Skip to main content Accessibility help
×
×
Home

Abnormalities in serum biomarkers correlate with lower cardiac index in the Fontan population

  • Bradley S. Marino (a1), David J. Goldberg (a2), Adam L. Dorfman (a3), Eileen King (a4), Heidi Kalkwarf (a5), Babette S. Zemel (a6), Margaret Smith (a1), Jesse Pratt (a4), Mark A. Fogel (a2), Amanda J. Shillingford (a7), Barbara J. Deal (a8), Anitha S. John (a9), Caren S. Goldberg (a3), Timothy M. Hoffman (a10), Marshall L. Jacobs (a11), Asher Lisec (a1), Susan Finan (a1), Lazaros K. Kochilas (a12), Thomas W. Pawlowski (a2), Kathleen Campbell (a13), Clinton Joiner (a14), Stuart L. Goldstein (a15), Paul Stephens (a2) and Alvin J. Chin (a2)...

Abstract

Background

Fontan survivors have depressed cardiac index that worsens over time. Serum biomarker measurement is minimally invasive, rapid, widely available, and may be useful for serial monitoring. The purpose of this study was to identify biomarkers that correlate with lower cardiac index in Fontan patients.

Methods and results

This study was a multi-centre case series assessing the correlations between biomarkers and cardiac magnetic resonance-derived cardiac index in Fontan patients ⩾6 years of age with biochemical and haematopoietic biomarkers obtained ±12 months from cardiac magnetic resonance. Medical history and biomarker values were obtained by chart review. Spearman’s Rank correlation assessed associations between biomarker z-scores and cardiac index. Biomarkers with significant correlations had receiver operating characteristic curves and area under the curve estimated. In total, 97 cardiac magnetic resonances in 87 patients met inclusion criteria: median age at cardiac magnetic resonance was 15 (6–33) years. Significant correlations were found between cardiac index and total alkaline phosphatase (−0.26, p=0.04), estimated creatinine clearance (0.26, p=0.02), and mean corpuscular volume (−0.32, p<0.01). Area under the curve for the three individual biomarkers was 0.63–0.69. Area under the curve for the three-biomarker panel was 0.75. Comparison of cardiac index above and below the receiver operating characteristic curve-identified cut-off points revealed significant differences for each biomarker (p<0.01) and for the composite panel [median cardiac index for higher-risk group=2.17 L/minute/m2 versus lower-risk group=2.96 L/minute/m2, (p<0.01)].

Conclusions

Higher total alkaline phosphatase and mean corpuscular volume as well as lower estimated creatinine clearance identify Fontan patients with lower cardiac index. Using biomarkers to monitor haemodynamics and organ-specific effects warrants prospective investigation.

Copyright

Corresponding author

Correspondence to: B. S. Marino, MD, MPP, MSCE, Professor of Pediatrics and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Heart Center Co-Director, Research and Academic Affairs, Divisions of Cardiology and Critical Care Medicine, Ann and Robert H. Lurie Children’s Hospital of Chicago, 225 East Chicago Avenue, Box 21, Chicago, IL 60611-2991, United States of America. Tel: +312 227 4373; Fax: +312 227 9640; E-mail: bradley.marino@northwestern.edu

References

Hide All
1. Mahle, WT, Spray, TL, Wernovsky, G, Gaynor, JW, Clark, BJ 3rd. Survival after reconstructive surgery for hypoplastic left heart syndrome: a 15-year experience from a single institution. Circulation 2000; 102: III136141.
2. Tweddell, JS, Ghanayem, NS, Mussatto, KA, et al. Mixed venous oxygen saturation monitoring after stage 1 palliation for hypoplastic left heart syndrome. Ann Thorac Surg 2007; 84: 13011310; discussion 1310–1301.
3. Mainwaring, RD, Lamberti, JJ, Uzark, K, Spicer, RL, Cocalis, MW, Moore, JW. Effect of accessory pulmonary blood flow on survival after the bidirectional Glenn procedure. Circulation 1999; 100: II151156.
4. Khairy, P, Fernandes, SM, Mayer, JE Jr, et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 2008; 117: 8592.
5. Schwartz, MC, Sullivan, L, John, AS, et al. Hepatic fibrosis in Fontan patients correlates with pre-Fontan morbidity. J Am Coll Cardiol 2011; 57: E411.
6. Mavroudis, C, Deal, BJ, Backer, CL, et al. Maxwell Chamberlain memorial paper for congenital heart surgery. 111 Fontan conversions with arrhythmia surgery: surgical lessons and outcomes. Ann Thorac Surg 2007; 84: 14571465; discussion 1465–1456.
7. Jayakumar, KA, Addonizio, LJ, Kichuk-Chrisant, MR, et al. Cardiac transplantation after the Fontan or Glenn procedure. J Am Coll Cardiol 2004; 44: 20652072.
8. Schumacher, KR, Stringer, KA, Donohue, JE, et al. Fontan-associated protein-losing enteropathy and plastic bronchitis. The Journal of Pediatrics 2015; 166: 970977.
9. Chin, AJ, Stephens, P, Goldmuntz, E, Leonard, MB. Serum alkaline phosphatase reflects post-Fontan hemodynamics in children. Pediatr Cardiol 2009; 30: 138145.
10. Kaushansky, K. Lineage-specific hematopoietic growth factors. N Engl J Med 2006; 354: 20342045.
11. Collins, N, Piran, S, Harrison, J, Azevedo, E, Oechslin, E, Silversides, CK. Prevalence and determinants of anemia in adults with complex congenital heart disease and ventricular dysfunction (subaortic right ventricle and single ventricle physiology). Am J Cardiol 2008; 102: 625628.
12. Whitehead, KK, Gillespie, MJ, Harris, MA, Fogel, MA, Rome, JJ. Noninvasive quantification of systemic-to-pulmonary collateral flow: a major source of inefficiency in patients with superior cavopulmonary connections. Circ Cardiovasc Imaging 2009; 2: 405411.
13. Mosteller, RD. Simplified calculation of body-surface area. N Engl J Med 1987; 317: 1098.
14. Schwartz, GJ, Brion, LP, Spitzer, A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 1987; 34: 571590.
15. Van Hoof, VO, Hoylaerts, MF, Geryl, H, Van Mullem, M, Lepoutre, LG, De Broe, ME. Age and sex distribution of alkaline phosphatase isoenzymes by agarose electrophoresis. Clin Chem 1990; 36: 875878.
16. Schwartz, MC, Sullivan, L, Cohen, MS, et al. Hepatic pathology may develop before the Fontan operation in children with functional single ventricle: an autopsy study. J Thorac Cardiovasc Surg 2012; 143: 904909.
17. Kiesewetter, CH, Sheron, N, Vettukattill, JJ, et al. Hepatic changes in the failing Fontan circulation. Heart 2007; 93: 579584.
18. Poelzl, G, Ess, M, Mussner-Seeber, C, Pachinger, O, Frick, M, Ulmer, H. Liver dysfunction in chronic heart failure: prevalence, characteristics and prognostic significance. Eur J Clin Invest 2012; 42: 153163.
19. Camposilvan, S, Milanesi, O, Stellin, G, Pettenazzo, A, Zancan, L, D’Antiga, L. Liver and cardiac function in the long term after Fontan operation. Ann Thorac Surg 2008; 86: 177182.
20. Ronco, C, McCullough, PA, Anker, SD, et al. Cardiorenal syndromes: an executive summary from the consensus conference of the acute dialysis quality initiative (ADQI). Contrib Nephrol 2010; 165: 5467.
21. National kidney foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1S266.
22. Al-Ahmad, A, Rand, WM, Manjunath, G, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2001; 38: 955962.
23. Dries, DL, Exner, DV, Domanski, MJ, Greenberg, B, Stevenson, LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2000; 35: 681689.
24. McAlister, FA, Ezekowitz, J, Tonelli, M, Armstrong, PW. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation 2004; 109: 10041009.
25. Anand, IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol 2008; 52: 501511.
26. Nanas, JN, Matsouka, C, Karageorgopoulos, D, et al. Etiology of anemia in patients with advanced heart failure. J Am Coll Cardiol 2006; 48: 24852489.
27. Opasich, C, Cazzola, M, Scelsi, L, et al. Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure. Eur Heart J 2005; 26: 22322237.
28. Jankowska, EA, Rozentryt, P, Witkowska, A, et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010; 31: 22322237.
29. Powell, AJ, Geva, T. Blood flow measurement by magnetic resonance imaging in congenital heart disease. Pediatr Cardiol 2000; 21: 4758.
30. Powell, AJ, Maier, SE, Chung, T, Geva, T. Phase-velocity cine magnetic resonance imaging measurement of pulsatile blood flow in children and young adults: in vitro and in vivo validation. Pediatr Cardiol 2000; 21: 104110.
31. Schaefer, WM, Lipke, CSA, Standke, D, et al. Quantification of left ventricular volumes and ejection fraction from gated 99mTc-MIBI SPECT: MRI validation and comparison of the emory cardiac tool box with QGS and 4D-MSPECT. J Nucl Med 2005; 46: 12561263.
32. Chin, AJ, Whitehead, KK, Watrous, RL. Insights after 40 years of the Fontan operation. World J Pediatr Congenit Heart Surg 2010; 1: 328343.
33. Goldberg, DJ, French, B, McBride, MG, et al. Impact of oral sildenafil on exercise performance in children and young adults after the Fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation 2011; 123: 11851193.
34. Seikaly, MG, Browne, R, Bajaj, G, Arant, BS Jr. Limitations to body length/serum creatinine ratio as an estimate of glomerular filtration in children. Pediatr Nephrol 1996; 10: 709711.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Cardiology in the Young
  • ISSN: 1047-9511
  • EISSN: 1467-1107
  • URL: /core/journals/cardiology-in-the-young
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed