Skip to main content

Coronary Artery Abnormalities in Hyper-IgE Syndrome

Abstract

Objective

Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency caused by autosomal dominant STAT3 mutations resulting in recurrent infections and connective tissue abnormalities. Coronary artery abnormalities have been reported infrequently. We aimed to determine the frequency and characteristics of coronary artery abnormalities.

Design

STAT3-mutated HIES patients (n = 38), ranging in age from 8 to 57 years, underwent coronary artery imaging by computed tomography or magnetic resonance imaging. Images were evaluated for tortuosity, dilation, and aneurysm. Charts were reviewed for cardiac risk factors. To allow blinded image interpretation, an age- and gender-matched non-HIES group was also evaluated (n = 33).

Results

Coronary artery tortuosity or dilation occurred in 70% of HIES patients, with aneurysms present in 37%, incidences much higher than in the literature and in our non-HIES group, in which 21% had tortuosity or dilation and 3% had aneurysms. Hypertension was more common in the HIES group than in the general population and was associated with vessel abnormalities. Atherosclerosis was uncommon and mild.

Conclusions

Coronary artery aneurysms and tortuosity are common in HIES, despite a paucity of atherosclerosis, suggesting that STAT3 plays an integral role in human vascular remodeling and atherosclerosis.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, et al. STAT3 mutations in the hyper-IgE syndrome. New Engl J Med. 2007;357:1608–19.

    PubMed  Article  CAS  Google Scholar 

  2. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448:1058–62.

    PubMed  Article  CAS  Google Scholar 

  3. Freeman AF, Holland SM. The hyper-IgE syndromes. Immunol Allergy Clin North Am. 2008;28:277–91.

    PubMed  Article  Google Scholar 

  4. Freeman AF, Collura-Burke CJ, Patronas NJ, Ilcus LS, Darnell D, Davis J, et al. Brain abnormalities in patients with hyperimmunoglobulin E syndrome. Pediatrics. 2007;119:e1121–5.

    PubMed  Article  Google Scholar 

  5. Alomar-Melero E, Martin TD, Janelle GM, Peng YG. Unusual giant right coronary artery aneurysm resembles an intracardiac mass. Anesth Analg. 2008;107(4):1161–2.

    PubMed  Article  Google Scholar 

  6. Gharib AM, Pettigrew RI, Elagha A, Hsu A, Welch P, Holland SM, et al. Coronary abnormalities in Hyper-IgE recurrent infection syndrome: depiction at coronary MDCT angiograph. AJR. 193;478–81.

  7. Ling JC, Freeman AF, Gharib AM, Arai AE, Lederman RJ, Rosing DR, et al. Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome. Clin Immunol. 2007;122:255–8.

    PubMed  Article  CAS  Google Scholar 

  8. Young TY, Jerome D, Gupta S. Hyperimmunoglobulinemia E syndrome associated with coronary artery aneurysms: deficiency of central memory CD4+ T cells and expansion of effector memory CD4+ T cells. Ann Allergy Asthma Immunol. 2007;98(4):389–92.

    PubMed  Article  CAS  Google Scholar 

  9. Olive M, Mellad JA, Beltran LE, Ma M, Cimato T, Noguchi AC, et al. p21Cip1 modulates arterial wound repair through the stromal cell-derived factor-1/CSCR4 axis in mice. J Clin Invest. 2008;118(6):2050–61.

    PubMed  CAS  Google Scholar 

  10. Gharib AM, Ho VB, Rosing DR, Herzka DA, Stuber M, Arai AE, et al. Coronary artery anomalies and variants: technical feasibility of assessment with coronary MR angiography at 3T. Radiology. 2008;247:220–7.

    PubMed  Article  Google Scholar 

  11. Datta J, White CS, Gilkeson RC, Meyer CA, Kansal S, Jani ML, et al. Anomalous coronary arteries in adults: depiction at multi-detector row CT angiography. Radiology. 2005;235:812–8.

    PubMed  Article  Google Scholar 

  12. Arnold R, Ley S, Ley-Zaporozhan J, Eichhorn J, Schenk JP, Ulmer H, et al. Visualization of coronary arteries in patients after childhood Kawasaki syndrome: value of multidetector CT and MR imaging in comparison to conventional coronary catheterization. Pediatr Radiol. 2007;37(10):998–1006.

    PubMed  Article  Google Scholar 

  13. Greil GF, Stuber M, Botnar RM, Kissinger KV, Geva T, Newburger JW, et al. Coronary magnetic resonance angiography in adolescents and young adults with Kawasaki disease. Circulation. 2002;105:908–11.

    PubMed  Article  Google Scholar 

  14. Kim WY, Danias PG, Stuber M, Flamm SD, Plein S, Nagel E, et al. Coronary magnetic resonance angiography for the detection of coronary stenoses. New Engl J Med. 2001;345:1863–9.

    PubMed  Article  CAS  Google Scholar 

  15. Miller JM, Rochitte CE, Dewey M, Arab-Zadeh A, Niinuma H, Gottlieb I, et al. Diagnostic performance of coronary angiography for the detection of coronary stenoses. New Engl J Med. 2008;359:2324–36.

    PubMed  Article  CAS  Google Scholar 

  16. Garcia MJ, Lessick J, Hoffmann MH. Accuracy of 16-row multidetector computed tomography for the assessment of coronary artery stenosis. JAMA. 2006;296:403–11.

    PubMed  Article  CAS  Google Scholar 

  17. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001;285:2486–97

    Google Scholar 

  18. Hoffmann MH, Shi H, Schmitz BL, Schmid FT, Lieberknecht M, Schulze R, et al. Noninvasive coronary angiography with multislice computed tomography. JAMA. 2005;293:2471–8.

    PubMed  Article  CAS  Google Scholar 

  19. Bullitt E, Gerig G, Pizer SM, Lin W, Aylward SR. Measuring tortuosity of the intracerebral vasculature from MRA images. IEEE Trans Med Imaging. 2003;22(9):1163–71.

    PubMed  Article  Google Scholar 

  20. Cohen P, O’Gara PT. Coronary artery aneurysms: a review of the natural history, pathophysiology, and management. Cardiol Rev. 2008;16(6):301–4.

    PubMed  Article  Google Scholar 

  21. Swaye PS, Fisher LD, Litwin P, Vignola PA, Judkins MP, Kemp HG, et al. Aneurysmal coronary artery disease. Circulation. 1983;67:134–8.

    PubMed  Article  CAS  Google Scholar 

  22. Burns CA, Cowley MJ, Wechsler AS, Vetrovec GW. Coronary aneurysms: a case report and review. Cathet Cardiovasc Diagn. 1992;27:106–12.

    PubMed  Article  CAS  Google Scholar 

  23. Judge DP, Dietz HC. Marfan’s syndrome. Lancet. 2005;366:1965–76.

    PubMed  Article  CAS  Google Scholar 

  24. Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, et al. Aneurysm syndromes in the TGF-beta receptor. New Engl J Med. 2006;355:788–98.

    PubMed  Article  CAS  Google Scholar 

  25. Watanabe A, Takashi S. The vascular type of Ehlers–Danlos syndrome. J Nippon Med Sch. 2008;75(5):254–61.

    PubMed  Article  Google Scholar 

  26. Zegers ES, Meursing BTJ. AJM Oude Ophuis. Coronary tortuosity: a long and winding road. Neth Heart J. 2007;5:191–5.

    Article  Google Scholar 

  27. Callewaert BL, Willaert A, Kerstjens-Frederikse WS, DeBacker J, Devriendt K, Albrecht B, et al. Familial arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008;29:150–8.

    PubMed  Article  CAS  Google Scholar 

  28. Gavin PJ, Crawford SE, Shulman ST, Garcia FL, Rowley AH. Systemic arterial expression of matrix metalloproteinases 2 and 9 in acute Kawasaki disease. Arterioscler Thromb Vasc Biol. 2003;23:576–81.

    PubMed  Article  CAS  Google Scholar 

  29. Pay S, Abbasov T, Erdem H, Musabak U, Simsek I, Pekel A, et al. Serum MMP-2 and MMP-9 in patients with Behcet’s disease: do their higher levels correlate to vasculo-Behcet’s disease associated with aneurysm formation? Clin Exp Rheum. 2007;25(4 Supplement 45):S70–5.

    CAS  Google Scholar 

  30. Senzaki H. The pathophysiology of coronary artery aneurysms in Kawasaki disease: role of matrix metalloproteinases. Arch Dis Childhood. 2006;91:847–51.

    Article  CAS  Google Scholar 

  31. Dogan A, Tuzun N, Turker Y, Akcay S, Kaya S, Ozaydin M. Matrix metalloproteinases and inflammatory markers in coronary artery ectasia: their relationship to severity of coronary artery ectasia. Coron Artery Dis. 2008;19(8):559–63.

    PubMed  Article  Google Scholar 

  32. Ikonomidis JS, Jones JA, Barbour JR, Stroud RE, Clark LL, Kaplan BS, et al. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome. Circulation. 2006;114(1 Suppl):I365–70.

    PubMed  Google Scholar 

  33. Kang HS, Kim SK, Cho BK, Kim YY, Hwang YS, Wang KC. Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial moyamoya disease. Neurosurgery. 2006;58(6):1074–80.

    PubMed  Article  Google Scholar 

  34. Lamblin N, Bauters C, Hermant X, Lablanche JM, Helbecque N, Amouyel P. Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9, and MMP-12 genes as determinants of aneurysmal coronary artery disease. J Am Coll Cardiol. 2002;40:43–8.

    PubMed  Article  CAS  Google Scholar 

  35. Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. New Engl J Med. 2009;360(12):1226–37.

    PubMed  Article  CAS  Google Scholar 

  36. Schroer N, Pahne J, Walch B, Wickenhauser C, Smola S. Molecular pathobiology of human cervical high-grade lesions: paracrine STAT3 activation in tumor-instructed myeloid cells drives local MMP-9 expression. Cancer Res. 2011;71:87–97.

    PubMed  Article  Google Scholar 

  37. Song Y, Qian L, Song S, et al. Fra-1 and Stat3 synergistically regulate activation of MMP-9 gene. Mol Immunol. 2008;45:137–43.

    PubMed  Article  CAS  Google Scholar 

  38. Tsareva SA, Moriggl R, Corvinus FM, Wiederanders B, Schütz A, Kovacic B, et al. Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction. Neoplasia. 2007;9(4):279–91.

    PubMed  Article  CAS  Google Scholar 

  39. Xie TX, Wei D, Liu M, et al. Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metasis. Oncogene. 2004;23:3550–60.

    PubMed  Article  CAS  Google Scholar 

  40. Gharavi NM, Alva JA, Mouillesseaux KP, Lai C, Yeh M, Yeung W, et al. Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. J Biol Chem. 2007;282(43):31460–8.

    PubMed  Article  CAS  Google Scholar 

  41. Zhou X, Li D, Yan W, Li W. Pravastatin prevents aortic atherosclerosis via modulation of signal transduction and activation of transcription 3 (STAT3) to attenuate interleukin-6 (IL-6) action in ApoE knockout mice. Int J Mol Sci. 2008;9:2253–64.

    PubMed  Article  CAS  Google Scholar 

  42. Pleis JR, Lucas JW. Summary Health statistics for U.S. adults: National health interview survey, 2007. National Center for Health Statistics. Vital Health Stat 2009;10(240)

  43. Forsdahl SH, Singh K, Solberg S, Jacobsen BK. Risk factors for abdominal aortic aneurysms: a 7-year prospective study: the Tromso study, 1994–2001. Circulation. 2009;119:2202–8.

    PubMed  Article  Google Scholar 

  44. Corunz J, Sidoti Pinto C, Tevaearai H, Egger M. Risk factors for asymptomatic abdominal aortic aneurysm. Eur J Public Health. 2004;14:343–9.

    Article  Google Scholar 

  45. Freeman AF, Kleiner DE, Nadiminti H, Davis J, Quezado M, Anderson V, et al. Causes of death in hyper-IgE syndrome. J Allergy Clin Immunol. 2007;119(5):1234–40.

    PubMed  Article  CAS  Google Scholar 

  46. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science. 2006;312:117–21.

    PubMed  Article  CAS  Google Scholar 

  47. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med. 2008;358(26):2787–95.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgement

This research was supported by the Intramural Research Programs of the NIAID, NIDDK, and NIH, Bethesda, MD 20892. The views expressed in this article are those of the authors and do not reflect the official policy of the US government.

Elizabeth Mannino Avila was supported by the Clinical Research Training Program, a public–private partnership supported jointly by the NIH and Pfizer (via a grant to the Foundation for NIH from Pfizer).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alexandra F. Freeman.

Additional information

Alexandra F. Freeman and Elizabeth Mannino Avila contributed equally to this manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 38 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Freeman, A.F., Avila, E.M., Shaw, P.A. et al. Coronary Artery Abnormalities in Hyper-IgE Syndrome. J Clin Immunol 31, 338–345 (2011). https://doi.org/10.1007/s10875-011-9515-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-011-9515-9

Keywords

  • Hyper-IgE syndrome
  • STAT3
  • coronary artery aneurysm
  • atherosclerosis
  • Job’s syndrome
  • tortuosity