associated liver disease are still incompletely understood. These gaps can also partially be explained by the relatively recent institution of routine liver evaluation in these patients; this is exemplified by shorter follow-up in the abnormal liver imaging group in our cohort compared with other clinical groups. Despite the small sample, the 5-year survival rate in this group deserves attention and calls for further data on the prognosis of Fontan-related liver disease in otherwise asymptomatic patients. Of note, 2 deaths in this group were due to hepatocellular carcinoma. Given the favorable results with percutaneous stenting of Fontan conduits,¹⁵ it has been our practice in recent years to actively seek and often intervene upon (even minor) abnormalities of the Fontan pathway in patients with liver disease/cirrhosis that appears out of proportion to the clinical scenario. Whether these interventions will have a positive impact on Fontan liver disease and clinical outcomes remains to be determined.

Future directions. The impact of interventions for Fontan pathway obstruction (particularly percutaneously) on clinical outcomes and whether these interventions might hasten or slow the progression of Fontan-related liver disease deserve further investigation. In addition, the natural history of Fontan-related liver disease and its underlying hemodynamics need to be better understood, especially among patients otherwise doing well clinically. Lastly, it should be highlighted that hemodynamic abnormalities were underwhelming among patients in the exercise intolerance group. We have published our initial experience in exercise invasive hemodynamics in adult Fontan patients, suggesting that the hemodynamics during exercise provide incremental information regarding the status of the Fontan circulation and pulmonary vasculature.¹⁶ It is possible that exercise invasive hemodynamics in this subset of Fontan patients might also uncover more significant elevation in Fontan and ventricular filling pressures, similar to patients with heart failure with preserved ejection fraction.

Study limitations. This is a retrospective, tertiary-care center cohort; therefore, biases might have affected our results. Although the charts have been carefully reviewed to ascertain the main indication for the invasive hemodynamic assessment, as expected, some patients had >1 indication; thus, some overlap between profiles might occur in real life. The definition of structural abnormalities of the Fontan circulation was based on the clinician, interventional cardiologist, and surgeon’s interpretation of the clinical data. It is possible then the prevalence of these abnormalities might have been underestimated.

Conclusion

Asymptomatic adult Fontan patients typically showed ventricular filling pressures <10 mm Hg and Fontan pressures <15 mm Hg and demonstrated excellent prognosis. Indication for catheterization predicted survival among our adult Fontan patients and the worst prognosis was noted among those presenting with fluid overload; conversely, symptomatic patients undergoing catheterization for atrial arrhythmias had better prognosis. The prevalence of abnormalities of the Fontan circuit approached 25% for the entire Fontan cohort and >45% of patients in the abnormal liver imaging group had features of obstruction of the Fontan.

Affiliations and Disclosures

From the ¹Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; ²Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; and ³Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grant K23 HL141448-01. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted June 13, 2021.

Address for correspondence: William R. Miranda, MD, Department of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Email: miranda.william@mayo.edu

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