Skip to main content
SpringerLink
Log in

Midregional pro-atrial natriuretic peptide: a novel marker of myocardial fibrosis in patients with hypertrophic cardiomyopathy

  • Original Paper
  • Published:
The International Journal of Cardiovascular Imaging Aims and scope Submit manuscript

Abstract

We aimed to determine the diagnostic performance of biomarkers in predicting myocardial fibrosis assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR) in patients with hypertrophic cardiomyopathy (HCM). LGE CMR was performed in 40 consecutive patients with HCM. Left and right ventricular parameters, as well as the extent of LGE were determined and correlated to the plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), carboxy-terminal pro-endothelin-1 (CT-proET-1), carboxy-terminal pro-vasopressin (CT-proAVP), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8). Myocardial fibrosis was assumed positive, if CMR indicated LGE. LGE was present in 26 of 40 patients with HCM (65%) with variable extent (mean: 14%, range: 1.3–42%). The extent of LGE was positively associated with MR-proANP (r = 0.4; P = 0.01). No correlations were found between LGE and MR-proADM (r = 0.1; P = 0.5), CT-proET-1 (r = 0.07; P = 0.66), CT-proAVP (r = 0.16; P = 0.3), MMP-9 (r = 0.01; P = 0.9), TIMP-1 (r = 0.02; P = 0.85), and IL-8 (r = 0.02; P = 0.89). After adjustment for confounding factors, MR-proANP was the only independent predictor associated with the presence of LGE (P = 0.007) in multivariate analysis. The area under the ROC curve (AUC) indicated good predictive performance (AUC = 0.882) of MR-proANP with respect to LGE. The odds ratio was 1.268 (95% confidence interval 1.066–1.508). The sensitivity of MR-proANP at a cut-off value of 207 pmol/L was 69%, the specificity 94%, the positive predictive value 90% and the negative predictive value 80%. The results imply that MR-proANP serves as a novel marker of myocardial fibrosis assessed by LGE CMR in patients with HCM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AF:

Atrial fibrillation

CMR:

Cardiovascular magnetic resonance imaging

EF:

Ejection fraction

HCM:

Hypertrophic cardiomyopathy

LA:

Left atrium

LGE:

Late gadolinium enhancement

LV:

Left ventricular

References

  1. Marian AJ, Roberts R (1995) Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 92(5):1336–1347

    PubMed  CAS  Google Scholar 

  2. Niimura H, Bachinski LL, Sangwatanaroj S et al (1998) Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 338(18):1248–1257

    Article  PubMed  CAS  Google Scholar 

  3. Schwartz K, Carrier L, Guicheney P et al (1995) Molecular basis of familial cardiomyopathies. Circulation 91(2):532–540

    PubMed  CAS  Google Scholar 

  4. Maron BJ, Spirito P (1998) Implications of left ventricular remodeling in hypertrophic cardiomyopathy. Am J Cardiol 81(11):1339–1344

    Article  PubMed  CAS  Google Scholar 

  5. Maron BJ (2002) Hypertrophic cardiomyopathy: a systematic review. JAMA 287(10):1308–1320

    Article  PubMed  Google Scholar 

  6. Varnava AM, Elliott PM, Sharma S et al (2000) Hypertrophic cardiomyopathy: the interrelation of disarray, fibrosis, and small vessel disease. Heart 84(5):476–482

    Article  PubMed  CAS  Google Scholar 

  7. Bottini PB, Carr AA, Prisant LM et al (1995) Magnetic resonance imaging compared to echocardiography to assess left ventricular mass in the hypertensive patient. Am J Hypertens 8(3):221–228

    Article  PubMed  CAS  Google Scholar 

  8. Lorenz CH, Walker ES, Morgan VL et al (1999) Normal human right and left ventricular mass, systolic function, and gender differences by cine magnetic resonance imaging. J Cardiovasc Magn Reson 1(1):7–21

    Article  PubMed  CAS  Google Scholar 

  9. Choudhury L, Mahrholdt H, Wagner A et al (2002) Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 40(12):2156–2164

    Article  PubMed  Google Scholar 

  10. Kim RJ, Judd RM (2003) Gadolinium-enhanced magnetic resonance imaging in hypertrophic cardiomyopathy: in vivo imaging of the pathologic substrate for premature cardiac death? J Am Coll Cardiol 41(9):1568–1572

    Article  PubMed  Google Scholar 

  11. Moon JC, Reed E, Sheppard MN et al (2004) The histologic basis of late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J Am Coll Cardiol 43(12):2260–2264

    Article  PubMed  Google Scholar 

  12. Germans T, van Rossum AC (2008) The use of cardiac magnetic resonance imaging to determine the aetiology of left ventricular disease and cardiomyopathy. Heart 94(4):510–518

    Article  PubMed  Google Scholar 

  13. Papavassiliu T, Schnabel P, Schroder M et al (2005) CMR scarring in a patient with hypertrophic cardiomyopathy correlates well with histological findings of fibrosis. Eur Heart J 26(22):2395

    Article  PubMed  Google Scholar 

  14. Kwon DH, Setser RM, Popovic ZB et al (2008) Association of myocardial fibrosis, electrocardiography and ventricular tachyarrhythmia in hypertrophic cardiomyopathy: a delayed contrast enhanced MRI study. Int J Cardiovasc Imaging 24(6):617–625

    Article  PubMed  Google Scholar 

  15. Lombardi R, Betocchi S, Losi MA et al (2003) Myocardial collagen turnover in hypertrophic cardiomyopathy. Circulation 108(12):1455–1460

    Article  PubMed  CAS  Google Scholar 

  16. Derchi G, Bellone P, Chiarella F et al (1992) Plasma levels of atrial natriuretic peptide in hypertrophic cardiomyopathy. Am J Cardiol 70(18):1502–1504

    Article  PubMed  CAS  Google Scholar 

  17. Fahy GJ, McCreery CJ, O’Sullivan F et al (1996) Plasma atrial natriuretic peptide is elevated in patients with hypertrophic cardiomyopathy. Int J Cardiol 55(2):149–155

    Article  PubMed  CAS  Google Scholar 

  18. Ogino K, Ogura K, Kinugawa T et al (2004) Neurohumoral profiles in patients with hypertrophic cardiomyopathy: differences to hypertensive left ventricular hypertrophy. Circ J 68(5):444–450

    Article  PubMed  Google Scholar 

  19. Hasegawa K, Fujiwara H, Koshiji M et al (1996) Endothelin-1 and its receptor in hypertrophic cardiomyopathy. Hypertension 27(2):259–264

    PubMed  CAS  Google Scholar 

  20. Hamada M, Shigematsu Y, Kawakami H et al (1998) Increased plasma levels of adrenomedullin in patients with hypertrophic cardiomyopathy: its relation to endothelin-I, natriuretic peptides and noradrenaline. Clin Sci (Lond) 94(1):21–28

    CAS  Google Scholar 

  21. Seidler T, Pemberton C, Yandle T et al (1999) The amino terminal regions of proBNP and proANP oligomerise through leucine zipper-like coiled-coil motifs. Biochem Biophys Res Commun 255(2):495–501

    Article  PubMed  CAS  Google Scholar 

  22. Hinson JP, Kapas S, Smith DM (2000) Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 21(2):138–167

    Article  PubMed  CAS  Google Scholar 

  23. Robertson GL, Mahr EA, Athar S et al (1973) Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma. J Clin Invest 52(9):2340–2352

    Article  PubMed  CAS  Google Scholar 

  24. Struck J, Morgenthaler NG, Bergmann A (2005) Copeptin, a stable peptide derived from the vasopressin precursor, is elevated in serum of sepsis patients. Peptides 26(12):2500–2504

    Article  PubMed  CAS  Google Scholar 

  25. Morgenthaler NG, Struck J, Thomas B et al (2004) Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma. Clin Chem 50(1):234–236

    Article  PubMed  CAS  Google Scholar 

  26. Morgenthaler NG, Struck J, Alonso C et al (2005) Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clin Chem 51(10):1823–1829

    Article  PubMed  CAS  Google Scholar 

  27. Morgenthaler NG, Struck J, Alonso C et al (2006) Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 52(1):112–119

    Article  PubMed  CAS  Google Scholar 

  28. Papassotiriou J, Morgenthaler NG, Struck J et al (2006) Immunoluminometric assay for measurement of the C-terminal endothelin-1 precursor fragment in human plasma. Clin Chem 52(6):1144–1151

    Article  PubMed  CAS  Google Scholar 

  29. Elmas E, Lang S, Erik Dempfle C et al (2007) High plasma levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8) characterize patients prone to ventricular fibrillation complicating myocardial infarction. Clin Chem Lab Med 45(10):1360–1365

    Article  PubMed  CAS  Google Scholar 

  30. Simonetti OP, Kim RJ, Fieno DS et al (2001) An improved MR imaging technique for the visualization of myocardial infarction. Radiology 218(1):215–223

    PubMed  CAS  Google Scholar 

  31. Sievers B, Kirchberg S, Addo M et al (2004) Assessment of left atrial volumes in sinus rhythm and atrial fibrillation using the biplane area-length method and cardiovascular magnetic resonance imaging with TrueFISP. J Cardiovasc Magn Reson 6(4):855–863

    Article  PubMed  Google Scholar 

  32. Bland JM, Altman DG (1986) Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1(8476):307–310

    Article  PubMed  CAS  Google Scholar 

  33. Moon JC, Mogensen J, Elliott PM et al (2005) Myocardial late gadolinium enhancement cardiovascular magnetic resonance in hypertrophic cardiomyopathy caused by mutations in troponin I. Heart 91(8):1036–1040

    Article  PubMed  CAS  Google Scholar 

  34. Teraoka K, Hirano M, Ookubo H et al (2004) Delayed contrast enhancement of MRI in hypertrophic cardiomyopathy. Magn Reson Imaging 22(2):155–161

    Article  PubMed  Google Scholar 

  35. Rudolph A, Abdel-Aty H, Bohl S et al (2009) Noninvasive detection of fibrosis applying contrast-enhanced cardiac magnetic resonance in different forms of left ventricular hypertrophy relation to remodeling. J Am Coll Cardiol 53(3):284–291

    Article  PubMed  Google Scholar 

  36. Adabag AS, Maron BJ, Appelbaum E et al (2008) Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol 51(14):1369–1374

    Article  PubMed  Google Scholar 

  37. Roldan V, Marin F, Gimeno JR et al (2008) Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy. Am Heart J 156(1):85–91

    Article  PubMed  CAS  Google Scholar 

  38. Takemura G, Fujiwara H, Mukoyama M et al (1991) Expression and distribution of atrial natriuretic peptide in human hypertrophic ventricle of hypertensive hearts and hearts with hypertrophic cardiomyopathy. Circulation 83(1):181–190

    PubMed  CAS  Google Scholar 

  39. McMurray J, Pfeffer MA (2002) New therapeutic options in congestive heart failure: part II. Circulation 105(18):2223–2228

    Article  PubMed  Google Scholar 

  40. Elmas E, Brueckmann M, Lang S et al (2008) Midregional pro-atrial natriuretic peptide is a useful indicator for the detection of impaired left ventricular function in patients with coronary artery disease. Int J Cardiol 128(2):244–249

    Article  PubMed  Google Scholar 

  41. von Haehling S, Jankowska EA, Morgenthaler NG et al (2007) Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic peptide in predicting survival in patients with chronic heart failure. J Am Coll Cardiol 50(20):1973–1980

    Article  Google Scholar 

  42. Nishikimi T, Yoshihara F, Mori Y et al (2003) Cardioprotective effect of adrenomedullin in heart failure. Hypertens Res 26(Suppl):S121–S127

    Article  PubMed  CAS  Google Scholar 

  43. Elmas E, Lang S, Dempfle CE et al (2008) Diagnostic performance of mid-regional pro-adrenomedullin as an analyte for the exclusion of left ventricular dysfunction. Int J Cardiol 128(1):107–111

    Article  PubMed  Google Scholar 

  44. Suzuki T, Hoshi H, Mitsui Y (1990) Endothelin stimulates hypertrophy and contractility of neonatal rat cardiac myocytes in a serum-free medium. FEBS Lett 268(1):149–151

    Article  PubMed  CAS  Google Scholar 

  45. Neunteufl T, Berger R, Pacher R (2002) Endothelin receptor antagonists in cardiology clinical trials. Expert Opin Investig Drugs 11(3):431–443

    Article  PubMed  CAS  Google Scholar 

  46. Spieker LE, Noll G, Ruschitzka FT et al (2001) Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J Am Coll Cardiol 37(6):1493–1505

    Article  PubMed  CAS  Google Scholar 

  47. Sakai S, Miyauchi T, Kobayashi M et al (1996) Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 384(6607):353–355

    Article  PubMed  CAS  Google Scholar 

  48. Behnes M, Papassotiriou J, Walter T et al (2008) Long-term prognostic value of mid-regional pro-adrenomedullin and C-terminal pro-endothelin-1 in patients with acute myocardial infarction. Clin Chem Lab Med 46(2):204–211

    Article  PubMed  CAS  Google Scholar 

  49. Serradeil-Le Gal C, Wagnon J, Valette G et al (2002) Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. Prog Brain Res 139:197–210

    Article  PubMed  CAS  Google Scholar 

  50. Khan SQ, Dhillon OS, O’Brien RJ et al (2007) C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester acute myocardial infarction peptide (LAMP) study. Circulation 115(16):2103–2110

    Article  PubMed  CAS  Google Scholar 

  51. Esposito A, De Cobelli F, Perseghin G et al (2009) Impaired left ventricular energy metabolism in patients with Hypertrophic Cardiomyopathy is related to the extension of fibrosis at gadolinium delayed enhanced MR imaging. Heart 95(3):228–233

    Article  PubMed  CAS  Google Scholar 

  52. Moon JC, McKenna WJ, McCrohon JA et al (2003) Toward clinical risk assessment in hypertrophic cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol 41(9):1561–1567

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

There is no potential conflict of interest to disclose for any of the co-authors.

Author information

Authors and Affiliations

  1. 1st Department of Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

    Elif Elmas, Christina Doesch, Stephan Fluechter, Miriam Freundt, Siegfried Lang, Thorsten Kälsch, Dariush Haghi, Martin Borggrefe & Theano Papavassiliu

  2. Department of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

    Stefan O. Schoenberg

  3. Department of Medical Statistics, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Ludolf-Krehl-Straße 13-17, 68167, Mannheim, Germany

    Christel Weiss

  4. Research Department, B.R.A.H.M.S. AG, Biotechnology Centre, Neuendorfstr. 25, 16761, Hennigsdorf, Germany

    Jana Papassotiriou & Jan Kunde

Authors
  1. Elif Elmas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christina Doesch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephan Fluechter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miriam Freundt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christel Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Siegfried Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thorsten Kälsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dariush Haghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jana Papassotiriou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jan Kunde
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stefan O. Schoenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin Borggrefe
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Theano Papavassiliu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christina Doesch.

Additional information

Elif Elmas and Christina Doesch have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elmas, E., Doesch, C., Fluechter, S. et al. Midregional pro-atrial natriuretic peptide: a novel marker of myocardial fibrosis in patients with hypertrophic cardiomyopathy. Int J Cardiovasc Imaging 27, 547–556 (2011). https://doi.org/10.1007/s10554-010-9704-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10554-010-9704-2

Keywords

Search

Navigation