Cardiac toxicity biomarkers

Wallace KB, Hausner E, Herman E, et al. Serum troponins as biomarkers of drug-induced cardiac toxicity. Tox Path. 2004 32 106-121. 

The timing of the urine collections is a critical factor in detecting renal injury. Tubular necrosis is an event more likely to occur early in a study, and therefore urine samples are best taken during this early period, whereas renal papillary necrosis is more likely to occur in a later part of a study (Heywood 1981). In some acute cardiac toxic events, the cardiac biomarkers increase within a few hours of injury, so sampling needs to be timed within this window because later samples may not show elevations of these biomarkers. 

Since then, approximately 70 studies have been reported in the literature, and far more have been conducted internally within pharmaceutical companies, documenting the effectiveness of cTn as a biomarker to identify, assess, and monitor preclinical cardiac toxicity (O Brien 2008). This has been demonstrated for several classes of drugs, including adrenergic agents, agonists of peroxisome proliferator-activated receptors (PPAR especially for alpha-PPARs), anthracyclines and other anticancer drugs, and phosphodiesterase inhibitors. 

Circulating cardiac troponin (cTn) is the most widely used biomarker for detection of myocardial injury (Newby et al. 2011). With regard to its employment in the context of drug-induced cardiotoxicity, most data to date have examined anthracycline-based chemotherapy, and so the broader applicability of these data is currently nncertain (Christenson et al. 2015). However, a notable 2004 publication from the Expert Working Gronp on Biomarkers of Drug-induced Cardiac Toxicity (Wallace et al. 2004) reported that troponin I (cTnl) and troponin T (cTnT) are sensitive, specific, and robust biomarkers of drug-induced cardiotoxicity. 

Christenson ES, James T, Agrawal V, Park BH (2015) Use of biomarkers for the assessment of chemotherapy-induced cardiac toxicity. Clin Biochem 48 223-235 Conway A, McCarthy AL, Lawrence P, Clark RA (2015) The prevention, detection and management of cancer treatment-induced cardiotoxicity a meta-review. BMC Cancer 15 366 Cummins M, Pavlakis N (2013) The use of targeted therapies in pancreatic neuroendocrine tumours patient assessment, treatment administration, and management of adverse events. Ther Adv Med Oncol 5 286-300... 

This is not to say that cardiotoxicity is not seen with biopharmaceuticals. Cardiomyopathy is now a well-recognized complication of trastuzumab and and has been reported with bevacizumab treatment, in particular in combination with other cytotoxic cancer therapies [20]. Myocarditis and pericarditis are a well-documented complications of vaccinia immunization [21], and could also complicate use of a pox-virus vector for other therapeutics. In 1995 Genetics Institute suspended phase 2 cancer trials of Interleukin-12 for serious tox-icities including cardiac arrhythmia. However, such toxicities are best detected by incorporation of biomarkers for myocardial damage such as troponin-T into preclinical and early clinical studies, and continual ECG monitoring for arrhythmia in preclinical and early clinical studies, not by in vitro explorations of electrophysiology. 

Ongoing progress in identifying new blood, urine, or other biofluid markers of toxicity - potentially assessable in current animal models - also provides optimism that such refinements will expand the translational usefulness of these preclinical studies.6-7 Recent examples of emerging or novel biomarkers that may become mainstream toxicity markers (as in research hospital clinical pathology assessments) are troponin markers for cardiac and skeletal muscle toxicity,32 and kidney biomarkers to delineate specific regional toxic effects in the renal tubule/parenchyma.33 Further development of these and similar assessable markers of toxicity will be pursued and usefully applied both pre-clinically and clinically. 

Andersson H, Steel D, Asp J et al (2010) Assaying cardiac biomarkers for toxicity testing... 

Interim blood sampling of rats may not be necessary when the dose levels are similar in the short- and longer-duration studies. The sample timings in the guidelines refer to the core tests, but some specialized tests require samples to be collected at times in relation to the toxic injury in acute studies (e.g., cardiac biomarkers) or to expected peaks in the circadian or reproductive cycle rhythms. Additional times for blood sampling should be avoided if the procedures could compromise the health of the animals. In all procedures, consideration should be given to the possible stress effects of the sample collection procedures and the amount of blood collected in relation to the total blood volume. 

For biomarkers such as the troponins and enzymes, timing and sample collection are particularly critical for the detection of cardiac injury, and consideration must be given to the half-life of the molecule and its mass. Although some data are available for humans, data are sparse for the same measurements in laboratory animals. In general, the half-lives of these molecules are less in smaller animals. The importance of sample times has been shown in several studies where myocardial lesions have been induced by the administration of toxic doses of sympathomimetics (O Brien et al. 1997a, 2006 York et al. 2007). 

O Brien, P. J. 2006. Blood cardiac troponin in toxic myocardial injury Archetype of a translational safety biomarker. Expert Reviews in Molecular Diagnosis 6 685-702. 

Tonomura, Y, S. Matsushima, E. Kashiwagi, K. Fujisawa, S. Takagi, Y. Nishimura, R. Fukushima, M. Torii, and M. Matsubara (2012). Biomarker panel of cardiac and skeletal muscle troponins, fatty acid binding protein 3 and myosin light chain 3 for the accurate diagnosis of cardiotoxicity and musculoskeletal toxicity in rats. Toxicology 302(2-3) 179-189. 

O Brien, 2008). Biomarkers of heart failure (Mittmann et al., 1998), including natriuretic peptides that increase in response to wall stress and ST2, reflective of ventricular remodeling and cardiac fibrosis may also be a consequence of toxicity and are detailed by Maisel (2012). 

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