Selective Use of Pulmonary Vasodilators in Patients with Fontan Physiology

Background Fontan-associated liver disease is a well-known sequela following the Fontan procedure for patients living with single-ventricle heart disease. Pulmonary vasodilators, such as phosphodiesterase type 5 inhibitors, have emerged as a potential therapeutic option for lowering central venous pressures by reducing pulmonary vascular resistance. Method We performed a single-center retrospective review of Fontan patients who were placed on pulmonary vasodilator therapy with prehemodynamic and posthemodynamic, MR elastography, and histologic assessments. Results A total of 125 patients with Fontan circulation underwent surveillance with cardiac catheterization during the review period. Fifty-three (42%) patients who did not have increased end-diastolic pressures at the time of cardiac catheterization were started on phosphodiesterase type 5 inhibitor therapy. Nine patients (17%) underwent posttherapy follow-up catheterization. The mean Fontan pressure decreased from 15.4 ± 3.3 mmHg to 13.3 ± 2.5 mmHg (p=0.026), after initiation of pulmonary vasodilatory therapy. There was no change in end-diastolic pressure, transpulmonary gradient, wedge pressure, pulmonary vascular resistance, cardiac index, or saturation. Eleven patients (21%) underwent pretherapy MR elastography testing with posttherapy follow-up MR elastography. We found no improvement in liver stiffness score following the application of pulmonary vasodilators. Three patients underwent pretherapy and posttherapy liver biopsies, with variable histological changes observed within the hepatic parenchyma. Conclusions These data demonstrate indeterminate results for the selective use of pulmonary vasodilators but highlight the need for large prospective randomized control trials of pulmonary vasodilator therapies to fully assess the benefit of such therapies in Fontan-associated liver disease.


Introduction
Te Fontan procedure, which was frst described in 1971, is generally accepted as the fnal staged palliation for patients with single ventricle physiology and has led to improved survival amongst this patient population [1,2]. Despite this, Fontan and Baudet initially cautioned that "this procedure is not an anatomical correction, which would require the creation of a right ventricle, but a procedure of physiological pulmonary blood fow restoration, with suppression of right and left blood fow mixing" [1]. Te absence of a subpulmonary ventricle and reliance on passive pulmonary blood fow directly lead to increased central venous pressure, and as such, this unfavorable physiologic state leads to chronic end-organ dysfunction, characterized by liver fbrosis, low bone density, renal disease, lymphatic dysfunction, lung disease, and cardiac dysfunction [3]. Te liver, which is particularly susceptible to high venous pressures, also sees impaired arterial fow as a result of decreased cardiac output, as seen in this cohort of patients [4]. Fontan-associated liver disease is likely due to a combination of these factors, including both elevated central venous pressure and impaired arterial fow [4]. Hepatic abnormalities have been seen in patients even before the Fontan operation and as early as 20-35 days postoperatively following Fontan as a result of this physiologic change [5][6][7]. Hepatic fbrosis exists in all patients following Fontan operation, and its severity is associated with time since Fontan operation and elevated Fontan pressures [8,9].
Troughout the last decade, many Fontan surveillance programs have evolved across the world, utilizing various invasive and noninvasive techniques to assess for Fontanassociated liver disease [3,[10][11][12]. As the full understanding of Fontan-associated liver disease continues to evolve, many management strategies have been developed aimed at optimizing this abnormal physiologic state. One such therapy, phosphodiesterase-5 inhibitors, acts on and promotes the cGMP-mediated cellular pathway, resulting in the creation of nitric oxide. Nitric oxide acts on receptors within the smooth muscle of the pulmonary vascular bed, causing relaxation of tissues, and thus, a drop in vascular resistance is achieved. Phosphodiesterase type 5 inhibitors have been shown to decrease pulmonary vascular resistance and improve cardiac output in patients with single-ventricle physiology [8,13]. Other large studies, such as the Fontan Udenafl Exercise Longitudinal (FUEL) trial, have shown no associated improvement in oxygen consumption at peak exercise with patients treated with phosphodiesterase type 5 inhibitors. Tis study only demonstrated some improvement in markers of exercise performance at the ventilatory anaerobic threshold but did not evaluate the efect of udenafl on Fontan hemodynamics or the extent of Fontanassociated liver disease [14].
Te purpose of this study is to describe the experience and outcomes of phosphodiesterase type 5 inhibitors on individuals living with Fontan physiology at Rady Children's Hospital, San Diego, and correlate the associated Fontan hemodynamic, liver magnetic resonance elastography, and hepatic histological fndings.

Materials and Methods
Tis was a 6-year (2014-2020) retrospective review of all patients who underwent the Fontan operation and subsequently had a cardiac catheterization or MR elastography to evaluate for Fontan-associated liver disease at Rady Children's Hospital, San Diego. Te practice at our institution is routine screening 5-10 years post-Fontan with cardiac catheterization, imaging of the liver by magnetic resonance elastography, and transjugular liver biopsy, when clinically indicated, or when Fontan pressure is greater than 15 mmHg or liver stifness score by MR elastography is greater than 5 kPa [15]. Patients with a Fontan pressure greater than 15 mmHg and an end-diastolic pressure less than 10 mmHg, resulting in a transpulmonary gradient of at least 7 mmHg, were placed on a phosphodiesterase type 5 inhibitor following cardiac catheterization. All patients in our analysis who were placed on phosphodiesterase type 5 inhibitor therapy were started on tadalafl. Tadalafl was started at a low dose (0.5 mg/kg/day) and if tolerated, it was increased to a maximum dose of 1 mg/kg/day or 40 mg/day. Te Institutional Review Board at Rady Children's Hospital San Diego approved the study. Data were collected by retrospective review of the medical records for patient demographics, cardiac diagnosis, medications, surgical procedures, hemodynamic data, MR elastography data, and histological data.
Only patients who were identifed to have been started on phosphodiesterase type 5 inhibitor therapy and who underwent pretherapy and posttherapy cardiac catheterization or MR elastography were included in the analysis. Continuous data were summarized as the mean or median with a standard deviation or range when appropriate or as numbers with percentages for discrete data. A two sample ttest was used for continuous data as appropriate. A p value of less than 0.05 was considered statistically signifcant.

Standardized Approach to a Cardiac Catheterization.
Cardiac catheterization was performed under general anesthesia with positive pressure ventilation. Hemodynamic measurements included standard pressure and saturation data under conditions of 21% FiO 2 . Typically, angiography was performed in addition to transcatheter interventions at the discretion of the primary operator based on catheterization fndings. Tese data were not utilized in the present study.

Magnetic Resonance Elastography.
Te liver assessment included magnetic resonance imaging and elastography. All MR elastography was performed on a 1.5-T system (GE 450 1.5-T, Waukesha, WI). Images were analyzed on a GE Advantage workstation by drawing a freehand region of interest encompassing the entire measurable part of the liver.

Results
A total of 125 patients (56% male, 44% female) with Fontan circulation underwent surveillance with cardiac catheterization during the review period. Of these 125 patients, 53 (42%) were started on phosphodiesterase type 5 inhibitor therapy during the review period. Of these 53 patients, a total of 9 (17%) were placed on phosphodiesterase type 5 inhibitor therapy at the time of cardiac catheterization and later underwent posttherapy follow-up catheterization. Of the 53 patients, a total of 11 (21%) were placed on phosphodiesterase type 5 inhibitor therapy at the time of initial MR elastography testing with posttherapy follow-up MR elastography. Te median time on phosphodiesterase type 5 inhibitor therapy for the two subgroups, catheterization and MR elastography evaluation, was 29.5 (4-60) and 26 (16-47) months, respectively. Primary diagnosis and dominant ventricle were variable. Table 1 provides the summary of the patient demographics.
Te mean Fontan pressure prior to phosphodiesterase type 5 inhibitor therapy was 15.4 mmHg and posttherapy was 13.3 mmHg, which was statistically signifcant (p � 0.026), with an equivalent systemic systolic blood pressure. Te mean wedge pressure prior to intervention was 9.2 mmHg and posttherapy was 8.6 mmHg (p � 0.447). Te mean transpulmonary gradient prior to phosphodiesterase type 5 inhibitor therapy was 6.2 mmHg and postphosphodiesterase type 5 inhibitor therapy was 4.8 mmHg (p � 0.247). Te mean systemic end-diastolic pressure (EDP) prior to phosphodiesterase type 5 inhibitor therapy was 7.8 mmHg and postphosphodiesterase type 5 inhibitor therapy was 7.2 mmHg (p � 0.525). Te mean indexed cardiac output prior to phosphodiesterase type 5 inhibitor therapy was 3.5 L/min/m 2 and postphosphodiesterase type 5 inhibitor therapy was 3.3 L/min/m 2 (p � 0.394). Te mean pulmonary vascular resistance prior to phosphodiesterase type 5 inhibitor therapy was 2.1 WU × m 2 and postphosphodiesterase type 5 inhibitor therapy was 1.6 WU × m 2 (p � 0.321). Te mean oxygen saturation in room air prior to phosphodiesterase type 5 inhibitor therapy was 91.6% and post-PDE5i therapy was 92% (p � 0.672). Te mean MR elastography stifness prior to phosphodiesterase type 5 inhibitor therapy was 4.65 kPa and postphosphodiesterase type 5 inhibitor therapy was 4.63 kPa (p � 0.958). Tables 2 and 3 provide the summary of these data. Tree patients underwent pretherapy and posttherapy liver biopsies. Each liver biopsy was scored based on the modifed Ishak congestive hepatic fbrosis (ICHF) scoring system [16], and the results are summarized in Table 4. Each patient had variable results, ranging from signifcant progression of their liver disease for one patient to improvement in their liver disease for another patient. Tere were no complications reported during any of the hemodynamic, MR elastography, or biopsy assessments.

Discussion
In this single-center study of patients with Fontan circulation who had been placed on pulmonary vasodilator therapy and subsequently underwent routine surveillance with cardiac catheterization or imaging of the liver by MR elastography, only Fontan pressure was statistically lower between the pretherapy and posttherapy groups. Although there was an improvement in wedge pressure, transpulmonary gradient, and end-diastolic pressure, these were not statistically signifcant. Several studies have been performed which profled the use of pulmonary vasodilators and their immediate and short-term efects on the hemodynamics of patients with Fontan circulation. One study, by Mori et al., found statistical improvement in the pulmonary vascular resistance of patients following three months of oral outpatient sildenafl [13]. Another study, by Tunks et al., demonstrated an immediate improvement in pulmonary vascular resistance, Fontan pressure, and cardiac index by cardiac catheterization following administration of IV sildenafl [10]. Despite these fndings, few studies have examined the long-term efect of oral pulmonary vasodilator therapy on the hemodynamic profles of patients following Fontan operation. While the current study did not show a statistical improvement in many of these factors, this may be due to the low sample size used in Data are provided as a median (range) or n (%).   Journal of Interventional Cardiology our study. Our hemodynamic data do not suggest that routine use of phosphodiesterase type 5 inhibitor therapy is benefcial, even in patients with elevated Fontan pressures and low enddiastolic pressures. Potential therapeutic benefts may be demonstrated in future studies with large randomized controlled trials. Liver fbrosis is a nearly universal fnding during a routine biopsy in this patient population. In a study by Patel et al., 57 patients with Fontan circulation underwent biopsy; all but one was found to have hepatic fbrosis and 19 of these patients (33.3%) demonstrated bridging fbrosis or cirrhosis [16]. While liver biopsy has historically been the gold standard for measuring the degree of liver involvement for these patients, liver stifness, as measured by MR elastography, has been shown to be correlated with histological fbrosis scoring systems and Fontan pressures [9,15,17]. Each of the patients who underwent a liver biopsy in our larger Fontan cohort was found to have some degree of liver fbrosis. Of the three individuals who underwent pretherapy and posttherapy liver biopsies to compare the efect of pulmonary vasodilators, the results were quite variable. One patient had signifcant progression of their liver disease, with severe portal fbrosis on their postbiopsy. In contrast, another patient demonstrated improvement, moving from 2A to 1 during the study period. Tis variability in fndings may refect the heterogeneity of liver disease within a patient's hepatic parenchyma, which has been well documented, and could suggest sampling errors with liver biopsy procurement [3,4]. Tis study was one of the frst to examine the efect of pulmonary vasodilator therapy on Fontan-associated liver disease using MRE of the liver and liver biopsies. Although we failed to demonstrate a statistical diference in liver stifness for patients who were placed on pulmonary vasodilator therapy, there was individual improvement seen in some of our patients. Overall, these data do not demonstrate a clear beneft or harm of pulmonary vasodilator therapy on Fontan-associated liver disease, as characterized by liver stifness and histological changes. To better delineate any efect of these drugs on Fontan-associated liver disease, larger prospective studies must be performed.
One of the major limitations of the current study was the small sample size, which afected our ability to achieve high power during our statistical analysis. Despite having a large sample of patients with Fontan circulation who had been started on pulmonary vasodilator therapy, only a few of these patients underwent posttherapy cardiac catheterization or MR elastography for an analysis to be performed. Another limitation of this study was the use of a retrospective analysis rather than a prospective study. By performing a retrospective analysis, we were unable to control any potential confounders, which ultimately likely led to poor statistical power. Another limitation was the variable time between pretherapy and posttherapy evaluations. Some of our patients remained on pulmonary vasodilator therapy for several years, while others were reevaluated just four months after initiation of pulmonary vasodilator therapy. Longer and more consistent therapy durations, which can be achieved easily in a prospective study, may demonstrate a stronger therapeutic efect.
Te current study shows that the selective use of pulmonary vasodilators in patients with Fontan circulation is associated with a reduction in Fontan pressure. While not statistically signifcant, a reduction in transpulmonary gradient, end-diastolic pressure, and pulmonary vascular resistance was also seen. No improvement was seen in MR elastography liver stifness scoring during our study. Some improvement, however, variable, was seen in the histological fndings of the liver following this therapy. Overall, this study is unable to support the routine use of phosphodiesterase type 5 inhibitor therapy in Fontan patients, even in those with elevated Fontan pressures and low end-diastolic pressures. Ultimately, there is a strong need for larger randomized control trials to determine whether pulmonary vasodilator therapy is associated with improved long-term outcomes in patients with Fontan-associated liver disease.

Data Availability
Te data used to support the fndings of this study are included within the article.

Conflicts of Interest
Te authors declare that there are no conficts of interest.