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Comparison of plasma metanephrines in patients with cyanotic and acyanotic congenital heart disease

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Abstract

Purpose

The co-occurrence of cyanotic congenital heart disease (CCHD) and PHEO/PGL has been reported, but the role of the hypoxic environment in the pathogenesis of PHEO/PGL remains unclear. Our aim was to compare plasma metanephrine and normetanephrine levels between patients with CCHD and patients with acyanotic congenital heart disease (ACCHD).

Methods

We performed a cross-sectional study in a prospective cohort of 44 patients with congenital heart disease (CHD) (31 (70.5%) females) with a median age of 37.5 (31.0–55.6) years at the time of evaluation. Thirty-two (73%) patients had CCHD and 12 (27%) patients had ACCHD. Morning blood samples for plasma determination of metanephrine and normetanephrine were collected.

Results

Plasma normetanephrine levels were significantly higher in patients with CCHD compared to ACCHD (p = 0.002). Ten (31.3%) patients with CCHD had plasma normetanephrine levels elevated above the reference range, while all ACCHD patients had normal levels. Patients with lower oxygen saturation and higher proBNP had significantly higher normetanephrine levels (ρ = −0.444, p = 0.003 and ρ = 0.449, p = 0.002, respectively). No chromaffin cell tumors were detected.

Conclusion

Increased plasma normetanephrine levels in patients with CCHD can be explained by the effect of hypoxia. Future research is needed to better understand the impact of chronic hypoxia in CCHD on increased sympathetic outflow, hyperplastic response of chromaffin tissue, and the role of somatic mutations in CCHD-PHEO/PGL pathogenesis related to hypoxia.

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References

  1. G.H. Anderson Jr, N. Blakeman, D.H. Streeten, The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J. Hypertens. 12(5), 609–615 (2014). https://doi.org/10.1097/00004872-199405000-00015

    Article  Google Scholar 

  2. J.W. Lenders, Q.Y. Duh, G. Eisenhofer, A.P. Gimenez-Roqueplo, S.K. Grebe et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99(6), 1915–1942 (2014). https://doi.org/10.1210/jc.2014-1498

    Article  CAS  PubMed  Google Scholar 

  3. F.A. Farrugia, A. Charalampopoulos, Pheochromocytoma. Endocr. Regul. 53(3), 191–212 (2019). https://doi.org/10.2478/enr-2019-0020

    Article  PubMed  Google Scholar 

  4. G. Eisenhofer, A. Prejbisz, M. Peitzsch, C. Pamporaki, J. Masjkur et al. Biochemical Diagnosis of Chromaffin Cell Tumors in Patients at High and Low Risk of Disease: Plasma versus Urinary Free or Deconjugated O-Methylated Catecholamine Metabolites. Clin. Chem. 64(11), 646–656 (2018). https://doi.org/10.1373/clinchem.2018.291369

    Article  CAS  Google Scholar 

  5. S.W. Olson, S. Yoon, T. Baker, L.K. Prince, D. Oliver et al. Longitudinal plasma metanephrines preceding pheochromocytoma diagnosis: a retrospective case-control serum repository study. Eur. J. Endocrinol. 174(3), 289–295 (2016). https://doi.org/10.1530/EJE-15-0651

    Article  CAS  PubMed  Google Scholar 

  6. A.M. Sinclair, C.G. Isles, I. Brown, H. Cameron, G.D. Murray et al. Secondary hypertension in a blood pressure clinic. Arch. Intern Med. 147(7), 1289–1293 (1987)

    Article  CAS  PubMed  Google Scholar 

  7. M. Ariton, C.S. Juan, T.W. AvRuskin, Pheochromocytoma: clinical observations from a Brooklyn tertiary hospital. Endocr. Pr. 6(3), 249–252 (2000). https://doi.org/10.4158/EP.6.3.249

    Article  CAS  Google Scholar 

  8. M. Omura, J. Saito, K. Yamaguchi, Y. Kakuta, T. Nishikawa, Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens. Res. 27(3), 193–202 (2004). https://doi.org/10.1291/hypres.27.193

    Article  PubMed  Google Scholar 

  9. F. Mantero, M. Terzolo, G. Arnaldi, G. Osella, A.M. Masini et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J. Clin. Endocrinol. Metab. 85(2), 637–644 (2000). https://doi.org/10.1210/jcem.85.2.6372

    Article  CAS  PubMed  Google Scholar 

  10. G. Mansmann, J. Lau, E. Balk, M. Rothberg, Y. Miyachi et al. The clinically inapparent adrenal mass: update in diagnosis and management. Endocr. Rev. 25(2), 309–340 (2004). https://doi.org/10.1210/er.2002-0031

    Article  PubMed  Google Scholar 

  11. L. Fishbein, I. Leshchiner, V. Walter, L. Danilova, A.G. Robertson et al. Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell. 31(2), 181–193 (2017). https://doi.org/10.1016/j.ccell.2017.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. A.P. Gimenez-Roqueplo, P.L. Dahia, M. Robledo, An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm. Metab. Res. 44(5), 328–333 (2012). https://doi.org/10.1055/s-0031-1301302

    Article  CAS  PubMed  Google Scholar 

  13. H.Q. Rana, I.R. Rainville, A. Vaidya, Genetic testing in the clinical care of patients with pheochromocytoma and paraganglioma. Curr. Opin. Endocrinol. Diabetes Obes. 21(3), 166–176 (2014). https://doi.org/10.1097/MED.0000000000000059

    Article  PubMed  Google Scholar 

  14. K. Yamamoto, N. Namba, T. Kubota, T. Usui, K. Takahashi et al. Pheochromocytoma complicated by cyanotic congenital heart disease: a case report. Clin. Pediatr. Endocrinol. 25(2), 59–65 (2016). https://doi.org/10.1297/cpe.25.59

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ogasawara T., Fujii Y., Kakiuchi N., Shiozawa Y., Sakamoto R., et al. Genetic analysis of pheochromocytoma and paraganglioma complicating cyanotic congenital heart disease [published online ahead of print, 2022 Jun 22]. J. Clin. Endocrinol. Metab. 2022;dgac362. https://doi.org/10.1210/clinem/dgac362

  16. M.J. Saldana, L.E. Salem, R. Travezan, High altitude hypoxia and chemodectomas. Hum. Pathol. 4(2), 251–263 (1973). https://doi.org/10.1016/s0046-8177(73)80012-7

    Article  CAS  PubMed  Google Scholar 

  17. D. van der Linde, E.E. Konings, M.A. Slager, M. Witsenburg, W.A. Helbing et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J. Am. Coll. Cardiol. 58(21), 2241–2247 (2011). https://doi.org/10.1016/j.jacc.2011.08.025

    Article  PubMed  Google Scholar 

  18. Y. Liu, S. Chen, L. Zühlke, G.C. Black, M.K. Choy et al. Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies. Int J. Epidemiol. 48(2), 455–463 (2019). https://doi.org/10.1093/ije/dyz009

    Article  PubMed  PubMed Central  Google Scholar 

  19. M.A. Gatzoulis, R. Alonso-Gonzalez, M. Beghetti, Pulmonary arterial hypertension in paediatric and adult patients with congenital heart disease. Eur. Respir. Rev. 18(113), 154–161 (2009). https://doi.org/10.1183/09059180.00003309

    Article  CAS  PubMed  Google Scholar 

  20. A.R. Opotowsky, L.E. Moko, J. Ginns, M. Rosenbaum, M. Greutmann et al. Pheochromocytoma and paraganglioma in cyanotic congenital heart disease. J. Clin. Endocrinol. Metab. 100(4), 1325–1334 (2015). https://doi.org/10.1210/jc.2014-3863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. T. Kita, T. Imamura, H. Date, K. Kitamura, S. Moriguchi et al. Two cases of pheochromocytoma associated with tetralogy of Fallot. Hypertens. Res. 26(5), 433–437 (2003). https://doi.org/10.1291/hypres.26.433

    Article  PubMed  Google Scholar 

  22. W.H. de Jong, K.S. Graham, J.C. van der Molen, T.P. Links, M.R. Morris et al. Plasma free metanephrine measurement using automated online solid-phase extraction HPLC tandem mass spectrometry. Clin. Chem. 53(9), 1684–1693 (2007). https://doi.org/10.1373/clinchem.2007.087114

    Article  CAS  PubMed  Google Scholar 

  23. P.G. Guyenet, Neural structures that mediate sympathoexcitation during hypoxia. Respir. Physiol. 121(2-3), 147–162 (2000). https://doi.org/10.1016/S0034-5687(00)00125-0

    Article  CAS  PubMed  Google Scholar 

  24. I. Vicario, R. Rigual, A. Obeso, C. Gonzalez, Characterization of the synthesis and release of catecholamine in the rat carotid body in vitro. Am. J. Physiol. Cell Physiol. 278(3), C490–C499 (2000). https://doi.org/10.1152/ajpcell.2000.278.3.C490

    Article  CAS  PubMed  Google Scholar 

  25. S.W. Mifflin, Arterial chemoreceptor input to nucleus tractus solitarius. Am. J. Physiol. 263(2 Pt 2), R368–R375 (1992). https://doi.org/10.1152/ajpregu.1992.263.2.R368

    Article  CAS  PubMed  Google Scholar 

  26. A.S. Hui, J.B. Striet, G. Gudelsky, G.K. Soukhova, E. Gozal et al. Regulation of catecholamines by sustained and intermittent hypoxia in neuroendocrine cells and sympathetic neurons. Hypertension 42(6), 1130–1136 (2003). https://doi.org/10.1161/01.HYP.0000101691.12358.26

    Article  CAS  PubMed  Google Scholar 

  27. F. Fischetti, B. Fabris, M. Zaccaria, A. Biagi, M. Calci et al. Effects of prolonged high-altitude exposure on peripheral adrenergic receptors in young healthy volunteers. Eur. J. Appl. Physiol. 82(5-6), 439–445 (2000). https://doi.org/10.1007/s004210000239

    Article  CAS  PubMed  Google Scholar 

  28. G. Strobel, M. Neureither, P. Bärtsch, Effect of acute mild hypoxia during exercise on plasma free and sulphoconjugated catecholamines. Eur. J. Appl Physiol. Occup. Physiol. 73(1-2), 82–87 (1996). https://doi.org/10.1007/BF00262813

    Article  CAS  PubMed  Google Scholar 

  29. M.S. Balter, K.R. Chapman, M.R. Maleki-Yazdi, F.H. Leenen, A.S. Rebuck, Effects of oxygen withdrawal on catecholamine release in patients on home oxygen therapy. Clin. Sci. (Lond.) 79(2), 155–159 (1990). https://doi.org/10.1042/cs0790155

    Article  CAS  Google Scholar 

  30. I. Ponz de Antonio, J. Ruiz Cantador, A.E. González García, J.M. Oliver Ruiz, Á. Sánchez-Recalde, et al., Prevalence of Neuroendocrine Tumors in Patients With Cyanotic Congenital. Heart Dis. Rev. espanola de. cardiologia (Engl. ed.) 70(8), 673–675 (2017). https://doi.org/10.1016/j.rec.2016.09.036

    Article  Google Scholar 

  31. B. Zhao, Y. Zhou, Y. Zhao, Y. Zhao, X. Wu et al. Co-Occurrence of Pheochromocytoma-Paraganglioma and Cyanotic Congenital Heart Disease: A Case Report and Literature Review. Front Endocrinol. (Lausanne) 9, 165 (2018). https://doi.org/10.3389/fendo.2018.00165

    Article  Google Scholar 

  32. D. Amorim-Pires, J. Peixoto, J. Lima, Hypoxia Pathway Mutations in Pheochromocytomas and Paragangliomas. Cytogenet Genome Res. 150(3-4), 227–241 (2016). https://doi.org/10.1159/000457479

    Article  CAS  PubMed  Google Scholar 

  33. A. Vaidya, S.K. Flores, Z.M. Cheng, M. Nicolas, Y. Deng et al. EPAS1 Mutations and Paragangliomas in Cyanotic Congenital Heart Disease. N. Eng. J. Med. 378(13), 1259–1261 (2018). https://doi.org/10.1056/NEJMc1716652

    Article  Google Scholar 

  34. C.M. White, Catecholamines and their blockade in congestive heart failure. Am. J. Health Syst. Pharm. 55(7), 676–682 (1998). https://doi.org/10.1093/ajhp/55.7.676

    Article  CAS  PubMed  Google Scholar 

  35. W.M. Manger, An overview of pheochromocytoma: history, current concepts, vagaries, and diagnostic challenges. Ann. N. Y. Acad. Sci. 1073, 1–20 (2006). https://doi.org/10.1196/annals.1353.001

    Article  CAS  PubMed  Google Scholar 

  36. G. Eisenhofer, G. Rivers, A.L. Rosas, Z. Quezado, W.M. Manger et al. Adverse drug reactions in patients with phaeochromocytoma: incidence, prevention and management. Drug Saf. 30(11), 1031–1062 (2007). https://doi.org/10.2165/00002018-200730110-00004

    Article  CAS  PubMed  Google Scholar 

  37. D.J. Myklejord, Undiagnosed pheochromocytoma: the anesthesiologist nightmare. Clin. Med. Res. 2(1), 59–62 (2004). https://doi.org/10.3121/cmr.2.1.59

    Article  PubMed  PubMed Central  Google Scholar 

  38. A. Prejbisz, J.W. Lenders, G. Eisenhofer, A. Januszewicz, Cardiovascular manifestations of phaeochromocytoma. J. Hypertens. 29(11), 2049–2060 (2011). https://doi.org/10.1097/HJH.0b013e32834a4ce9

    Article  CAS  PubMed  Google Scholar 

  39. D. Weismann, M. Peitzsch, A. Raida, A. Prejbisz, M. Gosk et al. Measurements of plasma metanephrines by immunoassay vs liquid chromatography with tandem mass spectrometry for diagnosis of pheochromocytoma. Eur. J. Endocrinol. 172(3), 251–260 (2015). https://doi.org/10.1530/EJE-14-0730

    Article  CAS  PubMed  Google Scholar 

  40. J.W.M. Lenders, M.N. Kerstens, L. Amar, A. Prejbisz, M. Robledo, D. Taieb et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J. Hypertens. 38(8), 1443–1456 (2020). https://doi.org/10.1097/HJH.0000000000002438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge all medical staff from the Department of Cardiology, University Medical Centre Ljubljana, Ljubljana, Slovenia for the management of patients with congenital heart disease.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection was performed by Katja Prokšelj, data analysis was performed by Katja Goricar. The first draft of the manuscript was written by Ana Podbregar and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Author notes

  1. These authors contributed equally: Mojca Jensterle, Ana Podbregar

Authors and Affiliations

  1. Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000, Ljubljana, Slovenia

    Mojca Jensterle, Ana Podbregar, Andrej Janež, Matej Rakusa & Katja Prokšelj

  2. Department of Endocrinology, Diabetes and Metabolic Disease, University Medical Center Ljubljana, Zaloska 7, 1000, Ljubljana, Slovenia

    Mojca Jensterle, Andrej Janež & Matej Rakusa

  3. University Rehabilitation Institute Republic of Slovenia, Linhartova cesta 51, 1000, Ljubljana, Slovenia

    Ana Podbregar

  4. University of Ljubljana, Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, Pharmacogenetics Laboratory, Vrazov trg 2, 1000, Ljubljana, Slovenia

    Katja Goricar

  5. Department of Cardiology, University Medical Center Ljubljana, Zaloska 7, 1000, Ljubljana, Slovenia

    Katja Prokšelj

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  1. Mojca Jensterle
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Correspondence to Katja Prokšelj.

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The study was conducted in accordance with the Declaration of Helsinki and approved by the Republic of Slovenia National Medical Ethics Committee with the reference number 0120-134/2019.

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Jensterle, M., Podbregar, A., Janež, A. et al. Comparison of plasma metanephrines in patients with cyanotic and acyanotic congenital heart disease. Endocrine 78, 580–586 (2022). https://doi.org/10.1007/s12020-022-03205-6

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  • DOI: https://doi.org/10.1007/s12020-022-03205-6

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