Biomarkers and the Fontan Circulation.

A lthough the dramatically improved survival of children with single-ventricle heart disease with Fontan circulation in the recent era is a tremendous accomplishment in pediatric cardiology and cardiac surgery, it has been accompanied by a growing realization that Fontan circulation is largely a state of compensated heart failure at risk for decompensation. Fontan failure occurs in numerous ways with unpredictable timing. Often heart transplantation is the only potential therapy, but patients who have undergone a Fontan palliation are at high risk for posttransplant morbidity and mortality, making it a nonideal therapeutic option. The ability to identify a patient heading for worsening Fontan failure would allow trials of therapy that could slow progression of the failing circulation. Predicting future Fontan failure could also identify patients needing transplant evaluation before the morbidities that accompany Fontan failure worsen their transplant candidacy. Recent attention has turned to how best to identify patients progressing toward Fontan failure before they reach late stages. With their article, “Galectin-3 Is Elevated and Associated With Adverse Outcomes in Patients With Single-Ventricle Fontan Circulation,” Opotowsky and colleagues made a significant contribution to the Fontan failure literature with their investigation into galectin-3 serum levels in Fontan patients. The authors found that Fontan patients with elevated galectin-3 serum levels are at higher risk of nonelective hospitalization or death. In addition, the authors offered fascinating hypotheses that galectin-3 is not only a biomarker for Fontan failure but also is potentially directly involved in the pathogenesis of Fontanrelated ascites, which, if true, offers a new therapeutic target in this difficult population. A biomarker that can identify those at risk for poor outcome while helping explain some of the mechanistic reasons for the poor outcomewould be particularly useful. This study was unique, relative to other studies of biomarkers in this cohort, in that it included longitudinal followup and outcomes data. This addition allows the results to be viewed within a broader context and adds to the importance of the study. Although the study by Opotowsky et al is sound and insightful, it is challenged by many of the same limitations that other investigations into Fontan biomarkers have encountered: (1) The patient numbers, although reasonable for a Fontan study, are still quite limited; (2) the differences found in serum concentrations between at-risk and standard Fontan patients were small; (3) the outcomes were limited in number; and (4) the serum concentrations were measured only once per patient, severely limiting the ability to understand how these galectin-3 levels vary over time and how they could be used for serial monitoring. Albeit a promising start, the results must be viewed as from an initial pilot study only; further study is warranted. Many other investigators have sought to identify biomarkers that could predict Fontan failure. Brain natriuretic peptide (BNP), a relatively sensitive biomarker for many other forms of heart failure, has limited utility in the Fontan population. In an analysis of the Pediatric Heart Network’s Fontan crosssectional study, Atz and colleagues found that BNP was within the normal range in the majority of patients with Fontan physiology, and high serum BNP had only weak associations with suboptimal Fontan outcomes. The authors concluded that routine use of BNP as a surveillance tool was not warranted. Similar to BNP, N-terminal pro-BNP has been shown to vary in Fontan patients with levels that are independent of cardiac functional status. Other neurohormonal activity markers have been studied. Kolcz and colleagues found a significant correlation between endothelin-1 serum concentrations and patient exercise performance, which could be used as a proxy for poor tolerance of Fontan circulation but is nonspecific. Kojima and colleagues examined the usefulness of red blood cell distribution width in Fontan patients and discovered a significant negative correlation with mixed venous saturation and positive correlation with central venous pressure. Red cell distribution width may thus be an easy marker for impaired cardiac index The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, C.S. Mott Children’s Hospital, Ann Arbor, MI (K.R.S.); Division of Cardiology, The Children’s Hospital of Philadelphia, PA (D.J.G.). Correspondence to: David J. Goldberg, MD, Division of Cardiology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Blvd, Philadelphia, PA 19104. E-mail: [email protected] J Am Heart Assoc. 2016;5:e002926 doi: 10.1161/JAHA.115.002926. a 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. 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