Fontan circulation was described as the final stage of palliation for congenital heart disease with univentricular physiology.¹ In this circulation, blood from the superior and inferior vena cava is bypassed to the pulmonary circulation, so that the dominant ventricle is responsible for systemic circulation. Since its description, this technique has increased the survival and quality of life of patients with univentricular physiology.^2,3

However, this type of circulation may be associated with significant morbidity.⁴ That is because the patient is predisposed to a chronic low output, with increased central venous pressure and congestive heart failure.5 These conditions can lead to pleural and pericardial effusion, gastrointestinal dysfunction, and protein-losing enteropathy (PLE).⁶

PLE is a severe condition derived from chronic venous hypertension leading to inflammation, tumor necrosis factor release, and consequent changes in the enterocyte membrane's composition. Related complications from this condition are hypoalbuminemia, hypocalcemia, hypogammaglobulinemia, and hypercoagulable states.⁶ PLE affects up to 10% of patients after Fontan surgery⁷ and can have mortality rates up to 60%.⁸ Thus, identifying patients at higher risk of developing PLE after Fontan operation is essential because it can impact on their management.

The use of diagnostic imaging methods is vital for the management of congenital heart diseases. Among them, the echocardiogram gained special prominence for its ability to provide anatomical and hemodynamic information, in addition to being less invasive. As such, identifying echocardiographic or ultrasonographic parameters that can provide information on the risk of a patient presenting PLE or could present PLE at the moment after Fontan surgery can be of paramount importance.

Therefore, this study aims to describe echocardiographic or ultrasonographic parameters associated with PLE in patients after Fontan surgery through a systematic review of the literature with meta-analysis.

Two investigators (Mourato, MF and Mourato, FA) extracted the data independently (Mourato, FA made the search strategy. Both authors analyzed each title/abstract of all articles to select those that would go to a full-text evaluation. Both authors analyzed the full text to select those that would go to qualitative and quantitative analysis). Discrepancies were resolved by consensus between these authors after discussion of previously determined inclusion criteria. The following data were collected from the selected articles: first author name, year of publication, study design, sample size (divided into with PLE, without PLE, and future PLE), and the average age of the sample when submitted to an echocardiogram/ultrasonography. The echocardiographic/ultrasonographic parameter used in each study was described in the Results section. When two or more studies offered information on the same echocardiographic/ultrasonographic parameter, quantitative analysis (meta-analysis) was performed.

The increasing survival of patients with Fontan circulation brings an increase in their risks of developing adverse events, such as PLE. These patients are usually submitted to several echocardiographic exams throughout their lives; accordingly, the use of parameters derived from this exam for diagnosis or prediction of adverse events may have a substantial impact on guiding their therapeutic approach. In this systematic review, the main echocardiographic findings associated with PLE in patients after the Fontan operation were described. In this analysis, we divided these parameters into two: parameters in the presence of PLE and parameters of future PLE.

Among the parameters in the presence of PLE, SMAR has been more often described in the literature and tended to be higher in patients who presented PLE. Patients after Fontan surgery have a lower cardiac output, on average 2.4 L/min/m².¹⁸ Of these, those who evolve with PLE have even lower rates of 1.5 – 2.0 L/min/m2.¹⁸ The state of low cardiac output leads to higher peripheral vascular resistance and, consequently, to vasoconstriction of the mesenteric circulation.18 The low mesenteric flow promotes the release of inflammatory cytokines that alter the enterocyte cell membrane, increasing intestinal permeability and promoting protein loss.^18,19 Thus, an increased mesenteric vascular resistance may be found in PLE.

In this context, Ryckik et al.,¹⁸ calculated the SMAR index in patients without Fontan circulation, with Fontan circulation but no PLE, and with Fontan circulation and PLE.¹² In their study, the control group had the lowest index value (0.74 ± 0.08). Patients with Fontan physiology had higher indices, being (0.88 ± 0.05) in those without PLE, and the highest (0.91 ± 0.03) in those with PLE (p <0.001). Subsequently, two studies also show a tendency for a higher index in patients with Fontan and PLE circulation, but without statistical significance.^11,12 The combined analysis of data from these articles (Figure 2) shows statistical relevance (p < 0.001). Thus, there is evidence that leads to crediting the SMAR index as a potential parameter. Nonetheless, we must view this finding with caution, because in one study¹³, it was not possible to distinguish patients with PLE from plastic bronchitis. For instance, one problem with the use of the SMAR index is its proximity between the two Fontan groups, besides the fact that the majority of patients with Fontan circulation have indices greater than usual (defined as a SMAR index between 0.75 and 0.917). This fact may make it hard to find specific cutoff points for PLE in these patients.

The ratio between the flow of the superior mesenteric artery and the celiac artery was lower in patients with PLE.¹⁴ Thus, the analysis of the mesenteric vascularization can be individualized, as the resistance in the celiac artery is generally low in normal circulatory physiology, but may vary in patients with Fontan circulation. This analysis might lead to a better assessment of the distribution of the mesenteric flow and, consequently, the determination of a higher risk of PLE.¹⁴ It is worth noting that this study also evaluated the SMAR, but no significant difference was observed between the groups.

Additionally, PLE after the Fontan operation usually occurs in two peaks, one earlier (in childhood) - which usually responds to therapy - and another later in life, which tends not to.⁶ It should be noted that the studies reviewed here included data from different age groups, with echocardiographic parameters based on SMAR being derived from younger patients (Table 1). These different parameters may reflect different mechanisms leading to PLE, with one more linked to poor mesenteric perfusion and the other involving additional hemodynamic changes that contribute to subsequent failure of the Fontan circulation. The prevalence of one or the other could be influenced by age. With this in mind, we performed a meta-regression analysis of the SMAR index mean difference between patients with and without PLE and their age; however, it showed no statistical significance (Figure 3).

Parameters of future PLE were found only in single studies. They are the celiac artery resistance index, estimated systolic pressure in the pulmonary artery, and change in the fractional area.

Low cardiac output leads to peripheral vasoconstriction. It may explain the fact that the RCA index, measured at the site of origin of three arteries responsible for the vascularization of a large part of the abdominal organs, was higher in patients with PLE.¹³ However, despite the statistical significance, such finding has limitations. The difference between the groups described by Du Bois et al.,¹³ was exceedingly small, like SMAR, and the analysis also included patients with plastic bronchitis (that is, the group was not homogeneous for PLE only).

Fontan physiology is characterized by high pressures and congestion of the venous system, which is ultimately influenced by the impedance of the pulmonary vessels.^5,20 Therefore, flow is directed by the pressure difference between the systemic and pulmonary systems, and small hemodynamic changes (such as an increase in pulmonary pressure) can impair the blood flow.^6,21 Furthermore, myocardial dysfunction, which leads to a reduction in cardiac output, is associated with a higher chance of Fontan circulation failure and the development of PLE.⁶

In this context, in a retrospective Mexican evaluation, it was shown that patients with Fontan circulation and PLE tend to have higher values of pulmonary systolic pressure (between 12-15 mmHg), with a risk ratio of 2.6 (p = 0.01).¹⁷ In another case-control study, it was shown that minor changes in the fractional area were associated with PLE since this measure is related to systolic function.¹⁶ Also, a lower left ejection fraction was correlated with the presence of PLE in patients after Fontan surgery.¹⁵ Therefore, echocardiographic changes in pulmonary pressure and systolic function may be associated with PLE as well.

It is worth noting that the parameters obtained in other procedures can also predict the risk of PLE. An example is an increase in central venous pressure (CVP) in the postoperative period of Fontan surgery.²² This is likely to occur because CVP leads to more significant venous congestion, altering the intestinal lymphatic drainage, thus leading to PLE. Another hemodynamic aspect that can predict the development of PLE is low pulmonary compliance, even when corrected by other hemodynamic variables.²³ Likewise, low pulmonary compliance is related to more extended pleural effusion periods, yet another risk factor for the onset of PLE.²⁴

Finally, this study has some limitations. The majority of the described parameters were present in only one study, not allowing a meta-analysis and reducing the quality of evidence presented (although the majority of the selected studies presented a Fair to Good qualification in the Quality Assessment Tool). Some clinical and surgical aspects of PLE in Fontan patients were not explored due to the lack of information about them in the selected studies (correlation of the parameters with fenestrated tunnel, for example). However, such limitations are a consequence of scarce literature on the topic.

This systematic review with meta-analysis demonstrated the echocardiographic/ultrasound parameters related to the presence and predictors of future PLE in patients with Fontan physiology. The SMAR index was the most frequently described in the literature and showed statistical significance after quantitative assessment. Other indexes, such as the ratio of the flow between the superior mesenteric artery and the celiac artery, may, at least in theory, present better results. Other echocardiographic findings, such as increased pulmonary systolic pressure and measures related to systolic function, are correlated with PLE, but only in single studies.