Associate Professor, Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden
Myocardial remodelling occurs in response to primary cardiac or extra-cardiac diseases, and can stimulate release of various circulating biomarkers. The potential of using these markers for diagnosing and monitoring dogs and cats with cardiac diseases in clinical practice has over the last years gained interest. Different biomarkers can provide information about different aspects of cardiovascular diseases: Some cardiac biomarkers will, at best, “only” have value for understanding pathophysiological aspects of heart disease, whereas others have a value in improving clinical management of patients. A combination of biomarkers (a so-called “multimarker” approach) has the potential to further improve assessment/handling of the individual cardiac patient: Each included marker can provide slightly different information from the pathologic features of the heart disease, and the combination of results can provide more information than one marker alone. The use of multimarker techniques is already widely used in veterinary medicine (such as a “hepatic panel”), and in the future we might also use such strategies for our cardiac patients.
This presentation will focus on cardiac troponin I (cTnl) and N-terminal pro-B-type natriuretic peptide (NTpro BNP), which are the circulating cardiac biomarkers most extensively investigated, and for which evidence exists for a value in the clinical situation
During progression of heart disease, comp lex neuroendocrine activation takes place in order to maintain cardiac output and adequate tissue perfusion. Important mechanisms include up-regulation of the sympathetic nervous system and the reninangiotensin-aldosterone system (RAAS). Although these compensatory mechanisms initially improve cardiovascular function, their activity leads to gradually increased peripheral vascular resistance and fluid retention with deterioration of myocardial function and promotion of adverse myocardial remodelling. Natriuretic peptides are produced and secreted into the plasma in response to volume expansion and pressure overload in the myocardial wall, but also in response to other stimuli such as angiotension II and endothelin-1. B-type natriuretic peptide (BNP) is the natriuretic peptide that has been most intensively studied in recent years. BNP is constitutively synthesized as high molecular weight precursors (proBNP) in atrial myocytes and small amounts of proBNP are intracellularly stored in membrane-bound granules for later release. Increased release requires increased synthesis (in response to stretching of myocardial walls), and in patients with myocardial disease, the major site of BNP production may then switch from the atria to the ventricles. In response to stress, proBNP is cleaved into two smaller peptides, which are released into plasma: One low molecular weight, biologically active segment in the C-terminal region (C-BNP), and one biologically inactive N-terminal segment (NT-proBNP). The bioactive C-BNP of each peptide is released in equimolar quantity to the inactive NT-proBNP. Due to the longer half-lives of inactive segments, in addition to that C-BNP is regarded as more sensitive to collection and storage methods, NT-proBNP is regarded as the more reliable analyte for diagnostic use.
The principal physiologic actions of BNP generally oppose those exerted by the RAAS and the sympathetic nervous system in order to protect the cardiovascular system from volume overload: Natriuresis and diuresis are induced by inhibited tubular sodium transport in the renal medullary-collecting ducts and suppression of renin release by the kidney and aldosterone release from the adrenal cortex. Additional action include vasorelaxation of systemic and pulmonary arterioles; leading to decreased systemic and pulmonic vascular resistance.
Plasma NT-proBNP concentrations correlate with pulmonary capillary wedge pressure, which is an indirect measurement of left atrial pressure. This is of value in a clinical situation as the left atrial pressure increase with increasing left sided cardiac volume overload. NT-proBNP has been established as an important biomarker in diagnosing and prognosticating congestive heart failure (CHF) in people, and NT-proBNP is also considered important in early detection of ventricular dysfunction. Results from different studies in dogs and cats indicate that increased NT-proBNP concentration can distinguish cats and dogs with CHF from those with noncardiac causes of dyspnea with a rather high degree of accuracy. Concentrations of natriuretic peptides have been shown to increase with increasing disease severity in dogs with myxomatous mitral valve disease (MMVD), and NT-proBNP concentration has been shown predicative of outcome. Furthermore, higher NT-proBNP concentrations have been found in dogs affected by the clinical stage of dilated cardiomyopathy (DCM) compared to dogs affected by pre-clinical DCM. Various studies indicate that NT-proBNP has a potential in distinguishing healthy cats from cats with pre-clinical cardiomyopathy, but the capacity of NT-proBNP for this purpose in a screening situation need to be further evaluated.
Although the use of NT-proBNP in dogs and cats seem promising, further studies need to be conducted in order to optimize the clinical use of this biomarker.
Cardiac troponins are myofibril proteins, which by regulating the calcium-mediated action between actin and myosin filaments in the myocytes are crucial for muscle contraction. The cardiac troponin complex is composed of three subunits, troponin C, T and I, of which cardiac troponin I (cTnl) is the only one uniquely expressed in the myocardium. Myocyte injury causes a release of troponins into the circulation. If the rate of release exceeds the rate of synthesis, the myocardium may become partially depleted of troponins, affecting the contractile function. In the veterinary community, several studies have convincingly shown the ability of cTnl to detect myocardial lesions where other conventional diagnostic methods fail. The value of cTnl as a cardiac biomarker in dogs and cats is supported by studies demonstrating increased circulating cTnl concentrations in animals with a variety of etiologies of cardiac injuries.
Several studies have been conducted in order to investigate the utility of cTnl in dogs and cats with primary heart disease, such as DCM (dogs), MMVD (dogs), hypertrophic cardiomyopathy (HCM, cats) and different congenital heart diseases. Studies in dogs affected by MMVD show that cTnl concentration, assessed by high-sensitivity tests, is associated with disease severity. However, although circulating cTnl concentration increase with increasing MMVD disease severity, a considerable overlap exist between different severity groups. Accordingly, cTnl concentration alone cannot effectively be used for cardiac disease severity assessment. Establishing prognosis in a single individual with a chronic cardiac disease is difficult. Increased cTnl concentrations have been shown linked to a worse outcome in dogs with primary cardiac diseases; however, the value of the test for prognostication of the individual patient need to be further evaluated.
Detection of secondary cardiac injury caused by extracardiac disease processes can be challenging. Extracardiac diseases, such as gastric torsion, pyometra and snake bite, causing secondary myocardial damage, have been shown to be associated with increased cTnl concentrations. cTnl concentration has, furthermore, been shown to be a predictor of short-term death in dogs with systemic inflammation (and without a primary cardiac disease). In order to reduce the risk of sudden death, or marked influence on long-time survival, dogs with evidence of myocardial injury may benefit from restricted exercise until the acute myocardial injury has healed.
Measurement of cTnl concentrations can be valuable both for detecting and monitoring myocardial injury. Assessment of circulating biomarkers are unlikely to perform well to establish a specific cardiac diagnosis, but altered biomarker concentrations can provide the impetus to pursue additional and more definitive diagnostics, and contribute to optimal case management.
1. Hamacher L, Dorfelt R, Muller M, Wess G. Serum cardiac troponin I concentrations in dogs with systemic inflammatory response syndrome. J Vet Intern Med. 2015;29(1):164–170.
2. Langhorn R, Oyama MA, King LG, Machen MC, Trafny DJ, Thawley V, et al. Prognostic importance of myocardial injury in critically ill dogs with systemic inflammation. J Vet Intern Med. 2013;27(4):895–903.
3. Wess G, Simak J, Mahling M, Hartmann K. Cardiac troponin I in Doberman Pinschers with cardiomyopathy. J Vet Intern Med. 2010;24(4):843–849.
4. Ljungvall I, Hoglund K, Tidholm A, Olsen LH, Borgarelli M, Venge P, et al. Cardiac Troponin I is associated with severity of myxomatous mitral valve disease, age, and C-reactive protein in dogs. J Vet Intern Med. 2010;2(4):153–159.
5. Oyama MA, Sisson DD. Cardiac troponin-1 concentration in dogs with cardiac disease. J Vet Intern Med. 2004;18(6):831–839.
6. Singletary GE, Rush JE, Fox PR, Stepien RL, Oyama MA. Effect of NT-pro BNP assay on accuracy and confidence of general practitioners in diagnosing heart failure or respiratory disease in cats with respiratory signs. J Vet Intern Med. 2012;26(3):542–546.
7. Hezzell MJ, Boswood A, Chang YM, Moonarmart W, Souttar K, Elliott J. The combined prognostic potential of serum high-sensitivity cardiac troponin I and N- terminal pro-8 -type natriuretic peptide concentrations in dogs with degenerative mitral valve disease. J Vet Intern Med. 2012;26(2):302–311.
8. Pelander L, Ljungvall I, Haggstrom J. Myocardial cell damage in 24 dogs bitten by the common European viper (Vipera berus). Vet Rec. 2010;166(22):687–690.