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Abstract

Cardiotoxicity due to tumoricidal drug use is defined as an asymptomatic reduction in left ventricular (LV) ejection fraction (EF) of ≥ 10% to <55% or as a reduction of the LVEF of ≥ 5% to <55% with symptoms of heart failure (HF). The implementation in routine practices the highly tumoricidal anthracycline drugs, taxanes, and trastuzumab cause progressive LV dysfunction and symptomatic HF in dose-dependent manner. Despite there is potent reversibility of tumoricidal drug-induced cardiotoxicity, this adverse effect frequently consists continuously and might lead to limited response to medical treatment and worse survival sufficiently. The aim of the mini review is consideration the clinical evidence that supports the use of cardiac biomarkers for early detection of cardiotoxicity. The review is reported that the identification of cancer patient with increased risk of early cardiotoxicity would allow not only prevention and diagnosis of chemotherapy related cardiotoxicity but also administration of optimal dose and duration of chemotherapy. The predictive role of brain natriuretic peptides, cardiac troponins, microRNAs, S100A1 and inflammatory biomarkers (C-reactive protein) is discussed.

Key words

 cardiotoxicity, anti-neoplastic chemotherapy, biomarkers, natriuretic peptides, C-reactive protein, troponins, risk stratification

Introduction

Cardiotoxicity as resulting in anti-neoplastic chemotherapy, radiation therapy, and targeted agents is well recognized and frequently considered an expected adverse effect [1]. The implementation in routine practice the highly tumoricidal anthracycline drugs, taxanes, and trastuzumab cause progressive left ventricular (LV) dysfunction and symptomatic heart failure (HF) in dose-dependent manner [2,3]. The improved survival rate raises the likelihood that patients will experience wide spectrum cardiotoxicity: from asymptomatic diastolic dysfunction to acute severe HF [4]. Although reversibility of tumoricidal drug-induced cardiotoxicity is possible [5,6], in generally, this adverse effect frequently consists continuously and might lead to limited response to medical treatment and worse survival sufficiently [7,8]. Despite the majority of patients with LVEF decline from cancer therapy could achieve full LVEF recovery and complete their cancer therapy, there is no consensual agreement regarding strategy to management cardiac dysfunction in this patient population [9]. Additionally, there are no developed clinical guidelines for early detection of cardiotoxicity too. It has been suggested that biomarkers, most prominently brain natriuretic peptides (BNPs), cardiac troponins, inflammatory biomarkers (C-reactive protein, soluble ST, galectin-3) and signature microRNAs might have utility to stratify the patients at risk of potential cardiac dysfunction at early stage before clinical manifestation [10,11]. The aim of the mini review is consideration the clinical evidence that supports the use of cardiac biomarkers for early detection of cardiotoxicity.

Definition of cardiotoxicity

According Cardiac Review and Evaluation Committee criteria cardiotoxicity due to tumoricidal drug use is generally characterized by an asymptomatic reduction in LVEF of ≥ 10% to <55% or, less often, as a reduction of the LVEF of ≥ 5% to <55% with symptoms of HF [12]. The cardiac dysfunction associated with anthracycline therapy leads to significantly decline of LVEF and frequently associates with asymptomatic and symptomatic HF, whereas trastuzumab-induced cardiotoxicity is most often reversible upon discontinuation of treatment and initiation of standard medical care for HF [13,14].

Molecular pathogenic mechanisms underlying anthracycline-induced cardiac toxicity

It is well known that pivotal role in anthracycline-induced cardiotoxicity belongs to oxidative stress, which mediates worse of myofilament protein synthesis, destroying structured protein, and cytoskeleton, and as well as apoptosis of cardiac myocytes [15-17]. Therefore, anthracycline is able to suppress reparative capable of cardiac myocytes via inhibition of cardiac progenitor cells mobbing and differentiation [18,19]. It has been suggested that calcium overload resulting in alterations in cardiac myocites metabolism leads to ultrastructural changes in cytoskeleton and mediates development of asymptomatic myocardial dysfunction and subsequently clinically manifested HF [20,21]. Thus, molecules that are able reflect these multiple faces of pathophysiology of cardiotoxicity are considered potent surrogate candidates in biomarkers with diagnostic and predictive value.

Biomarkers of cardiotoxicity

Radiotherapy and drug exposure with anthracyclines, monoclonal antibodies, fluoropyrimidines, taxanes, alkylating agents, vinka alkaloids were reported to induce different clinical manifestations of cardiotoxicity including development of cardiac dysfunction. In this context, some biomarkers may be used to evaluate cardiac damage and clinical events in follow up. The promising biomarkers of cardiotoxicity are reported in Table 1.

Biomarkers	Relation to pathophysiological process	Clinical relevance	Reference
NPs	Biomechanical stress	Could indicate acute subclinical cardiotoxicity	[28-30]
Troponins	Cardiac injury	Independent predictor of the cardiotoxicity	[25,32]
Oxidative stress components	Cardiac injury, inflammation	Lack of evidence regarding prediction of cardiotoxicity	[36]
hs-CRP	Inflammation	Prediction in decreased LV pump function and early cardiotoxicity	[37,38]
S100A1	Cardiomyocyte integrity	Prognostication in heart failure and early cardiotoxicity	[42-44]
miRNAs	Regulators of expression of protein-coding genes	Prognostication in early cardiotoxicity	[47-49]
Placental growth factor	Angiogenesis, neovascularization	Unknown	-
Soluble FMS-like tyrosine kinase receptor-1	Vascular remodeling	Unknown	-

Table 1. The promising biomarkers of cardiotoxicity

Abbreviations: NPs, natriuretic peptides; hs-CRP, high-sensitivity C-reactive protein; LV, left ventricular.

Brain natriuretic peptides

Because of assessment of the LVEF fails to detect subtle alterations in cardiac function in chemotherapy-treated patients, BNPs could predict future cardiac dysfunction. Current clinical guidelines serve measurement of BNP as a marker of biomechanical stress for diagnostic and predictive value in generally population patients at high risk of HF development and in those who have acute or symptomatic chronic HF with volume overload [22-25]. Theoretically, cardiac dysfunction as result in chemotherapy might reflect in stretching of cardiac wall and secretion of BNP in circulation. However, the received results were controversial and frequently relate to treatment regime, the adjuvant setting and concomitant therapy. Sawaya et al. [26] reported that NT-proBNP did not predict cardiotoxicity patients treated with anthracyclines and trastuzumab. Fallah-Rad et al. [27] were not able to find sufficient changes in serum concentrations of troponin T, C-reactive protein, and BNP among trastuzumab-treated patients with human epidermal growth factor receptor II-positive (HER2⁺) breast cancer.

Contrary, Cil et al. [28] have found a closely association between higher NT-proBNP levels and reduced LVEF in asymptomatic breast cancer patients after doxorubicin administration. Authors have shown that NT-proBNP could be an early indication of subclinical acute anthracycline cardiotoxicity. Ürun et al. [29] have believed that women with HER2⁺ breast cancer treated with trastuzumab could early stratify at risk of cardiotoxicity with of NT-proBNP (>300 ng/ml). Moreover, Horácek et al. [30] have reported that transient elevation of NT-proBNP may indicate acute subclinical cardiotoxicity in anthracycline-treated patients with acute myeloid leukemia. Thus, it seems to be that NT-proBNP could be useful in the early detection of anthracycline cardiotoxicity [31], while trastuzumab-induced cardiotoxicity is probably not defined by measurement of serum NT-proBNP [32].

High-sensitivity cardiac troponins

The results regarding predictive value of high-sensitivity cardiac troponins in anthracycline and trastuzumab cardiotoxicity are controversial. This controversial relates that anthracyclines, even in higher cumulative doses, do not usually cause detectable acute injury to cardiomyocyte structure. Indeed, Horacek et al. [32] reported that high-sensitivity cardiac troponin T was not elevated in patients treated for acute leukemia with anthracycline, although serum level of NT-proBNP was elevated sufficiently and could be useful in the early detection of anthracycline cardiotoxicity. In another study, in contrast to BNP, elevated high-sensitivity cardiac troponin I level was proposed an independent predictor of the development of cardiotoxicity at 6 months in cancer patients treated with anthracyclines and trastuzumab [25]. Additionally, there are evidences regarding that the early increase in high-sensitivity cardiac troponin I might offer additive information about the cardiotoxicity risk in cancer patients undergoing doxorubicin and trastuzumab therapy [33-35]. Interestingly, there was not a sufficient correlation between cTnT and oxidative stress parameters [36]. In this context, commonly used biomarkers of oxidative stress cannot reliably predict cardiovascular dysfunction, whereas circulating cardiac troponins remained attractive as a marker of cardiotoxicity. Overall, biochemical markers of structural and functional myocardial damage, such as cardiac troponins, might have utility in cardiotoxicity monitoring in doxorubicin- and trastuzumab-treated individuals.

High-sensitivity C-reactive protein

High-sensitivity C-reactive protein (hs-CRP) is discussed a predictive biomarker of increased risk of cardiotoxicity among cancer patients treated with anthracycline and trastuzumab [37]. Onitilo et al. [38] reported that elevated hs-CRP (≥ 3 mg/L) predicted decreased LVEF with a sensitivity of 92.9% and specificity of 45.7% in patients with early HER2⁺ breast cancer. Interestingly, author found that the maximum hs-CRP value was observed a median of 78 days prior to detection of cardiotoxicity by decreased LVEF, and those with normal levels were at lower risk for cardiotoxicity. This result opens a perspective to regular monitoring of hs-CRP level for identifying women with early-stage breast cancer at low risk for asymptomatic trastuzumab-induced cardiotoxicity. In contrast, Lipshultz et al. [39] did not find closely association between increased hs-CRP and any echocardiographic variables in doxorubicin-treated subjects with acute lymphoblastic leukemia, although cardiac troponin T and NT-proBNP were related to an abnormal LV thickness-to-dimension ratio, suggesting LV remodeling. In general, definitive validation studies are required to fully establish clinical utility of hs-CRP in cancer patients as biomarker of cardiotoxicity.

S100A1

S100A1 is a Ca²⁺ binding protein of the EF-hand type that belongs to a family of multifunctional proteins characterized by predominantly specific expressions in heart, to a lesser degree in skeletal muscle, and at low levels in most normal tissues [40]. There is evidence regarding ability of S100A1 to improve cardiac contractile performance both by regulating sarcoplasmic reticulum Ca²⁺ handling and myofibrillar Ca²⁺ responsiveness [41]. In animal studies down-regulation of S100A1 protein was shown to contribute to cardiac failure after acute myocardial infarction via impaired Ca²⁺cycling, β adrenergic signaling, induce oxidative stress and mitochondrial dysfunction and [42,43].

Eryilmaz et al. (2015) [44] reported that trastuzumab and lapatinib could induce cardiotoxicity via free-radical-induced alteration of the expressions affected both troponin I and S100A1. Because S100A1 is up-regulated only in cancers of kidneys, skin and ovary, authors concluded that S100A1 might become promising biomarker in assessing the state of myocardium exposed to toxicity accompanying to hs-CRP and cardiac troponins [44]. Whether S100A1 might help to detect subclinical cardiotoxicity at early stage is not clear.

MicroRNAs

MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that are able to modulate post-processing in target cells via regulating expression of protein-coding genes [45]. Wide spectrum of skeletal muscle- and cardiac-specific miRNAs (miRNA-12, miRNA-133a, miRNA-124 and miRNA 208) miRNAs has been investigated as circulating biomarkers of myotoxicity [46]. Because several miRNAs have exhibit tissue specificity, stability in extracellular space, high conservation between preclinical test species, and might express as response on direct tissue injury, it has been suggested that signature of microRNAs might be useful as biomarkers of cardiac injury [47,48]. Calvano, et al. [47] reported that miRNA-133a/b are sensitive and specific markers of skeletal muscle and cardiac toxicity and that miRNA-208 used in combination with miRNA-133a/b can be used to differentiate cardiac from skeletal muscle toxicity. Desai et al. [49] using a chronic doxorubicin cardiotoxicity mouse model found that pro-apoptotic miRNA-34a showed a significant dose-related up-regulated and was associated with down-regulation of hypertrophy-related miRNA-150. Authors suggested that these findings may lead to the development of biomarkers of earlier events in doxorubicin-induced cardiotoxicity that occur before the release of cardiac troponins [49]. By now, the development of miRNAs as clinical biomarkers has been hindered by the lack of standardization [50]. In this context, extracellular miRNA-based biomarkers have not been embraced as diagnostic tools, while their implication in early drug toxicity is considered as very attractive.

Future perspectives

Because of biomechanical stress biomarkers (BNP, NT-proBNP), markers of myocardial injury (cardiac troponis) and inflammation (hs-CRP) are not specific for cardiotoxicity and might not help to sufficiently individualize treatment by immediately identifying cardiac injury and HF, novel biomarkers are discovered widely. It has been suggested that several cardiac biomarkers reflected inflammatory reactions and oxidative stress, i.e. growth differentiation factor-15, myeloperoxidase, galectin-, miRNAs, and S100A1 could useful for prediction of the risk of early cardiotoxicity. Probably, biomarkers of angiogenesis (placental growth factor), vascular remodeling (soluble FMS-like tyrosine kinase receptor-1) might be demonstrated the benefit in this setting too. In this context, more investigations are required to consolidate our knowledge regarding utility of biomarkers of cardiotoxicity in cancer patients.

Conclusion

In conclusion, one can suggest that the identification of cancer patients with increased risk of early cardiotoxicity would allow not only prevention and diagnosis of chemotherapy related cardiotoxicity but also administration of optimal dose and duration of chemotherapy. However, the determining optimal biomarker(s) for risk stratification strategy is not completely clear and requires more investigations.

References

1. http://seer.cancer.gov/csr/1975_2012/
2. Marinko T, Dolenc J, Bilban-Jakopin C (2014) Cardiotoxicity of concomitant radiotherapy and trastuzumab for early breast cancer. Radiol Oncol 48: 105-112. [Crossref]
3. Patnaik JL, Byers T, Diguiseppi C, Dabelea D, Denberg TD (2011) Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res 13: R64. [Crossref]
4. Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR (2007) Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 50: 1435-1441. [Crossref]
5. Guglin M, Cutro R, Mishkin JD (2008) Trastuzumab-induced cardiomyopathy. J Card Fail 14: 437-444. [Crossref]
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6. Ewer MS, Vooletich MT, Durand JB, Woods ML, Davis JR, et al. (2005) Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 23: 7820-7826. [Crossref]
7. Hooning MJ, Botma A, Aleman BM, Baaijens MH, Bartelink H, et al. (2007) Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 99: 365-375. [Crossref]
8. Thakur A, Witteles RM (2014) Cancer therapy-induced left ventricular dysfunction: interventions and prognosis. J Card Fail 20: 155-158. [Crossref]
9. Geiger S, Lange V, Suhl P, Heinemann V, Stemmler HJ (2010) Anticancer therapy induced cardiotoxicity: review of the literature. Anticancer Drugs 21: 578-590. [Crossref]
10. Tian S, Hirshfield KM, Jabbour SK, Toppmeyer D, Haffty BG, et al. (2014) Serum biomarkers for the detection of cardiac toxicity after chemotherapy and radiation therapy in breast cancer patients. Front Oncol 4: 277. [Crossref]
11. Khouri MG, Douglas PS, Mackey JR, Martin M, Scott JM, et al. (2012) Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues. Circulation 126: 2749-2763. [Crossref]
12. Martin M, Esteva FJ, Alba E, Khandheria B, Perez-Isla L, et al. (2009) Minimizing cardiotoxicity while optimizing treatment efficacy with trastuzumab: review and expert recommendations. Oncologist 14: 1–11. [Crossref]
13. Tan-Chiu E, Yothers G, Romond E, Geyer CE, Jr, Ewer M, et al. (2005) Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23: 7811–7819. [Crossref]
14. Ganame J, Claus P, Eyskens B, Uyttebroeck A, Renard M, et al. (2007) Acute cardiac functional and morphological changes after Anthracycline infusions in children. Am J Cardiol 99: 974-977. [Crossref]
15. De Keulenaer GW, Doggen K, Lemmens K (2010) The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ Res 106: 35-46. [Crossref]
16. Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, et al. (2002) Conditional mutation of the ErbB (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci USA 99: 8880-8885. [Crossref]
17. Lim CC, Zuppinger C, Guo X, Kuster GM, Helmes M, et al. (2004) Anthracyclines induce calpain-dependent titin proteolysis and necrosis in cardiomyocytes. J Biol Chem 279: 8290-8299. [Crossref]
18. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56: 185-229. [Crossref]
19. De Angelis A, Piegari E, Cappetta D, Marino L, Filippelli A, et al. (2010) Anthracycline cardiomyopathy is mediated by depletion of the cardiac stem cell pool and is rescued by restoration of progenitor cell function. Circulation 121: 276-292. [Crossref]
20. Yeh ET, Bickford CL (2009) Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 53: 2231-2247. [Crossref]
21. Chen B, Peng X, Pentassuglia L, Lim CC, Sawyer DB (2007) Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol 7: 114-121. [Crossref]
22. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr., et al. (2013) 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 62: e147–e239. [Crossref]
23. Dworzynski K, Roberts E, Ludman A, Mant J4; Guideline Development Group of the National Institute for Health and Care Excellence (2014) Diagnosing and managing acute heart failure in adults: summary of NICE guidance. BMJ 349: g5695. [Crossref]
24. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, et al. (2012) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 14: 803-869. [Crossref]
25. Moe GW, Ezekowitz JA, O'Meara E, Lepage S, Howlett JG, et al. (2015) The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications. Can J Cardiol 31: 3-16. [Crossref]
26. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, et al. (2011) Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol 107: 1375-1380. [Crossref]
27. Fallah-Rad N, Walker JR, Wassef A, Lytwyn M, Bohonis S, et al. (2011) The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy. J Am Coll Cardiol 57: 2263-2270. [Crossref]
28. Cil T, Kaplan AM, Altintas A, Akin AM, Alan S, et al. (2009) Use of N-terminal pro-brain natriuretic peptide to assess left ventricular function after adjuvant doxorubicin therapy in early breast cancer patients: a prospective series. Clin Drug Investig 29: 131-137. [Crossref]
29. Ürun Y, Utkan G, Yalcin B, Akbulut H, Onur H, et al. (2015) The role of cardiac biomarkers as predictors of trastuzumab cardiotoxicity in patients with breast cancer. Exp Oncol 37: 53-57. [Crossref]
30. Horácek JM, Pudil R, Tichý M, Jebavý L, Strasová A, et al. (2005) The use of biochemical markers in cardiotoxicity monitoring in patients treated for leukemia. Neoplasma 52: 430-434. [Crossref]
31. Kittiwarawut A, Vorasettakarnkij Y, Tanasanvimon S, Manasnayakorn S, Sriuranpong V (2013) Serum NT-proBNP in the early detection of doxorubicin-induced cardiac dysfunction. Asia Pac J Clin Oncol 9: 155-161. [Crossref]
32. Horacek JM, Pudil R, Jebavy L, Tichy M, Zak P, et al. (2007) Assessment of anthracycline-induced cardiotoxicity with biochemical markers. Exp Oncol 29: 309-313. [Crossref]
33. Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, et al. (2014) Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 63: 809-816. [Crossref]
34. Katsurada K, Ichida M, Sakuragi M, Takehara M, Hozumi Y, et al. (2014) High-sensitivity troponin T as a marker to predict cardiotoxicity in breast cancer patients with adjuvant trastuzumab therapy. Springerplus 3: 620. [Crossref]
35. Pistillucci G, Ciorra AA, Sciacca V, Raponi M, Rossi R, et al. (2015) [Troponin I and B-type Natriuretic Peptide (BNP) as biomarkers for the prediction of cardiotoxicity in patients with breast cancer treated with adjuvant anthracyclines and trastuzumab]. Clin Ter 166: e67-71. [Crossref]
36. Mladenka P, Filipský T, Ríha M, Vávrová J, Holecková M, et al. (2014) The relationship of oxidative stress markers and parameters of myocardial function in a rat model of cardiotoxicity. Free Radic Biol Med 75 Suppl 1: S42.
37. Zethelius B, Berglund L, Sundström J, Ingelsson E, Basu S, et al. (2008) Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med 358: 2107-2116. [Crossref]
38. Onitilo AA, Engel JM, Stankowski RV, Liang H, Berg RL, et al. (2012) High-sensitivity C-reactive protein (hs-CRP) as a biomarker for trastuzumab-induced cardiotoxicity in HER2-positive early-stage breast cancer: a pilot study. Breast Cancer Res Treat 134: 291-298. [Crossref]
39. Lipshultz SE, Miller TL, Scully RE, Lipsitz SR, Rifai N, et al. (2012) Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J Clin Oncol 30: 1042-1049. [Crossref]
40. Duarte-Costa S, Castro-Ferreira R, Neves JS, Leite-Moreira AF (2014) S100A1: a major player in cardiovascular performance. Physiol Res 63: 669-681. [Crossref]
41. Most P, Bernotat J, Ehlermann P, Pleger ST, Reppel M, et al. (2001) S100A1: a regulator of myocardial contractility. Proc Natl Acad Sci USA 98: 13889-13894. [Crossref]
42. Most P, Seifert H, Gao E, Funakoshi H, Völkers M, et al. (2006) Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction. Circulation 114: 1258-1268. [Crossref]
43. Willis BC, Salazar-Cantu A, Silva-Platas C, Fernandez-Sada E, Villegas CA, et al. (2014) Impaired oxidative metabolism and calcium mishandling underlie cardiac dysfunction in a rat model of post-acute isoproterenol-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 308:  H467–477.  [Crossref]
44. Eryilmaz U, Demirci B, Aksun S, Boyacioglu M, Akgullu C, et al. (2015) S100A1 as a Potential Diagnostic Biomarker for Assessing Cardiotoxicity and Implications for the Chemotherapy of Certain Cancers. PLoS One 10: e0145418. [Crossref]
45. Hruštincová A, Votavová H, Dostálová Merkerová M (2015) Circulating MicroRNAs: Methodological Aspects in Detection of These Biomarkers. Folia Biol (Praha) 61: 203-218. [Crossref]
46. Laterza OF, Lim L, Garrett-Engele PW, Vlasakova K, Muniappa N, et al. (2009) Plasma MicroRNAs as sensitive and specific biomarkers of tissue injury. Clin Chem 55: 1977-1983. [Crossref]
47. Calvano J, Achanzar W, Murphy B, DiPiero J, Hixson C, et al. (2015) Evaluation of microRNAs-208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats. Toxicol Appl Pharmacol. [Crossref]
48. Tonomura Y, Mori Y, Torii M, Uehara T (2009) Evaluation of the usefulness of biomarkers for cardiac and skeletal myotoxicity in rats. Toxicology 266: 48-54.
49. Desai VG, C Kwekel J, Vijay V, Moland CL, Herman EH, et al. (2014) Early biomarkers of doxorubicin-induced heart injury in a mouse model. Toxicol Appl Pharmacol 281: 221-229. [Crossref]
50. Wang W, Shi Q, Mattes WB, Mendrick DL, et al. (2015) Translating extracellular microRNA into clinical biomarkers for drug-induced toxicity: from high-throughput profiling to validation. Biomark Med 9: 1177-1188. [Crossref]