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Do We Really Need Another Biomarker for Heart Failure?
Accepted Manuscript Title: Do We Really Need Another Biomarker for Heart Failure? Author: April Stempien-Otero PII: DOI: Reference:
S1071-9164(17)30111-2 http://dx.doi.org/doi: 10.1016/j.cardfail.2017.04.018 YJCAF 3954
To appear in:
Journal of Cardiac Failure
Please cite this article as: April Stempien-Otero, Do We Really Need Another Biomarker for Heart Failure?, Journal of Cardiac Failure (2017), http://dx.doi.org/doi: 10.1016/j.cardfail.2017.04.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Do we really need another biomarker for heart failure? April Stempien-Otero, MD University of Washington, Department of Medicine, Seattle, Washington
Correspondence: April Stempien-Otero UW Research - South Lake Union Complex 850 Republican Street, Brotman 142 Box 358050 Seattle, WA 98109 UNITED STATES Tel: 206-616-9054 Email: [email protected] No conflicts of interest to declare
Page 1 of 4
A Pubmed search of the terms “heart failure” and “biomarker” yields 9898 results. This cavalcade of studies correlating plasma proteins, hormone levels, DNA, RNA, and microRNA’s (both cell free and exosomal) to the presence, absence, or severity of heart failure obscures the important role of biomarker studies in advancing heart failure therapeutics. Indeed, the oldest citation in the above search is entitled, “Catecholamine metabolite excretion in infants with heart failure.” (1) This paper serves as a reminder that it was the search for molecules present in excess in heart failure that gave us the first clues to the role of neurohormonal activation in the disease and subsequently the development of the our most effective therapies to date.
Ironically, however, neurohormones proved to be impractical biomarkers for predicting the course or severity of disease. They are difficult to measure and affected by intra-subject variance. When was the last time you sent a patient for a blood test with instructions to maintain a supine position for 30 minutes? Impractical to say the least. Thus, the search for a reproducible biomarker continued and approximately 20 years after the first descriptions of neurohormonal activation in heart failure were reported, the correlation between brain natriuretic peptide (BNP) and human heart failure was uncovered (2). Within a decade, a reproducible test for the presence or absence of heart failure was available, although the utility of BNP for guiding heart failure management over time remains unsettled.
This road from bench to bedside is the golden ticket driving the field to this day. Unfortunately, multiple other biomarkers have proven less facile in translation. For example, levels of tumor necrosis factor-alpha correlate well with severity of heart failure (3), yet inhibition failed to modify outcomes. Moreover, although many other markers of inflammation have been found that
Page 2 of 4
similarly correlate with heart failure severity; our understanding of the complex roles of myocardial leukocytes in heart failure remains incomplete. Recent data support the concept that the discovery of a correlation between yet another biomarker of inflammation and heart failure outcomes will not substantially move this field forward (4).
What do we really need in biomarker studies? We need studies to help us apply the biomarkers we have. For example, studies linking specific biomarkers to pharmacogenomics could help predict responses to current therapies and identify groups at risk of rapid progression due to therapy resistance. Likewise, using the precepts of precision medicine to examine changes in biomarkers over time in individual patients could be of great benefit in reducing hospitalizations. Finally, there are elements of advanced heart failure that may predominate in one patient over another such as dilation or fibrosis that could predict individualized outcomes and responses to novel therapies. Specific mechanistic markers such as Galactin-3 for fibrosis could identify patients who may most benefit from anti-fibrotic therapies and guide the design of more efficient clinical trials.
In summary, reports of this or that factor as a readout of the presence of disease can wait. Although at the JCF we remain interested in papers that include data on novel biomarkers, we also maintain that rigorous trials of the utility of a biomarker to change the course of heart failure cannot come soon enough.
Page 3 of 4
References 1. Catecholamine metabolite excretion of infants with heart failure. Lees MH, J Pediatr. 1966 Aug;69(2):259-65. 2. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shirakami G, Jougasaki M, Obata K, Yasue H, et al. J Clin Invest. 1991 Apr;87(4):1402-12. 3. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure Levine B, Kalman J, Mayer L, Fillit HM, Packer M. N Engl J Med. 1990 Jul 26;323(4):236-41. 4. Limited added value of circulating inflammatory biomarkers in chronic heart failure. Nymo SH, Aukrust P, Kjekshus J, McMurray JJ, Cleland JG, Wikstrand J, Muntendam P, Wienhues-Thelen U, Latini R, Askevold ET, Gravning J, Dahl CP, Broch K, Yndestad A, Gullestad L, Ueland T; CORONA Study Group. JACC Heart Fail. 2017 Apr;5(4):256264
Page 4 of 4
S1071-9164(17)30111-2 http://dx.doi.org/doi: 10.1016/j.cardfail.2017.04.018 YJCAF 3954
To appear in:
Journal of Cardiac Failure
Please cite this article as: April Stempien-Otero, Do We Really Need Another Biomarker for Heart Failure?, Journal of Cardiac Failure (2017), http://dx.doi.org/doi: 10.1016/j.cardfail.2017.04.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Do we really need another biomarker for heart failure? April Stempien-Otero, MD University of Washington, Department of Medicine, Seattle, Washington
Correspondence: April Stempien-Otero UW Research - South Lake Union Complex 850 Republican Street, Brotman 142 Box 358050 Seattle, WA 98109 UNITED STATES Tel: 206-616-9054 Email: [email protected] No conflicts of interest to declare
Page 1 of 4
A Pubmed search of the terms “heart failure” and “biomarker” yields 9898 results. This cavalcade of studies correlating plasma proteins, hormone levels, DNA, RNA, and microRNA’s (both cell free and exosomal) to the presence, absence, or severity of heart failure obscures the important role of biomarker studies in advancing heart failure therapeutics. Indeed, the oldest citation in the above search is entitled, “Catecholamine metabolite excretion in infants with heart failure.” (1) This paper serves as a reminder that it was the search for molecules present in excess in heart failure that gave us the first clues to the role of neurohormonal activation in the disease and subsequently the development of the our most effective therapies to date.
Ironically, however, neurohormones proved to be impractical biomarkers for predicting the course or severity of disease. They are difficult to measure and affected by intra-subject variance. When was the last time you sent a patient for a blood test with instructions to maintain a supine position for 30 minutes? Impractical to say the least. Thus, the search for a reproducible biomarker continued and approximately 20 years after the first descriptions of neurohormonal activation in heart failure were reported, the correlation between brain natriuretic peptide (BNP) and human heart failure was uncovered (2). Within a decade, a reproducible test for the presence or absence of heart failure was available, although the utility of BNP for guiding heart failure management over time remains unsettled.
This road from bench to bedside is the golden ticket driving the field to this day. Unfortunately, multiple other biomarkers have proven less facile in translation. For example, levels of tumor necrosis factor-alpha correlate well with severity of heart failure (3), yet inhibition failed to modify outcomes. Moreover, although many other markers of inflammation have been found that
Page 2 of 4
similarly correlate with heart failure severity; our understanding of the complex roles of myocardial leukocytes in heart failure remains incomplete. Recent data support the concept that the discovery of a correlation between yet another biomarker of inflammation and heart failure outcomes will not substantially move this field forward (4).
What do we really need in biomarker studies? We need studies to help us apply the biomarkers we have. For example, studies linking specific biomarkers to pharmacogenomics could help predict responses to current therapies and identify groups at risk of rapid progression due to therapy resistance. Likewise, using the precepts of precision medicine to examine changes in biomarkers over time in individual patients could be of great benefit in reducing hospitalizations. Finally, there are elements of advanced heart failure that may predominate in one patient over another such as dilation or fibrosis that could predict individualized outcomes and responses to novel therapies. Specific mechanistic markers such as Galactin-3 for fibrosis could identify patients who may most benefit from anti-fibrotic therapies and guide the design of more efficient clinical trials.
In summary, reports of this or that factor as a readout of the presence of disease can wait. Although at the JCF we remain interested in papers that include data on novel biomarkers, we also maintain that rigorous trials of the utility of a biomarker to change the course of heart failure cannot come soon enough.
Page 3 of 4
References 1. Catecholamine metabolite excretion of infants with heart failure. Lees MH, J Pediatr. 1966 Aug;69(2):259-65. 2. Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shirakami G, Jougasaki M, Obata K, Yasue H, et al. J Clin Invest. 1991 Apr;87(4):1402-12. 3. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure Levine B, Kalman J, Mayer L, Fillit HM, Packer M. N Engl J Med. 1990 Jul 26;323(4):236-41. 4. Limited added value of circulating inflammatory biomarkers in chronic heart failure. Nymo SH, Aukrust P, Kjekshus J, McMurray JJ, Cleland JG, Wikstrand J, Muntendam P, Wienhues-Thelen U, Latini R, Askevold ET, Gravning J, Dahl CP, Broch K, Yndestad A, Gullestad L, Ueland T; CORONA Study Group. JACC Heart Fail. 2017 Apr;5(4):256264
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