ReviewCardiac biomarkers in heart failure
Introduction
Heart failure (HF) is a syndrome characterized by the inability of the heart to meet the circulatory demands of the body leading to many symptoms including dyspnea and fatigue. HF can arise from a host of conditions involving the myocardium or heart valves. HF occurs in about equal frequency with and without a reduced ventricular ejection fraction (EF). Each of these categories accounts for approximately 50% of all cases [1]. Regardless of category, HF is staged according to the American College of Cardiology/American Heart Association guidelines (Table 1) [2]. Additionally, a patient's functional status can be classified according to the New York Heart Association classification (Table 1) [2]. As can be seen from Table 1, there is overlap between HF stage and NYHA classification of symptoms.
HF is a burgeoning health and healthcare problem. There are an estimated 20 million affected individuals worldwide [3], of which 5.7 million are in the United States [4]. HF accounts for over one million hospitalizations in the United States, over three million physician office visits, and nearly 57,000 deaths annually [4]. In Canada hospitalizations for heart failure were reported as more than 106,000 annually [5]. The prevalence of HF is expected to continue to rise as early detection therapies for myocardial infarction (MI), valvular diseases and arrhythmias improve, thereby allowing patients to survive longer [3].
Despite its high prevalence, the diagnosis of HF remains difficult as none of the signs and symptoms are specific or particularly sensitive. Due to this, history and physical examination may not be sufficient to reach the diagnosis. Traditional adjuncts to diagnosis include echocardiography, stress testing, and various forms of radionuclide imaging. Each of these has their short-comings and for this reason, diagnostic aids in the form of blood-based biomarkers have been sought. Much research for the past decade has examined numerous possible biomarkers and in general these biomarkers can be broken down into six categories: markers of inflammation; extracellular matrix turnover and remodeling markers; markers of biochemical strain; markers of neurhormonal activation; markers of nutrition and metabolism; and markers of cardiomyocyte injury (Table 2). Given the large number of candidates, a systematic manner of assessing biomarkers and identifying those most likely to be relevant was needed. In 2007 Morrow and de Lemos [6] put forth three criteria for the evaluation of new biomarkers: first, the marker must be able to be measured reliably, quickly, and at reasonable cost; second, the marker must provide additional information that the physician cannot obtain from a historical and physical examination; and third, the marker must influence clinical decision-making.
Few biomarkers have successfully fulfilled each of these criteria. However, there are several promising targets. In this review, we will focus on markers that are either available for utilization by clinicians or have at least been evaluated rigorously in multiple research studies.
Section snippets
Markers of inflammation
Inflammation is now widely accepted as a component of the pathogenesis and progression of HF. This, however, has not always been the case. Initially, attempts were made to explain HF from a purely hemodynamic perspective. This “hemodynamic hypothesis” was unable to adequately explain the progression of HF so alternative explanations were sought. In 1996, Seta et al. put forth the “cytokine hypothesis.”[7] In this, they suggested that the progression of HF is, at least in part, explained by the
Procollagen
Collagen scar formation has been found to play an important role in the remodeling of cardiac tissue following MI and in the development of HF. For this reason markers of collagen synthesis and turnover have been studied as a non-invasive methodology to determine the extent of cardiac fibrosis.
Procollagen type III amino-terminal propeptide (PIIINP), a marker of collagen synthesis, is one of the most studied fibrosis markers. In the setting of acute MI, PIIINP has been shown to be elevated in
Natriuretic peptides
The natriuretic peptides are a group of neurohormones which affect body fluid homeostasis via natriuresis and diuresis [69]. The natriuretic peptides also decrease vasoconstriction by decreasing angiotensin II and norepinephrine synthesis [69]. There are two main types of natriuretic peptides: BNP and A-type natriuretic peptide (ANP). The most extensively studied of these peptides is BNP.
BNP is synthesized as a pre-prohormone and is released in response to volume overload and wall stress [89]
Copeptin
Arginine vasopressin (vasopressin; antidiuretic hormone; AVP; ADH) is a peptide hormone synthesized in the hypothalamus and stored in the posterior pituitary gland. ADH is known to have both antidiuretic and vasoconstrictive properties. Levels of ADH have been shown to be elevated in patients with HF [113], [114]. The excess ADH can lead to hyponatremia, fluid accumulation, and systemic vasoconstriction. Unfortunately, it is difficult to measure ADH levels as a large proportion of the hormone
Cardiac troponins
There are several markers of cardiomyocyte injury including the cardiac troponins, heart fatty acid binding protein, creatinine kinase MB and myosin light chain 1. As the troponins are currently the most clinically relevant they will be the focus of this section. The cardiac troponins are cardiac isoforms of proteins from the troponin-tropomyosin complex found in cardiomyocytes and there are two main types: cardiac troponin T (cTnT) and cardiac troponin I (cTnI). These proteins are known to be
Conclusion
During the last decade extensive research has been conducted in biomarkers and HF. While BNP and the cardiac troponins are ubiquitous in clinical practice, there are a host of other promising biomarkers which have the potential to be diagnostic, prognostic, and therapeutic aids extending from an asymptomatic general population to those hospitalized with acute HF. It is unlikely that any single one of the markers will prove to be the sole necessary aid in all HF settings. As data continues to
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