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Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial.
Eur J Heart Fail. 2018 09; 20(9):1290-1299.EJ

Abstract

BACKGROUND

Myocardial fibrosis is characterized by excessive cross-linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross-linking and/or deposition.

METHODS AND RESULTS

We investigated 381 HFpEF patients from the multicentre, randomized, placebo-controlled Aldo-DHF trial with measures of the E:e' ratio. The ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1, an inverse index of myocardial collagen cross-linking) and serum carboxy-terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1-year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP-1 and PICP tertiles at baseline. While CITP:MMP-1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP-1 levels, this ratio was significantly reduced in the remaining spironolactone-treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP-1 levels but was reduced in the remaining spironolactone-treated patients.

CONCLUSIONS

A biochemical phenotype of high collagen cross-linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross-linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients.

Authors+Show Affiliations

University of Navarra, CIMA, Program of Cardiovascular Diseases, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain, CIBERCV, Carlos III Institute of Health, Madrid, Spain.Institute for Internal Medicine and Cardiology, Charité Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.Institute for Internal Medicine and Cardiology, Charité Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.Institute for Internal Medicine and Cardiology, Charité Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.University of Navarra, CIMA, Program of Cardiovascular Diseases, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain, CIBERCV, Carlos III Institute of Health, Madrid, Spain.University of Navarra, CIMA, Program of Cardiovascular Diseases, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain, CIBERCV, Carlos III Institute of Health, Madrid, Spain.Department of Cardiology and Pneumology, University of Göttingen Medical Centre Göttingen, Göttingen, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.Department of Cardiology and Pneumology, University of Göttingen Medical Centre Göttingen, Göttingen, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany.Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.Institute for Internal Medicine and Cardiology, Charité Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany. Berlin Institute of Health (BIH), Berlin, Germany. Deutsches Herzzentrum Berlin (DHZB), Department of Cardiology, Berlin, Germany.University of Navarra, CIMA, Program of Cardiovascular Diseases, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain, CIBERCV, Carlos III Institute of Health, Madrid, Spain. University of Navarra Clinic, Departments of Cardiology and Cardiac Surgery, and Nephrology, Pamplona, Spain.Institute for Internal Medicine and Cardiology, Charité Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany. Department of Cardiology and Pneumology, University of Göttingen Medical Centre Göttingen, Göttingen, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany. Berlin Institute of Health (BIH), Berlin, Germany.

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29709099

Citation

Ravassa, Susana, et al. "Biomarker-based Phenotyping of Myocardial Fibrosis Identifies Patients With Heart Failure With Preserved Ejection Fraction Resistant to the Beneficial Effects of Spironolactone: Results From the Aldo-DHF Trial." European Journal of Heart Failure, vol. 20, no. 9, 2018, pp. 1290-1299.
Ravassa S, Trippel T, Bach D, et al. Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial. Eur J Heart Fail. 2018;20(9):1290-1299.
Ravassa, S., Trippel, T., Bach, D., Bachran, D., González, A., López, B., Wachter, R., Hasenfuss, G., Delles, C., Dominiczak, A. F., Pieske, B., Díez, J., & Edelmann, F. (2018). Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial. European Journal of Heart Failure, 20(9), 1290-1299. https://doi.org/10.1002/ejhf.1194
Ravassa S, et al. Biomarker-based Phenotyping of Myocardial Fibrosis Identifies Patients With Heart Failure With Preserved Ejection Fraction Resistant to the Beneficial Effects of Spironolactone: Results From the Aldo-DHF Trial. Eur J Heart Fail. 2018;20(9):1290-1299. PubMed PMID: 29709099.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial. AU - Ravassa,Susana, AU - Trippel,Tobias, AU - Bach,Doris, AU - Bachran,Diana, AU - González,Arantxa, AU - López,Begoña, AU - Wachter,Rolf, AU - Hasenfuss,Gerd, AU - Delles,Christian, AU - Dominiczak,Anna F, AU - Pieske,Burkert, AU - Díez,Javier, AU - Edelmann,Frank, Y1 - 2018/04/30/ PY - 2017/12/18/received PY - 2018/02/19/revised PY - 2018/03/12/accepted PY - 2018/5/1/pubmed PY - 2019/2/9/medline PY - 2018/5/1/entrez KW - Biomarkers of myocardial fibrosis KW - Carboxy-terminal propeptide of procollagen type I KW - Carboxy-terminal telopeptide of collagen type I KW - Heart failure with preserved ejection fraction KW - Left ventricular diastolic function KW - Matrix metalloproteinase-1 KW - Spironolactone SP - 1290 EP - 1299 JF - European journal of heart failure JO - Eur. J. Heart Fail. VL - 20 IS - 9 N2 - BACKGROUND: Myocardial fibrosis is characterized by excessive cross-linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross-linking and/or deposition. METHODS AND RESULTS: We investigated 381 HFpEF patients from the multicentre, randomized, placebo-controlled Aldo-DHF trial with measures of the E:e' ratio. The ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1, an inverse index of myocardial collagen cross-linking) and serum carboxy-terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1-year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP-1 and PICP tertiles at baseline. While CITP:MMP-1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP-1 levels, this ratio was significantly reduced in the remaining spironolactone-treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP-1 levels but was reduced in the remaining spironolactone-treated patients. CONCLUSIONS: A biochemical phenotype of high collagen cross-linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross-linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients. SN - 1879-0844 UR - https://www.unboundmedicine.com/medline/citation/29709099/Biomarker_based_phenotyping_of_myocardial_fibrosis_identifies_patients_with_heart_failure_with_preserved_ejection_fraction_resistant_to_the_beneficial_effects_of_spironolactone:_results_from_the_Aldo_DHF_trial_ L2 - https://doi.org/10.1002/ejhf.1194 DB - PRIME DP - Unbound Medicine ER -