Novel biomarkers in chronic heart failure

| Understanding of chronic heart failure (HF) has progressed from a syndrome of disordered hemodynamics caused by alterations in the structure of the heart to one that involves intertwined molecular pathways in disarray. Accordingly, the assessment and treatment of patients with chronic HF has shifted from a focus on hemodynamics to modification of maladaptive molecular processes. Accumulating evidence shows that molecular biomarkers of disease could provide a unique window into the pathophysiology of chronic HF, potentially improving our ability to predict adverse outcomes, provide novel drug targets, and even help gauge therapeutic efficacy. The more ‘traditional’ biomarkers such as cardiac troponin, natriuretic peptides, and C‐reactive protein have been studied in large cohorts of patients with chronic HF and have relatively established clinical applications. In this Review, we summarize the properties, clinical data, and potential applications of some emerging biomarkers that could uniquely indicate the level of biomechanical stretch, inflammation, ventricular remodeling, myocardial injury, and renal dysfunction that occurs in chronic HF. We will also discuss the potential role for these biomarkers within a multimarker‐based strategy that could, in the future, lead to better care for these patients. Ahmad, T. et al. Nat. Rev. Cardiol. 9, 347–359 (2012); published online 27 March 2012; doi:10.1038/nrcardio.2012. 37 Introduction Chronic heart failure (HF) is a complex clinical syndrome that represents the end stage of various cardiac diseases and is characterized by the inability of the heart to meet the metabolic demands of the body. Chronic HF is a major cause of world-wide morbidity and mortality, affecting more than 5.6 million people in the USA, and 23 million people worldwide.1 Although chronic HF has existed at least since the days of Hippocrates in ancient Greece when physicians recorded its cardinal signs and symptoms, how we describe, evaluate, and treat this syndrome has changed substantially alongside several paradigm shifts in our understanding of the disease.2 For example, over the past 2 decades, the once-held view of chronic HF as a syndrome of disordered hemodynamics and fluid balance caused by alterations in the structure of the heart has been succeeded by a view of the disease that involves molecular pathways in disarray.2 Chronic HF is now seen as a systemic illness that involves interplay between myocardial factors, systemic inflammation, renal dysfunction, and neurohormonal activation. Our assessment and treatment of patients with chronic HF has, thus, progressed from a focus on improving hemodynamics to measuring and modifying the maladaptive molecular processes that contribute to progression of disease.3 In this Review, we summarize the properties, clinical data, and potential applications of some emerging biomarkers that uniquely capture the levels of biomechanical stretch, inflammation, ventricular remodeling, myocardial injury, and renal dysfunction that occur in chronic HF. We will also discuss the potential role for these biomarkers within a multimarker-based strategy that could lead to more-effective care of patients with chronic HF. We have restricted our discussion to those novel biomarkers that have shown substantial promise as prognostic or therapeutic tools, and have been evaluated in large cohorts of patients with chronic HF. The ‘biomarker’ paradigm in chronic HF The ‘traditional’ clinical evaluation of patients with suspected chronic HF involves a combination of medical history, physical examination, chest radiography, electro cardiography, and standard laboratory assessments. These approaches have been shown to be somewhat unreliable,4 and the need to classify chronic HF on a molecular level has prompted the widespread use of natriuretic peptides for the diagnosis, assessment, and treatment of chronic HF.4–7 B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are two peptides derived from the same precursor molecule that is synthesized by ventricular myocytes in response to hemodynamic stress. These natriuretic peptides are extremely useful in determining whether HF is the cause of acute dyspnea. Additionally, their measurement in patients with chronic HF provides powerful information about prognosis, which has led to their investigation as targets for HF therapy, with the concept that HF management ‘guided’ by natriuretic peptides would be superior to standard HF therapy alone.8 The measurement of natriuretic peptides in combination with other established biomarkers of chronic HF that indicate myocardial Competing interests M. Fiuzat, G. M. Felker and C. O’Connor declare associations with the following companies: BG Medicine, Critical Diagnostics, and Roche. See the article online for full details of the relationships. T. Ahmad declares no competing interests. REVIEWS © 2012 Macmillan Publishers Limited. All rights reserved 348 | JUNE 2012 | VOLUME 9 www.nature. com/nrcardio necrosis (cardiac troponins; cTn) and inflammation (C-reactive protein measured with a high-sensitivity assay; hs-CRP) appear to improve risk prediction.9,10 Nevertheless, the complexity of biochemical networks that underlie the pathophysiology of chronic HF suggests that not even measurement of established markers accurately reflects all the features of the disease, and that the combined use of several indices might be required for comprehensive characterization of this syndrome. Over the past 2 decades, new classes of blood-derived biomarkers have emerged that could provide improved insight into the complex processes that characterize the disease (Figure 1 and Table 1). 3 The discovery and clinical implementation of these biomarkers could present novel opportunities to improve understanding of chronic HF and the care of patients with this disease. Specifically, applying a multimarker approach that reflects the variety of molecular processes involved in chronic HF might allow for improved diagnosis, treatment, and manage ment (Figure 2). Although the term ‘biomarker’ can be used to indicate the results of standard laboratory tests, physiological tests, and tissue biopsies as well as genetic variants and clinical images, for the purposes of this Review, we will focus on some of the protein-based, individual, novel biomarkers that have been evaluated over the past decade in large cohorts of patients with chronic HF. Although no formal categories of biomarkers exist, we will classify novel biomarkers according to the broad categories of patho physiological processes that they represent with the caveat that, owing to the interactive nature of the biology of chronic HF, some overlap may exist (Figure 1). Several bio markers have been characterized for each of these processes; these vary greatly in ease of measurement, cost, turnaround time, and evaluation in the clinical setting. Myocardial stress Mid-regional pro-adrenomedullin Adrenomedullin is a 52-amino-acid peptide with potent vasodilatory and natriuretic effects, first isolated in 1993 from human pheochromocytomas.11 Various cells within the cardiovascular system, including vascular endo thelial cells, smooth muscle cells, cardiac fibroblasts, and myocytes, have been shown to secrete adrenomedullin, and Key points ■ Chronic heart failure is a major health problem that results from maladaptive signaling within intertwined molecular pathways ■ Several novel biomarkers have been identified that allow measurement of the multitude of molecular processes involved in the pathophysiology of chronic heart failure ■ The clinical use of biomarkers could result in improved diagnosis, risk assessment, and treatment of patients with chronic heart failure ■ Considerable interest exists in the use of a multimarker strategy for parallel evaluation of traditional and novel biomarkers in patients with chronic heart failure ■ The goal of a multimarker strategy would be to classify chronic heart failure on a molecular basis and tailor therapies accordingly ■ New therapies for chronic heart failure could emerge from the measurement of novel biomarkers in patients with this condition mRNA levels of this hormone are upregulated in response to hemodynamic stress.11 The cardiovascular effects of adrenomedullin occur via increased concentrations of its second messenger cAMP in vascular smooth muscle and by simulation of endothelial cells to release nitric oxide.12 Upregulation of adrenomedullin in cardiac disease appears to represent a cardioprotective mechanism, especially given its favorable effects on cardiac hemodynamics.13,14 Plasma levels of adrenomedullin are elevated in chronic HF as well as in various other diseases, including athero sclerosis, arterial hypertension, pulmonary hypertension, glomerulonephritis, chronic renal failure, and sepsis.14 In patients with chronic HF, adrenomedullin level is positively correlated with NYHA classification and left ventricular end diastolic pressure (LVEDP). 15–17 Initial clinical studies showed that adrenomedullin level has independent prognostic utility in patients with systolic HF and identified patients who would benefit from β-blocker therapy.17,18 However, clinical application of adrenomedullin measurement has been impeded by unreliability of plasma measurements; the peptide has a plasma half-life of 22 min and is bound to a specific protein in the plasma.19 Fortunately, assays are now available that can detect the stable prohormone, fragment mid-regional pro-adrenomedullin (MR-proADM), levels of which mirror those of the mature hormone.20 Several studies in patients with varying degrees of chronic HF have shown that an elevated level of MR-proADM is strongly associated with adverse outcomes, independent of established risk factors such as increased levels of BNP and creatinine, reduced left ventricular ejection fraction (LVEF), and NYHA class.14,17,21 However, data from preliminary studies are conflicting