The Fontan procedure is the final palliative operation for patients with single ventricle physiology. The first published description of the Fontan procedure in 1971 detailed a strategy to divert systemic venous return, via the caval veins, directly to the lungs.Reference Fontan and Baudet1 Since then, numerous modifications have resulted in a significant decrease in peri-procedural morbidity and mortality.Reference Bridges, Mayer and Lock2–Reference Rogers, Glatz and Ravishankar4 At present, the Fontan procedure is the standard of care for functionally univentricular hearts and has enabled survival beyond childhood with relatively normal oxygen saturations. This success, however, has been accompanied by a concomitant realisation of the long-term consequences and late co-morbidities associated with total cavopulmonary circulation, including protein-losing enteropathy, plastic bronchitis, liver fibrosis, and alterations in bone and muscle development.Reference Rychik, Goldberg and Rand5–Reference Avitabile, Goldberg and Zemel8 Recent efforts have focussed upon developing targeted therapies to mitigate the ill-effects inherent to Fontan physiology.Reference Goldberg, French and McBride9–Reference Rhodes, Ubeda-Tikkanen and Clair11 In this review, we discuss some of the limitations of Fontan physiology and the role for pulmonary vasodilators as part of an overall treatment strategy.
Fontan physiology
The total cavopulmonary configuration is designed to place the single functioning ventricle as the pump providing oxygenated blood to the systemic circulation, whereas pulmonary blood blow is derived from passive blood return from the caval veins. This physiological arrangement introduces a number of significant limitations. First, in the absence of a pre-pulmonary pump, ventricular preload is limited by passive blood flow across the pulmonary vascular bed, making the preload dependent upon the gradient between the systemic venous pressure and the ventricular end-diastolic pressure. As a result, the overall cardiac output is diminished and the circulation remains in a chronic state of systemic venous hypertension.Reference Gewillig and Goldberg12 In this construct, small changes in pulmonary vascular resistance or in the relaxation properties of the ventricle can have a profound influence upon ventricular preload and ultimately cardiac output.
Although the Fontan operation may be adequate to support the circulatory needs of the univentricular patient in the early years after palliation, current data suggest a progressive deterioration in circulatory efficiency over time.Reference Rychik, Goldberg and Rand5 Furthermore, even when the circulation is relatively well tolerated, we are learning that there are differences in growth,Reference Cohen, Zak and Atz13 bone and muscle mass,Reference Avitabile, Goldberg and Zemel8, Reference Avitabile, Leonard and Zemel14 and pubertal development,Reference Avitabile, Leonard and Zemel14 relative to a population with normal cardiac anatomy, suggesting that a chronic state of low cardiac output and systemic venous hypertension may have subtle consequences, even in the absence of overt Fontan failure.
Changing the physiology: the role of pulmonary vascular resistance
The adequacy with which the Fontan physiology is able to support the circulatory needs of the body has many dependent variables. As discussed, after total cavopulmonary connection, ventricular preload is dependent upon the difference between the central venous pressure and the end-diastolic pressure of the ventricle and the resistance across the pulmonary vascular network. Pulmonary vascular resistance then becomes one of the primary modulators of ventricular preload and cardiac output.Reference Gewillig and Goldberg12 This is considerably different from the physiology we see in biventricular patients. Although the normal heart has the ability to maintain adequate cardiac output in the setting of mild increases in pulmonary vascular resistance, this is poorly tolerated in Fontan patients and leads to diminished cardiac output.Reference Gewillig and Goldberg12 Not surprisingly, elevated PVR likely has a significant role in the so-called Fontan failure.Reference Mitchell, Campbell and Ivy15 In fact, the concept of minimising the negative effects of pulmonary vascular resistance to maintain adequate cardiac output is an underlying principle of the Fontan fenestration, an innovation that led to a substantial decrease in peri-operative morbidity and mortality.Reference Bridges, Mayer and Lock2
In addition to the absence of a pre-pulmonary pump driving pulmonary blood flow, the Fontan circulation also changes the pulmonary blood flow physiology from pulsatile to non-pulsatile. Such changes can have an influence upon pulmonary vascular resistance, exerting an effect at the endothelial cell level. Data from both human and animal studies suggest that changes in pulsatile flow may affect endothelial cell-mediated nitric oxide release and overall vasoreactivity.Reference Henaine, Vergnat and Bacha16, Reference Khambadkone, Li, de Leval, Cullen, Deanfield and Redington17 This is consistent with reports of elevated pulmonary vascular resistance in patients years after the Fontan procedure, which was shown to be responsive to exogenous nitric oxide.Reference Khambadkone, Li, de Leval, Cullen, Deanfield and Redington17
In attempts to characterise these differences at the molecular level, a number of studies have demonstrated abnormal expressions of endothelial-derived factors in the pulmonary vasculature in failing Fontan patients. Some of these include over-expressions of nitric oxide synthase, endothelin-1, and endothelin receptors, as well as reduced expression of bone morphogenetic protein receptor type 2.Reference Ishida, Kogaki and Ichimori18–Reference Levy, Danel, Laval, Leca, Vouhe and Israel-Biet20 Other post-mortem studies have demonstrated a different vascular re-modelling phenotype of failing Fontans, including a small smooth muscle medial layer, smooth muscle cell apoptosis, and eccentric intimal fibrosis.Reference Ridderbos, Wolff and Timmer21 Although limited by small sample sizes and differing in conclusions, these studies have underscored the importance of the following: (1) understanding the molecular mechanisms involved in the pulmonary haemodynamics of a Fontan patient and specifically the pulmonary vascular resistance, (2) understanding the short-term and long-term consequences of this physiology, and (3) identifying the molecular targets that will modulate the physiology more favourably in the short term and long term in Fontan patients.
The use of pulmonary vasodilators in Fontan patients
Clinical and basic science data have provided substantial rationale for the efforts to pharmacologically modify PVR in Fontan patients. Many of the current strategies under use and investigation have borrowed upon the years of experience of current pulmonary hypertension therapies; one of the first studies to evaluate the use of oral medication to modulate pulmonary vascular resistance in Fontan patients was published in 2008, assessing the effects of sildenafil upon exercise capacity.Reference Giardini, Balducci, Specchia, Gargiulo, Bonvicini and Picchio22 Sildenafil is a phosphodiesterase-5 inhibitor that limits the breakdown of cyclic guanosine monophosphate. This cyclic nucleotide is normally produced in response to nitric oxide, and has vasodilatory and anti-proliferative effects upon vascular smooth muscle cells.Reference Archer, Weir and Wilkins23 The study showed improved peak oxygen uptake after one dose of sildenafil.Reference Giardini, Balducci, Specchia, Gargiulo, Bonvicini and Picchio22
A subsequent randomised, double-blind, cross-over trial – sildenafil after Fontan operation – was conducted to evaluate the effect of 6 weeks of sildenafil therapy on exercise performance and echocardiographic indices of myocardial performance. This study demonstrated improved ventilatory efficiency at peak and submaximal exercise without any significant change in oxygen consumption.Reference Goldberg, French and McBride9 Looking at performance measures by echocardiography, 6 weeks of sildenafil therapy resulted in a significantly improved myocardial performance index, a measurement of overall global ventricular function, and a trend towards improvement in the product of velocity time integral and heart rate, a proxy for cardiac output.Reference Goldberg, French and Szwast24 In addition, these studies demonstrated the safety and relative tolerability of short-term sildenafil use. An additional recent study using cardiac MRI showed improved cardiac index and stroke volume and a decrease in pulmonary resistance with exercise after a single dose of sildenafil. There was no change in the end-diastolic volume index, however.Reference Van De Bruaene, La Gerche and Claessen25 Studies carried out thus far about sildenafil use in the Fontan population have been designed to evaluate the short-term benefits. Further studies designed on a larger scale, looking at the long-term effect of this drug upon outcomes, are needed.
Endothelin-1 is a drug target that has been identified with the hopes of modulating pulmonary vascular resistance in Fontan patients. Endothelin-1 is a potent peptide produced by endothelial cells that plays a role in vasoconstriction and cell proliferation. It acts through two distinct endothelin receptors, type A and B.Reference Archer, Weir and Wilkins23 In addition to the immunohistochemical evidence of increased levels of endothelin-1 and its receptor in the pulmonary arteries of failed Fontan patients, there have been published reports of elevated circulating plasma levels of endothelin-1 in Fontan patients with increased central venous pressure.Reference Ishida, Kogaki and Ichimori18, Reference Hiramatsu, Imai and Takanashi26 Drugs such as bosentan and ambrisentan are endothelin-1 receptor antagonists and have been used to improve pulmonary haemodynamics in patients with pulmonary arterial hypertension.Reference Archer, Weir and Wilkins23
In 2014, a randomised, placebo-controlled, double-blind trial, evaluating the effect of bosentan on exercise capacity in Fontan patients was carried out (TEMPO trial). After 14 weeks of treatment, patients treated with bosentan demonstrated improved peak oxygen consumption, exercise test time, and decreased pro-BNP levels.Reference Hebert, Mikkelsen and Thilen10 Although the TEMPO trial results are encouraging, they are in direct contrast to a previous open-label trial of bosentan in adult Fontan patients, which showed no difference in exercise capacity after 6 months of treatment.Reference Schuuring, Vis and van Dijk27 Interpreting these discrepancies is difficult due to study methodology, patient dropout, and the differences between adult and paediatric physiology. It does highlight, however, the need for additional studies to better understand the long-term effects, optimal age, and treatment window of endothelin receptor antagonism. The TEMPO trial also reported a statistically significant decrease in haemoglobin concentrations in the treatment group. This and other known side-effects such as hepatotoxicity and teratogenicity in female patients of child-bearing age require careful consideration before initiating treatment.
The prostacyclin pathway is another pathway that has been exploited to improve pulmonary vascular resistance in patients with pulmonary hypertension. Prostacylcin is generated by endothelial cells, causes vasorelaxation, and inhibits smooth muscle cell proliferation through the increased production of cyclic adenosine monophosphate.Reference Archer, Weir and Wilkins23 Prostacyclin analogues have been generated to modulate pulmonary vasculature vasoreactivity. Multiple modes of delivery have been developed due to the short half-life and relative instability of the drug. Exogenous prostacyclin can currently be delivered through continuous intravenous infusion (epoprostenol), subcutaneously (treprostinil), orally (beraprost), and by inhalation (iloprost). A randomised, double-blinded, placebo-controlled trial of inhaled iloprost was conducted to evaluate the effect of prostacyclin upon exercise performance. The study demonstrated a significant increase in peak oxygen consumption and peak oxygen pulse after one dose of iloprost.Reference Rhodes, Ubeda-Tikkanen and Clair11 It is currently unclear what effects chronic exogenous prostacyclin may have upon Fontan physiology and warrants further investigation.
Special cases of Fontan failure: protein-losing enteropathy and plastic bronchitis
Notwithstanding the successful reduction in peri-operative and longer-term morbidity and mortality,Reference Rogers, Glatz and Ravishankar4, Reference Hirsch, Goldberg and Bove28 the physiological limitations of the Fontan circulation may have significant negative impacts upon multiple organ systems and overall quality of life.Reference Rychik, Goldberg and Rand5 Protein-losing enteropathy and plastic bronchitis are two potentially lethal co-morbidities that occur in the setting of the elevated venous and lymphatic pressures, characteristics that are an inherent to Fontan physiology. A number of treatment strategies have emerged to try to relieve the symptoms of protein-losing enteropathy and plastic bronchitis, including steroids for protein-losing enteropathy,Reference Thacker, Patel, Dodds, Goldberg, Semeao and Rychik29 inhaled agents aimed at dissolving casts for plastic bronchitis,Reference Avitabile, Goldberg, Dodds, Dori, Ravishankar and Rychik7 and interventions to decrease central venous and lymphatic pressure for both disease states.Reference Thacker, Patel, Dodds, Goldberg, Semeao and Rychik29–Reference Uzun, Wong, Bhole and Stumper31 Interventions targeting central venous pressure may include the creation of a Fontan fenestration, surgically or in the catheterisation laboratory, the use of pharmacotherapy, or both. There are now case reports for protein-losing enteropathy and plastic bronchitis demonstrating symptomatic improvement after the initiation of sildenafil treatment, likely as a result of decreasing systemic venous/lymphatic pressure and increasing cardiac output, such that the resultant state is just below the threshold at which these complications occur.Reference Haseyama, Satomi, Yasukochi, Matsui, Harada and Uchita30, Reference Uzun, Wong, Bhole and Stumper31
Conclusion
The Fontan operation was a paradigm-shifting innovation. Over the years since its initial description, there have been many improvements such that both short-term and long-term mortality have decreased substantially; however, morbidity and late mortality are still pressing concerns. Although a targeted approach to modify pulmonary vascular resistance in Fontan patients has demonstrated promising initial results, more studies are required to truly understate the role of these agents, as well as their long-term safety, in this population.
Acknowledgements
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