Skip to main content
SpringerLink
Log in

ACE-Inhibition Benefit on Lung Function in Heart Failure is Modulated by ACE Insertion/Deletion Polymorphism

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

The benefit of angiotensin converting enzyme (ACE) inhibition in chronic heart failure (HF) is partially due to its effects on pulmonary function and particularly on lung diffusion, the latter being counteracted by acetylsalicylic acid (ASA). Tissue ACE activity is largely determined by an insertion/deletion (I/D) polymorphism resulting in three possible genotypes (DD, ID and II). It is not clear if ACE inhibitor therapy could exert different effects in these genotypes. The aim of the study was to understand whether I/D polymorphism interferes with ACE inhibitor’s protection of the lungs in HF during acute fluid overload.

Methods

100 HF patients (left ventricular ejection fraction ≤40 %) in stable clinical conditions, treated with enalapril but without ASA performed pulmonary function tests including lung diffusion (DLco) and its subcomponents, membrane diffusion (Dm) and capillary volume (Vcap), and a cardiopulmonary exercise test before and immediately after rapid infusion of 500 cc saline.

Results

ACE I/D genotype prevalence was: DD = 28, ID =55 and II = 17 cases. No significant differences in major pulmonary function and exercise parameters were observed before saline infusion among ACE genotypes. After fluid challenge, DD patients presented a higher DLco and Dm reduction than ID and II (DLco −2.3 ± 1.3 vs. -0.8 ± 1.9 and −0.6 ± 1 mL/mmHg/min, p < 0.0001 and p < 0.01; Dm −7 ± 5 vs. -3.2 ± 7.4 and −1.3 ± 5 mL/mmHg/min, p < 0.05, respectively) and a higher increase in VE/VCO2 slope than II (1.8 ± 1.9 vs. -0.8 ± 2.3, p = 0.01).

Conclusions

ACE DD genotype is associated with higher vulnerability of the alveolar-capillary membrane to acute fluid overload in HF patients treated with ACE inhibitors.

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

References

  1. Guazzi M, Marenzi G, Alimento M, Contini M, Agostoni P. Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation. 1997;95(7):1930–6.

    Article  CAS  PubMed  Google Scholar 

  2. Guazzi M, Agostoni P. Angiotensin-converting enzyme inhibition restores the diffusing capacity for carbon monoxide in patients with chronic heart failure by improving the molecular diffusion across the alveolar capillary membrane. Clin Sci (Lond). 1999;96(1):17–22.

    Article  CAS  Google Scholar 

  3. Guazzi M, Pontone G, Agostoni P. Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors. Am Heart J. 1999;138(2 Pt 1):254–60.

    Article  CAS  PubMed  Google Scholar 

  4. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Abraham MR, Olson LJ, Joyner MJ, Turner ST, Beck KC, Johnson BD. Angiotensin-converting enzyme genotype modulates pulmonary function and exercise capacity in treated patients with congestive stable heart failure. Circulation. 2002;106(14):1794–9.

    Article  CAS  PubMed  Google Scholar 

  6. Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51(1):197–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. McNamara DM, Holubkov R, Postava L, Janosko K, MacGowan GA, Mathier M, et al. Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. J Am Coll Cardiol. 2004;44(10):2019–26.

    Article  CAS  PubMed  Google Scholar 

  8. Andersson B, Sylven C. The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure. J Am Coll Cardiol. 1996;28(1):162–7.

    Article  CAS  PubMed  Google Scholar 

  9. Bedi M, McNamara D, London B, Schwartzman D. Genetic susceptibility to atrial fibrillation in patients with congestive heart failure. Heart Rhythm. 2006;3(7):808–12.

    Article  PubMed  Google Scholar 

  10. Paolillo S, Pellegrino R, Salvioni E, Contini M, Iorio A, Bovis F, et al. Role of alveolar beta2-adrenergic receptors on lung fluid clearance and exercise ventilation in healthy humans. PLoS One. 2013;8(4):e61877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Robertson HT, Pellegrino R, Pini D, Oreglia J, DeVita S, Brusasco V, et al. Exercise response after rapid intravenous infusion of saline in healthy humans. J Appl Physiol. 2004;97(2):697–703.

    Article  PubMed  Google Scholar 

  12. Puri S, Dutka DP, Baker BL, Hughes JM, Cleland JG. Acute saline infusion reduces alveolar-capillary membrane conductance and increases airflow obstruction in patients with left ventricular dysfunction. Circulation. 1999;99(9):1190–6.

    Article  CAS  PubMed  Google Scholar 

  13. Guazzi M, Agostoni P, Bussotti M, Guazzi MD. Impeded alveolar-capillary gas transfer with saline infusion in heart failure. Hypertension. 1999;34(6):1202–7.

    Article  CAS  PubMed  Google Scholar 

  14. Guazzi M, Agostoni P, Guazzi MD. Alveolar-capillary gas exchange and exercise performance in heart failure. Am J Cardiol. 2001;88(4):452–7.

    Article  CAS  PubMed  Google Scholar 

  15. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.

    Article  CAS  PubMed  Google Scholar 

  16. Huang YC, Helms MJ, MacIntyre NR. Normal values for single exhalation diffusing capacity and pulmonary capillary blood flow in sitting, supine positions, and during mild exercise. Chest. 1994;105(2):501–8.

    Article  CAS  PubMed  Google Scholar 

  17. Kiss D, Popp W, Wagner C, Havelec L, Sertl K. Comparison of the single breath with the intrabreath method for the measurement of the carbon monoxide transfer factor in subjects with and without airways obstruction. Thorax. 1995;50(8):902–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cotes JE, Dabbs JM, Elwood PC, Hall AM, McDonald A, Saunders MJ. Iron-deficiency anaemia: its effect on transfer factor for the lung (diffusiong capacity) and ventilation and cardiac frequency during sub-maximal exercise. Clin Sci. 1972;42(3):325–35.

    Article  CAS  PubMed  Google Scholar 

  19. Hughes JM, Bates DV. Historical review: the carbon monoxide diffusing capacity (DLCO) and its membrane (DM) and red cell (theta.Vc) components. Respir Physiol Neurobiol. 2003;138(2–3):115–42.

    Article  CAS  PubMed  Google Scholar 

  20. Roughton FJ, Forster RE. Relative importance of diffusion and chemical reaction rates in determining rate of exchange of gases in the human lung, with special reference to true diffusing capacity of pulmonary membrane and volume of blood in the lung capillaries. J Appl Physiol. 1957;11(2):290–302.

    CAS  PubMed  Google Scholar 

  21. Agostoni P, Bianchi M, Moraschi A, Palermo P, Cattadori G, La Gioia R, et al. Work-rate affects cardiopulmonary exercise test results in heart failure. Eur J Heart Fail. 2005;7(4):498–504.

    Article  PubMed  Google Scholar 

  22. Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, et al. Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American heart association. Circulation. 2010;122(2):191–225.

    Article  PubMed  Google Scholar 

  23. Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol. 1986;60(6):2020–7.

    CAS  PubMed  Google Scholar 

  24. Ribichini F, Steffenino G, Dellavalle A, Matullo G, Colajanni E, Camilla T, et al. Plasma activity and insertion/deletion polymorphism of angiotensin I-converting enzyme: a major risk factor and a marker of risk for coronary stent restenosis. Circulation. 1998;97(2):147–54.

    Article  CAS  PubMed  Google Scholar 

  25. Fatini C, Abbate R, Pepe G, Battaglini B, Gensini F, Ruggiano G, et al. Searching for a better assessment of the individual coronary risk profile. The role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms. Eur Heart J. 2000;21(8):633–8.

    Article  CAS  PubMed  Google Scholar 

  26. Contini M, Apostolo A, Cattadori G, Paolillo S, Iorio A, Bertella E, et al. Multiparametric comparison of CARvedilol, vs. NEbivolol, vs. BIsoprolol in moderate heart failure: the CARNEBI trial. Int J Cardiol. 2013;168(3):2134–40.

    Article  PubMed  Google Scholar 

  27. Mutlu GM, Sznajder JI. Mechanisms of pulmonary edema clearance. Am J Physiol Lung Cell Mol Physiol. 2005;289(5):L685–95.

    Article  CAS  PubMed  Google Scholar 

  28. Piepoli MF, Guazzi M, Boriani G, Cicoira M, Corra U, Dalla Libera L, et al. Exercise intolerance in chronic heart failure: mechanisms and therapies. Part II. Eur J Cardiovasc Prev Rehabil. 2010;17(6):643–8.

    Article  PubMed  Google Scholar 

  29. Wasserman K, Hansen JE, Sue DY, Stringer WW, Whipp BJ. Clinical Exercise Testing. Principles of Exercise Testing and Interpretation Including Pathophysiology and Clinical Applications. 5th ed.: Lippincott Williams & Wilkins; 2012. p. 154–80.

  30. Di Marco F, Guazzi M, Vicenzi M, Santus P, Cazzola M, Pappalettera M, et al. Effect of enalapril on exercise cardiopulmonary performance in chronic obstructive pulmonary disease: a pilot study. Pulm Pharmacol Ther. 2010;23(3):159–64.

    Article  PubMed  Google Scholar 

  31. van Veldhuisen DJ, Genth-Zotz S, Brouwer J, Boomsma F, Netzer T, Man In TVAJ, et al. High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril. J Am Coll Cardiol. 1998;32(7):1811–8.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centro Cardiologico Monzino, IRCCS, Milano, Italy

    Mauro Contini, Elisa Compagnino, Gaia Cattadori, Damiano Magrì, Marina Camera, Anna Apostolo, Stefania Farina, Pietro Palermo, Elena Tremoli, Cesare Fiorentini & Piergiuseppe Agostoni

  2. Department of Clinical and Molecular Medicine, University “La Sapienza”, Rome, Italy

    Damiano Magrì

  3. Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden

    Karl Gertow

  4. Department of Clinical Sciences and Community Health, Cardiovascular Section, University of Milan, Milan, Italy

    Cesare Fiorentini & Piergiuseppe Agostoni

  5. Centro Cardiologico Monzino, Department of Clinical Sciences and Community Health, Cardiovascular Section, University of Milan, Via Parea 4, 20138, Milano, Italy

    Piergiuseppe Agostoni

Authors
  1. Mauro Contini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisa Compagnino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gaia Cattadori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Damiano Magrì
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marina Camera
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anna Apostolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefania Farina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pietro Palermo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Karl Gertow
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Elena Tremoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cesare Fiorentini
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Piergiuseppe Agostoni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Piergiuseppe Agostoni.

Ethics declarations

Conflict of Interest

None.

Clinical Trial Registration

URL https://clinicaltrials.gov/ct2/show/NCT00361127; Clinical Trial Gov n° NCT00361127

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Contini, M., Compagnino, E., Cattadori, G. et al. ACE-Inhibition Benefit on Lung Function in Heart Failure is Modulated by ACE Insertion/Deletion Polymorphism. Cardiovasc Drugs Ther 30, 159–168 (2016). https://doi.org/10.1007/s10557-016-6645-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-016-6645-6

Keywords

Search

Navigation