Heart and combined heart-liver transplantation after Fontan palliation - timing of transplant referral affects outcomes

Fontan palliation represents the standard of care for univentricular physiology, improving outcomes so most of these patients are nowadays surviving into adulthood. However, the abnormal hemodynamics resulting from the absence of a subpulmonary pump invariably lead to circulatory failure, named failing Fontan. In the absence of effective medical or surgical treatment, heart transplantation emerges in most cases as the cornerstone of therapy, considering combined heart-liver transplantation (CHLT) in cases of advanced Fontan associated liver disease (FALD). The optimal timing to refer for transplant evaluation, selection of optimal candidates and precise criteria to consider CHLT or heart transplantation remain unanswered questions to be elucidated.

Recently, Lewis et al have analyzed a retrospective cohort of adult Fontan patients who underwent HT or CHLT across 15 centers in the United States and Canada, focusing in adult patients (≥16 years at the time of transplant referral) with history of Fontan completion transplanted between 1995 and 2021, finally including 131 Fontan patients post heart (n=91) and combined heart and liver (n=40) transplantation (1), searching for predictors and causes of post-transplant morbidity and mortality. Very importantly, authors wanted to define the impact of timing of transplant referral relative to the onset of Fontan failure on posttransplant outcomes. For this purpose, they used an arbitrary definition of the first time a patient presented with “failing” Fontan physiology - first time an individual had worsening fluid retention, new-onset ascites, need for escalating dose of diuretic agents, refractory arrhythmia, diagnosed as“failing Fontan” by their treating cardiologist, or requiring hospital admission for diuresis or heart failure management - to the moment of transplant evaluation.

• Interesting findings included:
  Overall survival was 79% and 66% at 1- and 5- years post-transplant respectively, but in last surgical era (after 2010) improved to 87% and 76%, not so far from global heart transplant, estimated as 90% and 80% respectively (2).
• Main causes of death included multiorgan dysfunction (28%), bleeding (18%), and primary graft failure (13%), as expected from the technical difficulties of transplantation in this population, requiring mechanical circulatory support in 14% of patients and renal replacement therapy in 23%. This is in contrast with global post-transplant outcomes, where primary graft failure (41%) and multiorgan dysfunction (18%) are the leading causes of mortality.
• Among preoperative predictors of death, both at 1- and 5- years post-transplant, they found that the time from diagnosis of Fontan failure to transplant evaluation was significantly associated with decreased survival at both 1 and 5 years post-transplantation; presence of venovenous collaterals (which may increase the bleeding risk), low extremities varicosities, NYHA functional class IV and mean arterial pressure <65 mmHg, all of them markers of more advanced disease were also related with outcomes. Interestingly, cardiac diagnosis, single ventricle morphology and function, or atrioventricular valve insufficiency were not related to mortality, since probably they are related to time to onset of Fontan failure but do not influence the outcome of transplantation.
• Authors performed a sensitivity analysis excluding patients with CHLT and still the increasing time from diagnosis of Fontan failure to transplant evaluation remained significantly associated with 1- and 5-year post-transplant mortality, presence of venovenous collaterals and bilateral lower extremity varicosities remained significantly associated with post-transplant mortality at both 1 and 5 years post-transplantation, whereas NYHA functional class IV remained a significant predictor of 5-year post-transplant mortality.
• Finally, the authors perform comparisons between HT and CHLT in this cohort and a specific analysis of the influence of FALD in an accompanying paper in same issue (3). In this case they use a FALD score including 4 items: liver cirrhosis by image techniques (not by biopsy), presence of varices, splenomegaly and need of performing at least two paracenteses along medical history, with one point for each one. A FALD score over 2 worsens post-transplant outcome with a HR 14.6 (p = 0.015) after adjusting for surgical era. In this analysis they compare heart transplant with CHLT after adjusting by surgical era and FALD score, finding superior outcomes in cases of CHLT in those patients with FALD score >= 2 (HR 0.33, p= 0.04).

The results of this work, carried out in a relatively large cohort of adult patients with Fontan circulation, highlight the importance of choosing the right moment to refer patients for transplant evaluation when they show signs of Fontan failure, both for isolated cardiac transplantation, as well as for CHLT, before evidence of advanced disease that increases mortality after transplantation occurs. As limitations, the authors acknowledge that since it was a retrospective study, selection bias could have occurred and that many of the data could not be collected and therefore could not be analyzed. Caution should also be exercised in the interpretation of the accompanying article, in which CHLT does not appear to be associated with increased risk compared with HT and may offer benefit in patients with clear evidence of cirrhosis or portal hypertension.

Nevertheless, the results suggest that an early referral to transplant evaluation, a decision taken by physicians, may be the easier intervention to improve post-transplant outcomes. This work serves as a starting point for new prospective studies in the current era of transplantation to decide the correct time to refer patients, assessment of risk factors and also establishing standardized post-transplant management protocols.