Role of Troponins in CardioOncology

Opinion Statement

Troponins are an integral part of the diagnosis of acute coronary syndromes in cardiology. It is also useful in many other acute cardiological conditions, such as acute pulmonary embolism. In cardio-oncology, it is part of the definition of either cancer disease or cancer therapy related cardiovascular toxicity. Change in troponin value is one of the diagnostic criteria for mild and moderate cancer therapy related cardiac dysfunction. Diagnosis of myocarditis is also based on troponin elevation. However, an ideal cut-off points for precise diagnostic value and indication for cardiology treatment have not yet been defined.It is still difficult to make therapeutic decisions in cardio-oncology about the initiation, intensification or modification of cardiac therapy based on the dynamics of troponin changes.

Introduction

The cardiac troponin (cTn) complex comprises three distinct protein subunits: troponin C (TnC), which binds calcium and modulates thin filament activation; troponin I (cTnI), which inhibits actin-stimulated myosin ATPase activity; and troponin T (cTnT), which functions as a structural linker, anchoring the troponin complex to tropomyosin.During myocardial relaxation, the cTn complex suppresses the interaction between myosin and actin filaments. During this phase, cTnI binds to actin, thereby stabilizing the troponin–tropomyosin complex through inhibition of cross-bridge formation.Following cell membrane depolarization, intracellular calcium ions increase, and calcium binds to the N-terminal domain of TnC, inducing a conformational alteration of the complex.These events result in cTnI displacement, permitting myosin–actin interaction and, consequently, cardiac muscle contraction [1–3].

Biomarkers of myocardial injury, i.e. troponin I (cTnI) and troponin T (cTnT), are released into the bloodstream even in the presence of minimal cardiomyocyte damage. Serum cTn levels correlate with the extent of myocardial injury and are generally considered cardiac-specific, reflecting their expression predominantly in cardiomyocytes and their infrequent elevation in other conditions [4].Elevated troponin I levels serve as a biomarker of increased risk for early cardiac injury [5] and frequently predict left ventricular dysfunction in patients undergoing chemotherapy [6]. In asymptomatic cancer patients, elevated cTn levels reflect complex underlying processes not limited to acute coronary syndromes, suggesting the involvement of additional pathophysiological mechanisms [7].

Troponins in the ESC Guidelines on Cardio-oncology

The European Society of Cardiology (ESC) guidelines on cardio-oncology [8] indicate the use of troponins in three main clinical dimensions: (1) as an element of the definition of cancer therapy related cardiovascular toxicity (CTR-CVT) (Table 1); (2) as an element of the baseline cardiovascular risk stratification in patients qualified for potentially cardiotoxic therapy (Table 2), (3) as a tool for monitoring cardiac safety during oncological therapy for the early detection of cardiovascular complications (Table 3).

Table 1.

Role of troponins in the definition of CTR-CVT based on the 2022 ESC guidelines on cardio-oncology [8]

Clinical situation	Detailed role of cardiac troponin
Pre-existing CVD or at risk of CTRCD	cTn and NP increased : • cTnI/T > 99th percentile, • BNP ≥ 35 pg/mL, • NT-proBNP ≥ 125 pg/mL.
Asymptomatic CTRCD - Moderate	New LVEF reduction by > 10% points to an LVEF of 40– 49% AND either new relative decline in GLS by > 15% from baseline OR new rise in cardiac biomarkers 1) to abnormal value cTnI/cTnT > 99th percentile, BNP ≥ 35 pg/mL, NT-proBNP ≥ 125 pg/mL 2) or new significant rise from baseline beyond the biological and analytical variation of the assay used
Asymptomatic CTRCD - Mild	LVEF ≥ 50% AND new relative decline in GLS by > 15% from baseline AND/OR new rise in cardiac biomarkers 1) to abnormal value cTnI/cTnT > 99th percentile, BNP ≥ 35 pg/mL, NT-proBNP ≥ 125 pg/mL 2) or new significant rise from baseline beyond the biological and analytical variation of the assay used
ICI myocarditis	cTn elevation (new or significant change from baseline) with 1 major criterion or 2 minor criteria, after exclusion of ACS and acute infectious myocarditis based on clinical suspicion Both troponin I and troponin T can be used; however, clinical observations suggest that troponin T may be falsely elevated in patients with concomitant myositis and without myocarditis
Severity of myocarditis	Steroid refractory: non-resolving or worsening myocarditis (clinical worsening or persistent troponin elevation after exclusion of other aetiologies) despite high-dose methylprednisolone
AL-CA, amyloid light-chain cardiac amyloidosis;	Echocardiography, NP, and cTn are recommended for the diagnosis of AL-CA in patients with plasma cell dyscrasia.

Table 2.

Indications for troponins at baseline evaluationbefore cancer therapy in the 2022 ESC guidelines on cardio-oncology [8]

Type of planned cancer therapy	Class of recommendation for troponins evaluation
GENERAL	¬ Baseline measurement of NP (including B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and/or cTn (includes any of troponin I, troponin T, or hs-cTnT) is recommended in all patients with cancer at risk of CTRCD if these biomarkers are going to be measured during treatment to detect CTRCD
Anthracyclines	¬ Recommended in very high and high risk patients ¬ Should be considered in moderate and low risk patients
HER2-targeted therapies	¬ Recommended in very high and high risk patients ¬ May be considered in moderate and low risk patients ¬ Should be considered (Class IIa, Level A) in low- and moderate-risk patients post-anthracycline chemotherapy but prior to starting HER2-targeted therapies
Multiple myeloma therapies	¬ Recommended at baseline in patients with amyloid light-chain cardiac amyloidosis
ICI, immune checkpoint inhibitors	¬ Recommended in all patients
CAR-T, chimeric antigen receptor T cell;
TIL, tumour-infiltrating lymphocytes

Table 3.

Troponins in cardiovascular toxicity monitoring in cancer patients [8]

Type of planned cancer therapy	Class of recommendation for troponins evaluation
Anthracyclines	➤ recommended before every cycle chemotherapy and 3 and 12 months after therapy completion in high and very high-risk patients ➤ should be considered every two cycles and within 3 months after therapy completion in moderate-risk patients and in low-risk patients receiving a cumulative dose of ≥ 250 mg/m2 of doxorubicin or equivalent ➤ may be considered every two cycles and within 3 months after therapy completion in low-risk patients
HER2-targeted therapies	➤ should be considered every 2–3 cycles during therapy and 3 and 12 months after the end of therapy in high- and very high-risk HER2 + EBC patients ➤ may be considered every 3 months, and 12 months after therapy in low- and moderate-risk HER2 + EBC patients.
Multiple myeloma therapies	➤ recommended every 3–6 months in patients with amyloid light-chain cardiac amyloidosis
Immune checkpoint inhibitors (ICI)	➤ should be considered before doses 2, 3, and 4, and if normal, reduce to every three doses until completion of therapy to detect subclinical ICI-related CV toxicity
Chimeric antigen receptor T cell and tumour infiltrating lymphocytes therapies	➤ recommended in patients who develop cytokine release syndrome (CRS) ≥ 2
Pregnant women with cancer treated with anthracycline-based chemotherapy	➤ may be considered at baseline and after 12th week, 20th week of pregnancy, after next every 4–8 weeks, and after 34th week of pregnancy

High-sensitivity cardiac troponin T (hs-cTnT) may be utilized for risk stratification in cancer patients, with pre-treatment hs-cTnT demonstrating predictive value [8–10]. The recommended minimum diagnostic panel for cardio-oncological patients should include, among other parameters, hs-cTnT [11]. Cardiac troponin measurement is used as a tool to detect myocardial injury caused by anthracyclines, trastuzumab, and tyrosine kinase inhibitors [12, 13]; immune checkpoint inhibitor–related myocarditis [14]; myocardial amyloidosis [15]; and clonal haematopoiesis of indeterminate potential, which may in turn contribute to atrial fibrillation [16].The measurement of hs-TnI has also been utilized to monitor the efficacy of preventive atorvastatin treatment in patients receiving anthracycline therapy [17].

Potential false-positive and, less commonly, false-negative cTn results should be considered, including those attributable to cross-linking antibodies (i.e., heterophilic antibodies), fibrin clots, cross-reactivity with troponin T released from myositis skeletal muscles, and analytical interference related to cTn–immunoglobulin complexes, referred to as macrotroponin [18]. Kounis syndrome may develop following anticancer drugs and presents as an acute coronary syndrome (ACS) characterized by elevated cardiac troponins seen in allergic reactions [19]. Elevated troponins may also be observed in patients with primary cardiac tumours in the absence of coronary artery disease (CAD) [20]. High-sensitivity cardiac troponin T, a biomarker of cardiomyocyte injury, exhibits a dose-dependent increase and serves as a predictor of cardiovascular events (CVEs) [21]; cTnT and cTnI rise during and immediately following irradiation of the cardiac region. There is a positive correlation between elevated troponins and radiation dose, even in patients who have not previously received chemotherapy [3].

Distinguishing CAD from myocardial damage caused by cancer treatment, with troponin levels elevated in both cases, is a separate challenge. CAD and cancer often coexist. Both conditions share common risk factors, including age, obesity, and cigarette smoking.Many anticancer therapies, as well as the neoplastic process itself, can initiate and modify the course of CAD [22]. The coexistence of ACS and cancer poses a clinical challenge, and despite advances in oncological treatment, ACS is associated with an increased risk for 1-year mortality in patients with malignancies [23].

Current evidence remains insufficient to support the routine use of troponin measurements in patients considered cured of cancer [24]. Existing data on the management of individuals with elevated cardiac troponins are limited and conflicting [25]. The aim of this review was to analyse the literature on high-sensitivity troponins and their use in cardio-oncology.

Pre-treatment Measurement of High-sensitivity Troponin for Risk Stratification in Patients with Cancer

Cardiac troponin measurement is recommended as part of cardiovascular evaluation prior to initiating potentially cardiotoxic cancer therapy.Baseline cTn assessment enables monitoring of dynamic changes during treatment, with elevated pre-treatment levels predicting an increased risk of cardiac complications [26]. The primary aim of the study by Daniel Finke et al. was to identify parameters for stratifying cancer patients by their mortality risk. hs-cTnT emerged as one of the strongest mortality predictors, alongside key oncological parameters. High-sensitivity troponin T levels significantly correlate with left ventricular dysfunction and the risk of all-cause mortality. Pre-chemotherapy hs-cTnT is associated with a higher risk of all-cause mortality [8]. The GMMG-CONCEPT study (NCT03104842) assessed the predictive value of cardiac biomarkers in patients with newly diagnosed high-risk multiple myeloma (HRMM) treated with isatuximab, carfilzomib, lenalidomide, and dexamethasone for CVEs. Elevated NT-proBNP levels proved common and non-predictive of CVEs; by contrast, hs-TnI showed high negative predictive value for CVE among patients with newly diagnosed HRMM [27]. Analysis of data from 4,315 visits by 1,971 cancer patients enrolled in the Heidelberg Cardio-Oncology Registry (HEartCORE) between 2016 and 2020 determined cardiac biomarkers, accounting for age, cardiovascular risk factors (CVRF), and heart function, in relation to all-cause mortality (ACM) and cardiotoxicity. Measurements of hs-cTnT and NT-proBNP proved useful for ACM and cardiotoxicity risk stratification. Baseline hs-cTnT levels are particularly important; patients with elevated baseline plasma hs-cTnT (≥ 7 ng/L) or elevated age-adjusted NT-proBNP require more intensive cardiac surveillance. A key unresolved question remains whether functional assessments, including echocardiography, can be omitted in low-risk patients with hs-cTnT < 7 ng/L [28]. Cardiac troponin measurement is also a useful tool in ALL children. One study found that 29.78% of children exhibited elevated pre-treatment hs-cTnT levels; the proportion of high-risk relapse patients with elevated hs-cTnT was higher compared to the intermediate-risk group. This suggests that the neoplastic process itself, prior to cancer therapy initiation, may also contribute to subclinical myocardial dysfunction, predisposing paediatric patients to long-term cardiac damage [29].

Cardiac Troponin (cTn) Levels for Detecting Therapy-induced Myocardial Damage

Anthracyclines

Anthracycline therapy is commonly employed in the treatment of solid and haematologic malignancies.Despite their therapeutic efficacy, anthracyclines are well-known for their association with cardiotoxicity, which may limit their clinical use. Their mechanisms of action include interaction with topoisomerase II, DNA intercalation, generation of reactive oxygen species, and induction of inflammatory processes [30]. Troponin I may be utilized as a biomarker of anthracycline-induced myocardial injury [31, 32], and its measurement was recommended in the 2022 clinical guidelines of the European Society of Cardiology (ESC) for the detection of anthracycline-induced cancer therapy–related cardiac dysfunction (CTRCD) [31]. According to ESC, cTn assessment is suggested prior to treatment initiation, before the fifth treatment cycle, and at 1 year following treatment completion in low-to-moderate risk patients receiving anthracycline therapy; high-risk patients should have their cTn levels measured before each cycle or before the second, fourth, and sixth cycles, respectively, as well as at 3, 6, and 12 months after final cycle [33]. Increased troponin and BNP levels three months after anthracycline administration were independent predictors of cardiotoxicity [34].Studies are ongoing to limit the effects of anthracycline treatment, including dapagliflozin; if the results are confirmed, it may become a key agent in cardio-oncology care [35, 36]. Post-chemotherapy troponin levels were used to assess the effect of physical activity on the prevention of cardiac dysfunction in women with early-stage breast cancer (BC). The increase in troponin levels was lower in the exercise group compared with the non-exercise group [37].Statin therapy may reduce the risk of cardiotoxicity, as assessed by changes in left ventricular ejection fraction; however, troponin was not included as a standard parameter for monitoring the cardioprotective effect of atorvastatin [38–40].

Trastuzumab

Trastuzumab is a humanized monoclonal antibody that targets the human epidermal growth factor receptor type 2 (HER2) and was the first monoclonal antibody commonly used in cancer treatment. It binds to the extracellular domain of the HER2 receptor, thereby inhibiting the formation of dimers between HER2 and other receptors from the same family, which blocks the transfer of signals that stimulate tumour growth. Beyond direct HER2 inhibition, trastuzumab activates the immune system through its antigen-binding fragment (Fab) and Fc-mediated interaction with the CD16 receptor expressed on natural killer cells (NKCs), thereby initiating a cascade of antibody-mediated cellular cytotoxicity [41–43]. Although trastuzumab-related cardiotoxicity has been well-described in the literature, determining the predominant aetiologic contributor to cardiotoxicity in patients receiving concomitant anthracycline and trastuzumab therapy often poses challenge [43]. Elevated troponin levels during final anthracycline cycles, before starting trastuzumab, may indicate an increased risk of cardiac dysfunction. The relationship between elevated post-anthracycline hs-Tn levels and cardiotoxicity is more statistically significant compared to non-elevated levels [44].This supports the reported interdependence between these two agents. Trastuzumab impairs the regenerative capacity of cardiomyocytes after anthracycline-induced injury, which may contribute to heart failure (HF) [45]. Elevated troponin may precede a decline in left ventricular ejection fraction observed on echocardiography, suggesting the potential for early, subclinical identification of myocardial injury, much earlier compared to imaging modalities [46]. Another study involving 72 women with BC used hs-cTnT and N-terminal pro–B-type natriuretic peptide (NT-proBNP) to assess cardiotoxicity; however, these parameters showed no predictive value for cardiotoxicity [47].

Tyrosine Kinase Inhibitors (TKI)

Tyrosine kinase proteins may be overexpressed during carcinogenesis [48, 49]. Over recent decades, many agents have been developed to inhibit receptor tyrosine kinases. These drugs exert their effects primarily through binding to and blocking the adenosine triphosphate (ATP) binding site. Inhibition of receptor tyrosine kinases suppresses cancer cell proliferation while concomitantly promoting apoptosis [50–52]. These agents were developed to mitigate the adverse effects associated with non-selective chemotherapeutics, such as cisplatin, which, in addition to targeting malignant cells, also damage healthy tissues. In contrast to non-selective agents, TKIs offer greater specificity toward cancer cells by inhibiting receptor autophosphorylation [53]. TKI-induced cardiotoxicity may be related to endoplasmic reticulum (ER) stress. This process is induced by multiple TKIs; it promotes the expression of pro-inflammatory mediators and foetal cardiovascular genes, ultimately leading to cardiotoxicity [54] through mitochondrial dysfunction and apoptosis [55]. Clinically, this may manifest as HF, QT prolongation, hypertension (HT), fluid retention [56, 57], vasculitis and endothelial dysfunction [58], as well as CAD [59]. They may also downregulate cardiac troponin T2, which may negatively impact myocardial contractility [54]. Some authors recommend periodic assessment of NT-proBNP and cardiac troponin biomarkers to enhance detection of complications during treatment of renal cell carcinoma with vascular endothelial growth factor receptor tyrosine kinase inhibitors [60].

Immune Checkpoint Inhibitor-associated Myocarditis (ICI)

ICI therapy can result in cardiotoxicity, including myocarditis [61, 62], which can range from subclinical to severe [63]. The immune system plays a crucial role in detecting and combating various diseases, including malignancies. Although malignant cells are generally recognized and eliminated by the immune system, they may acquire adaptive mechanisms that enable immune evasion. One such mechanism involves upregulation of immune checkpoint molecules, which attenuates the immune response by inhibiting the physiological activation and maturation of T cells.Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), and CD80/CD86 are the critical immune checkpoint pathways [64–66]. Monoclonal antibodies targeting CTLA-4 (e.g., ipilimumab) or PD-1/PD-L1 (e.g., nivolumab, pembrolizumab, atezolizumab) enhance the immune response by restoring T-cell–mediated recognition and cytotoxicity against malignant cells. These agents have demonstrated clinical efficacy across multiple malignancies, including melanoma, non–small cell lung cancer, and renal cell carcinoma [67, 68].Treatment with immune checkpoint inhibitors (ICIs) is associated with the risk of myocarditis, a rare yet severe and frequently fatal complication [69, 70]. Monitoring of cTnI represents a sensitive diagnostic marker for ICI-induced myocarditis and is essential for early detection, thereby facilitating prompt initiation of therapy [71–73]. Other reports additionally recommend ECG [74], N-terminal pro–B-type natriuretic peptide (NT-proBNP), echocardiography, and an assessment of coronary artery calcification at predefined intervals over a two-year follow-up period [75]. In addition to symptomatic individuals, cases of asymptomatically elevated hs-cTnT have been reported, which are not consistently diagnosed as myocarditis [76–78]; some authors have suggested that cTnI may be superior to cTnT, given its greater specificity for myocardial injury [79–81]. It is recommended to determine baseline cardiac troponin prior to treatment onset [82, 83]. In patients receiving ICIs, elevated cTnI levels may represent the earliest manifestation of myocarditis and may range from asymptomatic to severe [84].Systematic monitoring of cTnI levels, alongside careful assessment of clinical symptoms, facilitates earlier therapeutic intervention in suspected myocarditis when cTnI increases or concerning symptoms occur [85]. During corticosteroid therapy, cardiac troponins serve as markers of treatment response; dropping levels allow for switching from intravenous to oral administration [86] and enable evaluation of high- versus low-dose regimen responses [87]. Other authors, based on a follow-up of six patients on steroid therapy, reported rapid and consistent creatine kinase (CK) level declines post-treatment initiation, while troponin levels fluctuated, tended to rise, and stayed elevated for months despite normalized CK [88].

Cardiac Amyloidosis

Systemic amyloidosis refers to a group of disorders marked by impaired tissue function from extracellular amyloid fibril deposition. Multiple proteins contribute to its development, most commonly immunoglobulin light chains [89] and transthyretin. Light chain amyloidosis (AL) arises from accumulation of misfolded immunoglobulin light chains produced by abnormal plasma cells. The disease is severe, with high mortality within the first year post-diagnosis. Transthyretin amyloidosis (ATTR; transthyretin normally transports thyroxine and retinol-binding protein) arises from abnormal transthyretin deposition as amyloid fibrils. Both types of amyloidosis typically manifest as biventricular hypertrophy and restriction [90–92]. Risk stratification currently relies, among others, on serum cardiac biomarkers NT-proBNP and cardiac troponin, whose measurements indirectly indicate cardiomyocyte damage [93–95]. For the AL subtype, their measurement is suggested as an initial diagnostic step [96]. NT-proBNP < 180 ng/L and hs-cTnT < 14 ng/L exclude the diagnosis both in the overall population and groups with left ventricular hypertrophy or suspected AL [97]. In ATTRwt-CM cases, hs-cTnI serves as a significant, independent prognostic factor for mortality [98].

Clonal Haematopoiesis of Indeterminate Potential (CHIP)

CHIP is characterized by expansion of bone marrow stem cells harbouring acquired mutations typical of haematologic malignancies. However, affected individuals lack overt features of haematologic cancer, and the cells show no dysplasia or cytopenia. CHIP carries an estimated 0.5%–1.0% leukaemia risk and doubled cardiovascular risk, independent of traditional factors like HT, smoking, and hypercholesterolemia [99, 100]. Accelerated atherosclerosis may result from increased production of proinflammatory mediators such as IL1B, IL6, and IL8, in mutated macrophages, which drive inflammatory cell influx into the vessel wall and accelerate plaque progression; a similar mechanism may underlie HF, involving enhanced proinflammatory activity in mutation-bearing macrophages [101–103]. A study assessing CHIP in CKD patients found no association between CHIP and coronary artery calcification, troponin I, or NT-proBNP levels [104]. Another study in patients with hypertrophic cardiomyopathy (HCM) and CHIP demonstrated elevated troponin I levels and a higher risk of major adverse cardiovascular events (MACE) [105].

Multiple Myeloma

Multiple myeloma (MM), also known as plasma cell myeloma (PCM), is a haematological malignancy defined by unregulated clonal plasma cell proliferation in the bone marrow, resulting in abnormal monoclonal antibodies or their fragments known as M proteins. A hallmark laboratory abnormality is hypercalcemia due to uncontrolled proliferation of these cells, causing bone destruction, renal failure, and impaired haematopoiesis and humoral immunity [106–108]. MM typically affects older individuals, placing them at higher CVD risk, which may arise during disease progression and treatment, manifesting as HF, arrhythmia, or hypertension (HT) [109]. Between 2015 and 2020, four of the many approved drugs showed an increased incidence of cardiotoxicity: elotuzumab, ixazomib, daratumumab, and panobinostat [110]. One analysis assessed the effect of isatuximab, carfilzomib, lenalidomide, and dexamethasone on CVE measured by NT-proBNP and hs-TnI levels. The study included 126 patients, with smoking and obesity identified as the major additional risk factors.It was found that elevated NT-proBNP levels are relatively common before treatment initiation and are not predictive of CVE; therefore, they should not be a reason for discontinuing carfilzomib in first-line treatment; in contrast, troponin I, which is rarely elevated before treatment initiation and has predictive value for CVE, may be useful in identifying patients at risk of cardiac complications [27].Cardiac AL amyloidosis may be secondary to MM, rapidly causing HF and increased mortality; abnormal troponin and NT-proBNP levels are also present [111]. Cardiac troponins are important in monitoring patients with most cancers, including MM, before and during treatment [112].

False Positive or False Negative Results, Case Examples

One of the papers reviewed describes a patient admitted for multiple complaints, including chest discomfort. Laboratory workup revealed elevated troponin despite normal ECG and echocardiogram, and unremarkable coronary angiography findings. The patient was diagnosed with MM, and the elevated troponin levels were attributed to macrotroponin complexes, which combine abnormal immunoglobulins with troponin. This is a rare cause of elevated troponin in MM patients. To avoid this, polyethylene glycol should be introduced to the patient’s serum, which will precipitate the immunoglobulins and allow for accurate troponin measurement [113].In another report, the authors describe a 72-year-old patient receiving nivolumab and ipilimumab for metastatic melanoma. Markedly elevated hs-cTnT levels (maximum 1128 ng/L; normal < 14 ng/L) prompted referral to the cardio-oncology unit for suspected myocarditis. Echocardiography and magnetic resonance imaging ruled out myocarditis, with the patient reporting no CV symptoms. Skeletal myositis was diagnosed in the absence of concomitant myocarditis [114].

Kounis Syndrome

It is defined as an acute coronary syndrome (ACS) triggered by allergic or anaphylactic reactions, often manifesting as chest pain, and primarily affecting men. Due to low awareness, it often goes undiagnosed [115–117]. Uncontrolled mast cell degranulation and platelet activation can cause coronary artery constriction, leading to ACS [118].

Kounis syndrome is an acute coronary syndrome triggered by allergic or hypersensitivity reactions and has been reported in association with several anticancer therapies. The underlying mechanisms include mast cell activation, release of inflammatory mediators, coronary vasospasm, and plaque destabilization. Cardiac troponin elevation is common and reflects myocardial injury resulting from myocardial ischemia. Although Kounis syndrome has been described after treatment with anthracyclines, taxanes, lenalidomide, and immune checkpoint inhibitors, the currently available evidence is limited mainly to individual case reports. Therefore, Kounis syndrome should be considered in the differential diagnosis of cancer patients who develop chest pain, allergic symptoms, and elevated troponin levels during anticancer treatment [19].

Irradiation of the Cardiac Region

Available evidence demonstrates that several breast cancer (BC) therapies are associated with myocardial dysfunction and/or cardiotoxicity, potentially leading to elevated cardiac troponin levels. During breast cancer treatment, mild cancer therapy–related cardiac dysfunction is defined as left ventricular ejection fraction ≥ 50%, a new global longitudinal strain decrease > 15%, and/or a new rise in cardiac troponin [25]. In selected cases, cardiac troponin may serve as a risk predictor in patients receiving radiotherapy (RT) for left-sided BC. Elevated hs-cTnT serum levels during adjuvant RT in chemotherapy-naïve patients indicate a correlation with cardiac radiation dose [119]. Similarly, increased hs-cTnI levels have been reported in patients with HER2-positive BC undergoing fractionated left-sided RT with concurrent anti-HER2 therapy. The levels of hs-cTnI are proportional to the radiation dose to the heart [120].

Primary Cardiac Tumours

Elevated cardiac troponin levels have also been reported in patients with primary cardiac tumours in the absence of obstructive coronary artery disease. Troponin release may result from myocardial infiltration, mechanical obstruction, myocardial strain, or associated inflammatory processes. However, current evidence is limited mainly to isolated case reports, and the diagnostic and prognostic role of troponins in primary cardiac tumours remains insufficiently defined [20, 121].

Fluoropyrimidine-associated Coronary Vasospasm

Fluoropyrimidines, particularly 5-fluorouracil (5-FU) and capecitabine, are among the most common causes of cancer therapy-related myocardial ischemia [122, 123]. The underlying mechanisms are thought to involve coronary vasospasm, endothelial dysfunction, and microvascular impairment [122, 124]. Patients may present with chest pain, electrocardiographic changes, and elevated cardiac troponin levels despite the absence of obstructive coronary artery disease [122, 123]. Troponin elevation reflects myocardial injury and may help distinguish clinically significant ischemia from transient vasospastic episodes without myocardial damage [122]. Because fluoropyrimidines remain widely used in gastrointestinal and other solid malignancies, clinicians should consider fluoropyrimidine-associated coronary vasospasm whenever troponin elevation occurs during treatment [122, 123]. Current ESC cardio-oncology guidelines recognize fluoropyrimidines as an important cause of cancer therapy-related cardiovascular toxicity and recommend prompt cardiological evaluation in patients developing ischemic symptoms during treatment [8].

Diagnostic Pitfalls-acute Coronary Syndrome in a Cancer Patient

Cancer coexisting with acute coronary syndrome presents a major clinical challenge. In the analysed cohort, cancer patients were less likely to report chest pain and had higher rates of HT, hyperlipidaemia, and elevated transaminases than controls; NSTEMI was more common than STEMI, with lower cardiac troponin levels [125].In cancer patients, hs-cTn (unlike hs-cTn I) showed reduced diagnostic accuracy for NSTEMI; the ESC 0/1-hour hs-cTnT and hs-cTnI algorithms had lower efficacy, resulting in twice as many patients remaining under follow-up instead of receiving invasive treatment [126]. Elevated cardiac troponin levels in cancer patients represent a complex phenomenon influenced by multiple factors, such as treatment (chemotherapy and RT), cancer-related inflammation, microcirculatory dysfunction, and coagulopathy; all these cardiotoxic factors may elevate troponin levels but do not clearly indicate acute coronary syndrome [127]. Dynamic hs-cTn changes are more suggestive of acute cardiac damage, evidenced by rapid hs-cTn increases or decreases, rather than chronic cardiomyocyte damage, which typically involves stably elevated levels [128].

Pulmonary Embolism

Cancer patients have an increased risk of venous thromboembolism and pulmonary embolism [129, 130], which may be the first manifestation of the disease and one of the main factors of mortality [131, 132], especially in the case of ALK + non-small cell lung cancer [133]. One literature analysis of Medline (OVID), EMBASE (OVID), and Cochrane Library (Wiley) databases assessed the incidence of venous thromboembolism (VTE) by solid tumour type, estimating an overall rate of 9.74% across solid cancers, with the highest for gastric cancer (15.43%) and lowest for prostate cancer (1.58%) [134]. Other studies provide a more general description of the distribution, identifying gastrointestinal malignancies as most common, followed by haematologic and genitourinary malignancies; lung and breast cancers carry particularly high VTE risk [135, 136]. Elevated cardiac troponin levels in pulmonary embolism arise from right ventricular overload and ischaemia, potentially causing cardiomyocyte necrosis and directly reflecting myocardial injury; they are strongly associated with increased short- and long-term mortality [137]. Elevated cardiac troponin is also identified as a predictor of clinical deterioration, including significant hypotension or the need for intensive care unit admission [138]. Another paper describes the relationship between elevated troponin and D-dimers in patients with cancer, atrial fibrillation, or COVID-19, demonstrating that increased biomarkers in each group were linked to higher 7-day mortality [139]. One study demonstrated that NT-proBNP and cTnT exhibit high negative predictive value (97–100%), enabling identification of low-risk patients; elevated troponin has been linked to a fivefold increase in the risk of short-term mortality, whereas long-term prognostic significance was observed only in patients without pulmonary embolism [140].

Summary

High-sensitivity cardiac troponins remain among the most sensitive biomarkers of myocardial injury, with their role in cardio-oncology under continued investigation. The analysis of selected 2020–2025 literature reports largely confirms that elevated troponin levels in cancer patients represent a prognostic factor for increased mortality in both solid and haematologic malignancies.The rapidly expanding use of targeted therapies underscores the need for research to identify genetic and pharmacogenomic determinants predisposing to cardiotoxic adverse events; further research is needed to clarify the role of predictive biomarkers that may enable more individualized therapeutic strategies [141]. High-quality studies evaluating troponin measurement in less common conditions, such as primary cardiac tumours, are currently lacking. Evidence supporting the validity and effectiveness of serial cardiac troponin measurements for monitoring and predicting tyrosine kinase inhibitor–induced cardiotoxicity remains limited.Likewise, in clonal haematopoiesis of undetermined potential, robust data linking CHIP with cardiac troponin levels remain insufficient, as most studies involve patients with pre-existing CVD. This constitutes a significant research gap and underscores the need for further investigations. The reviewed literature reveals discrepancies that make it difficult to clearly determine the superiority of one troponin isoform over another. An important unresolved issue is whether high-sensitivity troponin assays should be preferred over conventional troponin measurements in cardio-oncology practice. High-sensitivity assays enable earlier detection of myocardial injury and provide superior prognostic information in several cardio-oncology settings, including anthracycline therapy and immune checkpoint inhibitor-associated myocarditis. However, their higher analytical sensitivity may reduce specificity and increase the frequency of clinically challenging interpretations, particularly in patients with cancer-related inflammation, skeletal muscle involvement, renal dysfunction, or other comorbidities. Current ESC guidelines support the use of either troponin I or troponin T assays, although high-sensitivity assays are increasingly favored in contemporary cardio-oncology practice because of their greater ability to detect subclinical myocardial injury [8, 12, 14]. The 2022 European Society of Cardiology guidelines endorse cTnT or cTnI measurements and natriuretic peptides for initial CV risk assessment in patients scheduled for, among others, anthracyclines, anti-HER2 agents, endothelial growth factor inhibitors, and immune checkpoint inhibitors. This approach enables earlier initiation of cardioprotective therapy in these individuals. Troponin T exhibits lower myocardial specificity than troponin I, which may be particularly relevant in diagnosing immune checkpoint inhibitor–associated myocarditis; troponin T levels may elevate without true myocardial injury, potentially confounding clinical assessment and delaying therapeutic intervention [9].

Conclusions

Cardiac troponins play an important role in comprehensive cardio-oncological diagnosis; however, their diagnostic potential and utility in patient monitoring remain incompletely exploited, and their role in certain cardio-oncology areas requires further investigation (Fig. 1).

Fig. 1.

The currently documented role of troponins in cardio-oncology

Key References

• Liu Y, Liu H. Prediction of chemotherapy-mediated cardiotoxicity in patients with cancer by cardiac troponin I: A systematic review and meta-analysis. Int J Risk Saf Med. 2025 Feb;36(1):26-48.

  • This reference is of outstanding importance because this is a meta-analysis covering over 2,000 patients and showing the potential role of troponin I in predicting early cardiotoxicity in cancer patients undergoing chemotherapy.
• Lehmann LH, et al. Cardiomuscular Biomarkers in the Diagnosis and Prognostication of Immune Checkpoint Inhibitor Myocarditis. Circulation. 2023 Aug 8;148(6):473-486.

  • This reference is of importance because this original observation showing that cardiac troponin T is a better predictor of MACE than troponin I in patients with myocarditis related to immune checkpoint inhibitors.
• Romann SW, et al. Cardiological parameters predict mortality and cardiotoxicity in oncological patients. ESC Heart Fail. 2024 Feb;11(1):366-377.

  • This reference is of importance because the study revealed a higher Hs-cTnT predicted all cause mortality.
• Henriksen PA, et al. Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial. Circulation. 2023 Nov 21;148(21):1680-1690.

  • This reference is of importance because the randomized controlled study did not confirm a positive effect of cardioprotection (combination carvedilol and candesartan therapy) in patients with cardiac troponin I concentrations in the upper tertile during chemotherapy.

Author contributions

JH and SM wrote the primary main manuscript text.MZS and SS prepared tables.All authors reviewed and revised the manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.