University of Groningen
Circulating factors in heart failure
Meijers, Wouter
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Publication date: 2019
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Meijers, W. (2019). Circulating factors in heart failure: Biomarkers, markers of co-morbidities and disease factors. Rijksuniversiteit Groningen.
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Chapter 1
Introduction and aims of the thesis
Prologue
“The heart is really a miraculous organ. It beats 72 times a minute throughout our life, which means billions of times in our lifetime. And it never gets tired. It knows exactly how much blood to pump; it can increase its output by fivefold if we need more oxygen – for example, if we’re running or doing strenuous activity. You have 5 billion cells called myocytes, all beating in synchrony, in a perfectly coordinated manner, to maximise the heart’s pumping ability. It is an engineering feat that never ceases to amaze me.” – Dr. Roberto Bolli - Editor-in-Chief, Circulation Research.
Interactions
Cardiologists – as organ specialists – may become narrow minded and tend to focus on the heart only. However, the weight of scientific evidence that supports the view that the human heart has different interactions with itself and its surroundings is rapidly increasing. The fact that these interactions occur both in the heart as well as in other organs is marvelous. This must be acknowledged and act upon if we are prepared to discover the mysteries of the human heart in health and disease.
Heart failure
Every day in the Netherlands, more than 100 patients die of cardiovascular disease, and every year over 7500 patients die of heart failure (HF).1 Cardiovascular disease, and specifically HF, is one of the leading causes of morbidity and mortality in the Western world. The lifetime risk of acquiring HF is over 20% for people at the age of 40, and it imposes an enormous burden on the health care budget, driven by a high number of HF rehospitalisations.2 It is even expected that the prevalence of HF will rise in the future because of the ageing population and, paradoxically, because of successfully improved treatment options.
Directed by treatment guidelines from the European Society of Cardiology and the Heart Failure Association, physicians are faced with a difficult task to diagnose and treat this complex clinical syndrome.3 HF is characterised by abnormal cardiac structure and/ or function, with typical signs and symptoms. Challenges in the proper diagnosis of HF are due to the interplay between the heart and other (cardiac and non-cardiac) organs and tissues. As an example of a very typical dilemma: is the shortness of breath due to lung disease? Due to vascular disease? Due to atrial fibrillation? Or due to HF? Beside this organ interplay, HF presentation has changed over the past decades. While HF used to affect middle-aged men after a large myocardial infarction (MI), typically leading to HF with reduced ejection fraction (HFrEF), nowadays a large proportion of incident HF occurs in the elderly patient, frequently women, with primary drivers being hyperten-sion, ageing and diabetes, reflecting in HF with preserved ejection fraction (HFpEF). This “modern face” of HF appears to have a better prognosis, yet it is associated with an even more extreme burden of additional diseases.4
It is clear that HF is very heterogeneous disorder, but currently all HFrEF patients receive the same treatment regimen which consists of ACE-inhibitors, beta-blockers, mineralo-corticoid receptor antagonists, diuretics, and for some the addition of ivabradine and sacubitril/valsartan. Furthermore, patients will receive cardiac devices such as pacemak-ers, CRTs and ICDs. This “one size fits all” has proven to fail in HFpEF studies, and might
even fail or be less efficacious in some HFrEF patients.5–8 For this matter, better insight into the pathophysiological mechanisms underlying HF is a necessity.
One of the key processes in the pathophysiology of HF is cardiac remodeling, a generally unfavorable process in which the myocardium is converted into an, mostly irreversible, changed structural and functional state. It occurs in response to a change in size, shape and structure of cardiac muscle after elevation in hemodynamic load and/or cardiac injury, often accompanied or perpetuated by neuro-hormonal activation.9 Over time, remodeling may shift from a compensatory to a maladaptive process. Changes in both the cellular and extracellular matrix, such as myocyte hypertrophy, apoptosis or necrosis and fibroblast proliferation or activation, can occur.10 Measured molecules, also known as biomarkers, present due to these different processes might aid physicians to better understand the pathophysiology of HF and to better treat and tailor therapy for his/her specific patients.
Biomarkers
Plasma biomarkers can serve as a marker of organ damage or as a form of communica-tion from organs to convey informacommunica-tion about human physiology and pathology. The Oxford English Dictionary defines a biomarker as “a naturally occurring molecule, gene, or characteristic by which a particular pathological or physiological process, disease, etc. can be identified”. In cardiovascular medicine biomarkers are most often used regarding diagnosis, prognosis, monitoring, measuring treatment effect and risk stratification. Cardiac remodeling is characterised by up- and downregulation of a different set of biomarkers. With the help of a magnitude in biomarkers, we attempt to better under-stand processes in the pathophysiology of HF, such as inflammation, oxidative stress, extracellular matrix remodeling, neurohormones, myocyte injury and myocyte stress. HF biomarkers have dramatically impacted the way HF patients are evaluated and man-aged. Over the last decade, over 6500 studies have been published in the field of HF biomarkers.11 Unfortunately, the methodology and usefulness are questionable, and biomarkers were assessed in heterogeneous HF phenotypes that have substantially lim-ited clinical translation. To guide physicians in this tsunami of biomarkers I have investi-gated biomarkers at different important clinical decision-making moments. Biomarkers fit perfectly in the paradigm of HF being a systemic – and not only a heart – disease, and several chapters in this thesis will describe the importance of a holistic view in the study, measurement, and interpretation of biomarkers. For this purpose, natriuretic peptides (NPs), a known cardiac and HF specific biomarker, and also galectin-3, a more general and fibrotic marker, but profoundly linked to cardiac disease, were investigated.
nT-proBnP and galectin-3
NPs, including B-type NP (BNP) and the pro-hormone fragment N terminal proBNP (NT-proBNP) are secreted by cardiomyocytes in response to stretching, caused by increased (atrial or ventricular) volume and pressure. Importantly, NPs are cardio-specific markers, meaning that all NT-proBNP, detected at the plasma level, is produced in the heart. The physiologic actions of NPs include a decrease in systemic vascular resistance and central venous pressure as well as an increase in natriuresis.12 The net effect is a decrease in blood pressure and, thus, a decrease in afterload. As such, the release of NPs, although indicative of a maladaptive process, should be regarded as a beneficial response of the body. NT-proBNP and BNP have proven to be clinically useful to adequate diagnosis of HF. NPs are often used to identify those patients with acute HF who present at the emer-gency department with shortness of breath.13,14 NPs are also used in risk stratification, but the applicability for physicians in the treatment regimen is not always clear. In line, multiple trials have attempted a biomarker-based monitoring, but these demonstrated differential effects and biomarker-guided monitoring has not made it into standard care as of yet.15–17
Besides NPs, other biomarkers, including galectin-3, predict outcome in subjects with HF.18,19 Galectin-3 is a biomarker of fibrosis and inflammation and is implicated in a variety of processes associated with HF, including myofibroblast proliferation, tissue repair and ventricular remodeling.20 However, galectin-3 is produced at large amounts in extra-cardiac tissues (including kidney, fat tissue, liver and lung),21 meaning that galectin-3 is a good example of a biomarker associated with HF and a role in organ-organ interaction and cross-talk. In line with this, galectin-3 is elevated in response to hypertension, inflammation and tissue repair, and elevations in galectin-3 have been shown to precede renal disease,22 new onset heart failure23 and cardiovascular mortal-ity.24 This implicates that elevations in galectin-3 may have importance for other organs other than the primary site of production. Furthermore, besides a marker for fibrosis, galectin-3 might be an amendable biomarker and a target for therapy. The anti-fibrotic modality would be a new class of medication in HF management.25 Current studies with anti-galectin-3 agents in patients with lung fibrosis have generated promising results.26
organ cross-talk
To investigate the next level of biomarker-interactions, we studied the cross-talk be-tween HF and cancer development. Novel markers might emerge in this new and excit-ing field of research. Markers involved in multiple physiological and pathophysiological processes might connect disease development in different organs. Alpha 1-antichymo-trypsin (SERPINA3), was identified in our studies as a potential marker of interest. These
newly discovered HF biomarkers might connect heart disease to the development of different other diseases such as kidney, lung and liver disease, but also cancer.
Together, all the above-mentioned biomarkers, NT-proBNP, galectin-3 and SERPINA3 are of interest in HF research and will be investigated in this thesis. As depicted in Figure 1, the focus of this thesis will be on HF, biomarkers (both mechanistic insights and clinical utility), assays and heart-organ/heart-tissue interactions in the light of cancer develop-ment.
aims and outline of this thesis
As discussed, HF is a heterogeneous and complex syndrome and knowledge about biomarkers could help physicians to treat their patients properly based on a right diag-nosis, prognosis and risk stratification. With an interest in NPs as examples of established cardio-specific biomarkers, and on galectin-3, as a pleiotropic biomarker with high expression in extra-cardiac tissues we investigated in this thesis;
In part 1 - Practical and clinical utility of biomarkers in heart failure - The performance of NPs and galectin-3 in the post-discharge period - The performance of NPs and galectin-3 in identifying low-risk patients
In part 2 - Mechanism and interpretation of circulating biomarkers - The role of renal function in the clearance of galectin-3
- Provide additional information on biomarker level interpretations - The role of a biomarker as a target for therapy
In part 3 - Circulating factors and culprits: HF and cancer - The causal relationship between HF and cancer
- Provide an overview of possible mechanisms linking HF and cancer
Part 1 focusses on biomarkers, in particular galectin-3 and NT-proBNP. Each chapter
will present a different HF-related clinical utility for these biomarkers. In Chapter 2, we investigate one of the most vulnerable phases in HF, namely the post-discharge period. Early HF readmission rates are extremely high and physicians are unable to predict which patients will be rehospitalized on short notice. This deficit is a great health issue and places a major strain on our health care system. We demonstrate a potential role for galectin-3 to improve near-term management. Contrary to current literature, which focuses on high-risk patients, in Chapter 3a and discussed in Chapter 3b, we report that biomarkers can identify HF patients at low risk (instead of high risk) for adverse events. For this examination, we use a large panel of biomarkers and demonstrate that galectin-3 could be of importance in identifying patients after an episode of acute HF; this finding was validated in an independent HF cohort. In Chapter 4, we demonstrate the difficulty of using NPs in HFpEF patients, a largely unknown HF group.
Part 2 is aimed at the assumption that one requires knowledge about biomarker biology
to properly interpret biomarker levels. Since galectin-3 is related to kidney function, we demonstrated in Chapter 5 a novel mechanism as to why galectin-3 may be increased in renal dysfunction, studying three well-chosen cohorts, namely the general population, a chronic HF cohort and patients on hemodialysis, and combining this with an animal model in which we demonstrated renal excretion of galectin-3. In Chapter 6, we provide an overview of different galectin-3 assays and their pros and cons. Chapter 7 goes one step further and provides insight in the variability of biomarkers in healthy individuals and HF patients. Based on physiological biomarker level changes, we can distinguish between normal physiology and pathophysiology. A novel concept is to use the bio-marker as a target for therapy which is clearly described in chapter 8. In this review the challenges that emerge using anti-galectin-3 therapy is discussed, for example the window of opportunity when treating patients with anti-fibrotic therapy.
In Part 3, we touch upon the very interesting but undiscovered field of cardio-oncology, or what we would like to call onco-cardiology. In Chapter 9a, we demonstrate a causal
and direct relationship between HF and incidence cancer in translational research, which is further discussed in Chapter 9b. Chapter 10 shows an overview of the current known interplay between these two deadly diseases. Is it just a coincidence that patients suffer from both HF and cancer, or does one lead to the other? Finally, we discuss the findings and relevance of this thesis, as well as future perspective, in the General discussion and
RefeRenCes
1. Bots M, Buddeke J, Dis I van, Vaartjes I, Visseren F. Hart- en vaatziekten in Nederland, 2017. 2. Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D’Agostino RB, Kannel WB, Murabito JM, Vasan RS,
Benjamin EJ, Levy D. Lifetime risk for developing congestive heart failure: The Framingham Heart Study. Circulation 2002;106:3068-3072.
3. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, Meer P Van Der. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016;37:2129-2200. 4. Lam CSP, Gamble GD, Ling LH, Sim D, Leong KTG, Yeo PSD, Ong HY, Jaufeerally F, Ng TP, Cameron
VA, Poppe K, Lund M, Devlin G, Troughton R, Richards AM, Doughty RN. Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi-ethnic cohort study. Eur Heart J 2018;39:1770-1780.
5. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O’Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM, TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383–1392.
6. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A, I-PRESERVE Investigators. Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction. N Engl J Med 2008;359:2456–2467.
7. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ V, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock SJ, Committees CI and. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759–766. 8. Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JGF, Lip GYH, Coats AJS, Andersson
B, Kirchhof P, Lueder TG von, Wedel H, Rosano G, Shibata MC, Rigby A, Flather MD, Beta-Blockers in Heart Failure Collaborative Group. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014;384:2235–2243.
9. Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling. J Am Coll Cardiol 2000;35:569–582.
10. Braunwald E. Biomarkers in heart failure management. N Engl J Med 2008;358:2148-2159. 11. Januzzi JL, Felker GM. Surfing the biomarker tsunami at JACC: heart failure. JACC Heart Fail
2013;1:213–215.
12. Maeda K, Tsutamoto T, Wada A, Hisanaga T, Kinoshita M. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. Am Heart J 1998;135:825–832.
13. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AHB, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Her-rmann HC, McCullough PA. Rapid Measurement of B-Type Natriuretic Peptide in the Emergency Diagnosis of Heart Failure. N Engl J Med 2002;347:161-167.
14. Januzzi JL, Chen-Tournoux AA, Christenson RH, Doros G, Hollander JE, Levy PD, Nagurney JT, Nowak RM, Pang PS, Patel D, Peacock WF, Rivers EJ, Walters EL, Gaggin HK, ICON-RELOADED In-vestigators. N-Terminal Pro-B-Type Natriuretic Peptide in the Emergency Department: The ICON-RELOADED Study. J Am Coll Cardiol 2018;71:1191–1200.
15. Brunner-La Rocca H-P, Eurlings L, Richards AM, Januzzi JL, Pfisterer ME, Dahlström U, Pinto YM, Karlström P, Erntell H, Berger R, Persson H, O’Connor CM, Moertl D, Gaggin HK, Frampton CM, Nicholls MG, Troughton RW. Which heart failure patients profit from natriuretic peptide guided therapy? A meta-analysis from individual patient data of randomized trials. Eur J Heart Fail 2015;17:1252–1261.
16. Pfisterer M, Buser P, Rickli H, Gutmann M, Erne P, Rickenbacher P, Vuillomenet A, Jeker U, Dubach P, Beer H, Yoon S-I, Suter T, Osterhues HH, Schieber MM, Hilti P, Schindler R, Brunner-La Rocca H-P, TIME-CHF Investigators for the. BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 2009;301:383–392.
17. Troughton RW, Frampton CM, Brunner-La Rocca H-P, Pfisterer M, Eurlings LWM, Erntell H, Persson H, O’Connor CM, Moertl D, Karlstrom P, Dahlstrom U, Gaggin HK, Januzzi JL, Berger R, Richards AM, Pinto YM, Nicholls MG. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J 2014;35:1559–1567.
18. Lok DJA, Meer P van der, la Porte PWB-A de, Lipsic E, Wijngaarden J Van, Hillege HL, Veldhuisen DJ van. Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study. Clin Res Cardiol 2010;99:323–328.
19. Lok DJ, Lok SI, Bruggink-André de la Porte PW, Badings E, Lipsic E, Wijngaarden J van, Boer RA de, Veldhuisen DJ van, Meer P van der. Galectin-3 is an independent marker for ventricular remodel-ing and mortality in patients with chronic heart failure. Clin Res Cardiol 2013;102:103–110. 20. Suthahar N, Meijers WC, Silljé HHW, Ho JE, Liu FT, de Boer RA. Galectin-3 Activation and Inhibition
in Heart Failure and Cardiovascular Disease: An Update. Theranostics 2018;8:593-609.
21. Du W, Piek A, Schouten EM, Kolk CWA van de, Mueller C, Mebazaa A, A.Voors A, Boer RA de, Silljé HHW. Plasma levels of heart failure biomarkers are primarily a reflection of extracardiac produc-tion. Theranostics 2018;8:4155–4169.
22. O’Seaghdha CM, Hwang S-J, Ho JE, Vasan RS, Levy D, Fox CS. Elevated Galectin-3 Precedes the Development of CKD. J Am Soc Nephrol 2013;24:1470–1477.
23. Velde AR van der, Meijers WC, Ho JE, Brouwers FP, Rienstra M, Bakker SJL, Muller Kobold AC, Veldhuisen DJ van, Gilst WH van, Harst P van der, Boer RA de. Serial galectin-3 and future cardio-vascular disease in the general population. Heart 2016;102:1134–1141.
24. Boer RA de, Veldhuisen DJ van, Gansevoort RT, Muller Kobold AC, Gilst WH van, Hillege HL, Bakker SJL, Harst P van der. The fibrosis marker galectin-3 and outcome in the general population. J
Intern Med 2012;272:55–64.
25. Boer RA de, Velde AR van der, Mueller C, Veldhuisen DJ van, Anker SD, Peacock WF, Adams KF, Maisel A. Galectin-3: a modifiable risk factor in heart failure. Cardiovasc drugs Ther 2014;28:237– 246.
26. Mackinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, Simpson AJ, Forbes SJ, Hirani N, Gauldie J, Sethi T. Regulation of transforming growth factor-β1-driven lung fibrosis by galectin-3. Am J Respir Crit Care Med 2012;185:537–546.
