Cardiovascular Biomarkers in Cardio-Oncology

Serum biomarkers represent a reproducible, sensitive, minimally invasive and inexpensive method to explore possible adverse cardiovascular effects of antineoplastic treatments. They are useful tools in risk stratification, the early detection of cardiotoxicity and the follow-up and prognostic assessment of cancer patients.

troponin
natriuretic peptides
biomarkers
omics science
cancer
cardiotoxicity
heart failure
cardiac dysfunction
multiple myeloma

1. Introduction

Cardio-oncology is a discipline that studies the relationship between cancer and cardiovascular diseases (CVDs), and it is mostly focused on the prevention and management of cardiovascular damage resulting from anticancer therapies [1]. The possible cardiotoxic events induced by anticancer treatments include myocardial dysfunction, heart failure (HF), coronary artery disease, valvular disease, arrhythmias, pericardial disease, hypertension and thrombolytic events. In addition to the cardiotoxic effects of oncological therapies, it is believed that cancer and HF are linked by a bidirectional relationship, where one disease favors the other [2,3]. Serum biomarkers represent a reproducible, sensitive, minimally invasive and low-expensive method to explore these effects. They are useful tools in risk stratification, the early detection of cardiotoxicity, follow-up and prognostic assessment [2,4]. They may be good tools to identify patients at high risk of adverse cardiovascular effects before the initiation of therapy and to detect subclinical diseases during active therapy in combination with imaging, identifying patients who should receive cardioprotective therapies [5,6]. Troponins and natriuretic peptides have garnered the broadest evidence base for cardiotoxicity risk prediction, but other markers are being investigated. However, further studies are needed to assess the diagnostic and prognostic roles of other potential biomarkers, including inflammatory and other novel markers.

2. Cardiovascular Biomarkers: Troponins and Natriuretic Peptides

A biomarker, a biological molecule detected in blood, body fluids or tissues, is linked to vital parameters and imaging tests. These markers play a crucial role in revealing disease characteristics, serving as indicators of the risk and disease state and predicting outcomes, including the rate of progression [7]. Cardiac biomarkers, such as troponin and natriuretic peptides (NPs), play pivotal roles in assessing heart health, offering valuable insights into myocardial damage and HF.

NPs, notably brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), serve as widely utilized biomarkers in HF. Synthesized as prohormones, they undergo cleavage into active hormones (BNP and ANP) and inactive forms (NT-proBNP and MR-proANP). While BNP and ANP have short circulating half-lives, NT-proBNP and MR-proANP persist for longer, with renal clearance [8,9]. Considered the gold-standard biomarkers in HF, BNP and NT-proBNP receive Class IA recommendation in the guidelines of major societies, including the American Heart Association (AHA) and European Society of Cardiology (ESC) [10,11]. However, clinical interpretation is influenced by factors such as obesity, which lowers serum levels, and various conditions like age, heart diseases, valve disorders, atrial fibrillation and renal failure, which increase plasmatic concentrations [12,13]. BNP and NT-proBNP have similar clinical value for the evaluation of cardiac function, although NT-proBNP is more stable and does not appear to be affected by changes in anticoagulants, collection containers, body position or circadian rhythm [14]. They offer a non-invasive means to estimate intracardiac filling pressures and end-diastolic wall stress, enhancing the diagnostic accuracy when combined with clinical assessment, ECG, chest X-ray and echocardiography [11,15]. Several randomized clinical trials support the additional use of BNP or NT-proBNP concentrations, leading to improved medical and economic outcomes [16,17]. BNP and N-terminal pro-B-type natriuretic peptides (NT-proBNPs) are biomarkers of long-term cardiovascular dysfunction in asymptomatic patients [18,19,20,21] and represent an important screening tool for patients presenting with dyspnea during anticancer treatment. High diagnostic accuracy is observed in discriminating HF from other causes of dyspnea, with NP concentrations correlating with the likelihood of HF. The optimal cut-off concentrations for acute and chronic HF differ, with higher thresholds in cases of acute dyspnea [11]. NPs exhibit high prognostic accuracy in various conditions, including HF hospitalization, myocardial infarction, valvular heart disease, atrial fibrillation and pulmonary embolism. They also track variations in myocardial stress and dysfunction, making them valuable in conditions like Takotsubo syndrome and during cancer treatment. Myocardial ischemia triggers NP expression independently of mechanical stress, highlighting their role in HF worsening [11,22].

NPs are valuable markers for cardiotoxicity assessment. They can identify acute cardiotoxicity, particularly within 24 h of exposure to anthracycline chemotherapy [23]. While NPs are useful for HF screening in cancer patients with dyspnea, a cut-off value of 100 ng/L for NT-proBNP has high sensitivity [24,25]. Several studies indicate that elevated baseline NT-proBNP in cancer patients is a significant predictor of mortality risk [26,27,28,29].

Troponins are biomarkers that have always been used to diagnose acute coronary syndromes, but have proven to be useful in identifying cardiotoxicity. There are three types of troponins: troponin I, troponin T and troponin C. Cardiac troponin T (cTnT) and cardiac troponin I (cTnI), released during cardiac muscle cell injury, are heart-specific markers, but not disease-specific. Increased levels can be found in various conditions, both physiological (i.e., physical or psycho-emotional stress) and pathological, including chronic HF, diabetes, arterial hypertension, inflammatory heart disease, pulmonary embolism, chronic renal failure and sepsis. The methods of determining cTnT and cTnI have been continuously improved, increasing their analytical sensitivity and specificity [30]. Highly sensitive (hs) immunoassays are now available to determine hs-cTnT and hs-cTnI concentrations, detecting very low but diagnostically significant concentrations of circulating cardiac troponins, especially to identify subclinical cardiac damage [31,32,33]. Small changes in plasma high-sensitivity cTnI (hs-cTnI) below the 99th centile have prognostic value in various heart-related conditions. Temporal changes in high-sensitivity cardiac troponin concentrations help to differentiate acute from chronic cardiomyocyte injury, with a near-linear association between cTnT/cTnI concentrations and the risk of developing clinical HF, hospitalization, atrial fibrillation and death. Managing cardiomyocyte injury requires individualization based on dominant mechanisms, though this can be challenging [34].

In 2020, a meta-analysis of 61 trials involving 5691 adult cancer patients revealed that anticancer therapy often leads to an increase in troponin levels (OR 14.3, 95% CI 6.0–34.1; n = 3049). Elevated troponins were associated with a higher risk of left ventricular dysfunction (LVD) (OR 11.9, 95% CI 4.4–32.1; n = 2163) [35]. This underscores the potential of troponin assessment in identifying patients at risk for cardiotoxicity during cancer treatment. Moreover, beta-blockers, but not candesartan or low-dose enalapril, were found effective in preventing troponin rises when used as a primary prevention strategy in two independent prospective trials, emphasizing the role of troponin monitoring in evaluating the response to cardioprotective treatment [36,37,38]. The combination of these biomarkers provides a comprehensive evaluation of cardiac function, aiding clinicians in making informed decisions about diagnosis, risk stratification and treatment planning. Their distinct specificities contribute to a more nuanced understanding of cardiac conditions, enhancing the overall effectiveness of cardiovascular care.

3. Cardiovascular Biomarkers in Cancer Patients vs. Tumor Biomarkers in Heart Failure Patients

The recent investigations on the possible interplay between cardiovascular biomarkers and cancer have unveiled a complex relationship, challenging the traditional perspectives on the exclusive association of cardiac biomarkers, such as troponin and natriuretic peptides, with some cardiovascular diseases or with the development of cancer therapy-related cardiovascular toxicity (CTRCD). In fact, even though the most recent recommendations on the management of patients at risk of developing CTRCD suggest the broad use of troponin and natriuretic peptides to stratify cardiovascular risk (at baseline) and to identify the early development of toxicity (during follow-up) [39], some evidence suggests that the circulating levels of NPs and troponins can be elevated in patients with neoplasms, even prior to the introduction of cancer therapy, with no evidence of an abnormal cardiac status [26]. Indeed, it is known that malignant cells are able to produce vasoactive peptides, such as vasopressin [40] or endothelin-1 [41], as well as cardiac neurohormones, like atrial natriuretic peptide [42] and B-type natriuretic peptide (BNP) [43,44]. Importantly, BNP elevation cannot be always explained by the presence of an underlying cardiac or hemodynamic condition that would typically affect BNP levels [45]. Moreover, the levels of troponin T (TnT) and troponin I (TnI) have been recently demonstrated to be elevated in cancer patients [46,47], being the former also associated with a worse prognosis [46]. The evidence that such cardiovascular biomarkers tend to increase proportionally with the advancing tumor stage, even without other signs of cardiac damage or dysfunction [26], may reinforce the idea that, in some cases, the elevation of these biomarkers could be hypothesized to be driven by the neoplastic disease, rather than the presence of an underlying cardiopathy or the occurrence of CTRCD. Certainly, this should not discourage the clinical use of these biomarkers according to the most recent guidelines [39], especially taking into account that they seem to be useful in the prediction of prognosis [26,46]. Of note, even though elevated levels of cardiovascular biomarkers were found in subjects without evidence of manifest cardiac involvement, the association between late-stage cancer, cancer cachexia and cardiac wasting has been extensively described and may represent a possible explanation for this phenomenon [48,49,50].

Conversely, a reciprocal relationship may be identified within cardiovascular conditions, specifically HF, presenting elevated levels of tumor biomarkers [51]. In fact, it has emerged that patients affected by HF present with high serum levels in several biomarkers presumed to be tumor-related, such as CA19-9, CA125 and human epididymis protein 4 (HE4) [51,52,53,54,55,56]. The possible interconnections between HF and cancer extend far beyond HF being a manifestation of CTRCD, and they have been deeply investigated in the last few decades [57,58,59,60,61,62,63]. Interestingly, an analysis of 2079 patients affected by HF in the BIOSTAT-CHF cohort [64] proved that the blood levels of five out of the six tumor biomarkers that they investigated (CA125, CA15-3, CA19-9, CEA and CYFRA 21-1) were significantly correlated with all-cause mortality, while CA125 also showed a strong correlation with HF hospitalization risk, and CYFRA 21-1 had equivalent predictive utility for all-cause mortality when compared with NTproBNP levels [51]. In particular, CA125 is probably the most investigated tumor biomarker in this setting, having shown prognostic value in different cardiac settings, being elevated in response to both congestion and inflammatory stress conditions [65,66,67,68,69]. This tumor biomarker is also associated with hospitalization, a worse prognosis and elevated NTproBNP serum levels [65,66,67,68,69]. Likewise, in recent studies, HE4, which is a serum biomarker currently used to monitor the recurrence of epithelial ovarian cancer, has been demonstrated to be strongly associated with HF and it seems to represent an independent predictor of HF outcomes [70,71,72].

Thus, the associations between established tumor biomarkers and indices of HF severity, along with their independent prognostic value for the HF outcomes of these biomarkers, and between classic cardiovascular biomarkers and cancer patient prognosis, may suggest the presence of dysregulated pathophysiologic pathways common to both cancer and cardiovascular diseases [61]. As already mentioned, the existent correlation between these two conditions is well recognized in the scientific literature and, remarkably, it has been highlighted that cancer and cardiovascular disease share many risk factors, as well as a common underlying inflammatory condition [57,58,59,61,62,73]. Of note, this chronic phlogistic state has been also observed in clinical practice and reported in the literature, with the help of serum inflammatory markers such as C-reactive protein (CRP) and proinflammatory cytokines such as interleukin 6 (IL-6) in both cancer and HF [19,74,75,76,77,78]. As highlighted for the other biomarkers, IL-6 seems to play a role in predicting prognosis in HF patients [79], and it was also found, together with CRP, to be proportionally elevated to the cardiovascular peptides (such as NTproBNP) in a population of 555 individuals with different types and stages of cancer that had not yet undergone chemotherapy; in addition, similarly to the trend of cardiac biomarkers, IL-6 serum levels were found to be higher in patients with more advanced stages of cancer [26].

To summarize, the intricate interplay between cardiovascular biomarkers and cancer extends beyond their traditional roles, revealing a complex relationship influenced by systemic inflammation and shared risk factors and pathophysiological pathways. These biomarkers, while often utilized to detect potential cardiac toxicity from cancer therapies, can also rise independently, even before chemotherapy, being sometimes able to stratify risk and predict prognosis. Such a bidirectional association, where cancer patients exhibit elevated cardiovascular biomarkers and cardiac patients present increased levels of tumor biomarkers, underscores the need for a deeper understanding of these markers in the context of the more precise and targeted use of these tools in both clinical scenarios.

4. Role of Cardiovascular Biomarkers in the Risk Stratification and in the Identification of Chemotherapy-Induced Cardiotoxicity in Cancer Patients

In recent years, important advances have been made in the field of cardio-oncology [39]. The ESC Guidelines on Cardio-Oncology recommend cardiovascular (CV) toxicity risk stratification before starting potentially cardiotoxic cancer therapy [39,80]. Baseline CV risk stratification in cancer patients is important in order to prescribe cardioprotective treatment before starting antineoplastic treatment when needed, to schedule a cardiology referral before treatment and to plan the most appropriate surveillance program during and after treatment [39]. Cardiotoxicity risk is a dynamic variable related not only to traditional cardiovascular risk factors but also to treatment-related factors; therefore, it is advisable to conduct its assessment by using a dedicated cancer patient tool such as the HFA-ICOS risk score [39,80]. Few studies have so far validated this score in patients with solid or hematological tumors [81,82]. The HFA-ICOS risk score takes into consideration lifestyle risk factors, demographic and CV risk factors, previous CV diseases, previous and concomitant cardiotoxic cancer treatment and baseline cardiac biomarkers (elevated baseline troponin—Tn, elevated baseline brain natriuretic peptide—BNP or NT-proBNP) in patients receiving six of the most frequently used anticancer treatments [80]. Monitoring biomarkers, and particularly Tn and BNP/NT-proBNP, during cancer treatment aids in the early diagnosis of cardiotoxicity in cancer patients [34].

Symptomatic CTRCD is defined by the presence of HF symptoms; the diagnosis of asymptomatic CTRCD is based on the left ventricular ejection fraction (LVEF) reduction and/or relative decline in global longitudinal strain (GLS) and/or a new rise in cardiac biomarkers (cTnI/cTnT gammaGT; 99th percentile, BNP ≥ 35 pg/mL, NT-proBNP ≥ 125 pg/mL, or a new significant rise from baseline beyond the biological and analytical variations of the assay used) [39]. Several studies have shown the prognostic role of monitoring cardiac troponin. In particular, Cardinale et al. demonstrated, in patients treated with high-dose anthracyclines, that persistently negative troponin is able to identify low-risk patients who do not need close echocardiographic monitoring, while a persistent troponin elevation preceded an LVEF drop and identified high-risk patients [83,84,85]. In patients treated with trastuzumab, a troponin increase identified patients at risk of non-reversible left ventricular dysfunction [86]. In a recent meta-analysis, Michel et al. confirmed the predictive role of a troponin increase after anthracycline-based chemotherapy or human epidermal receptor 2 (HER2) inhibitor therapy for the development of left ventricular dysfunction.

Petricciulo et al. showed that, in patients treated with immune checkpoint inhibitors (ICI), baseline hs-TnT predicted a composite cardiovascular endpoint (cardiovascular death, stroke or transient ischemic attack, pulmonary embolism and new-onset HF) and the progression of cardiac involvement at 3 months, with 14 ng/L as the best cut-off [87]. In patients treated with ICI, guidelines recommend measuring baseline cardiac troponin to stratify cardiotoxicity risk; moreover, it should be monitored in order to detect ICI-induced myocarditis [39]. Less evidence exists regarding the increase in BNP/NT-proBNP as a marker for cancer therapy-related cardiotoxicity [20]. In fact, a BNP/NT-proBNP increase after chemotherapy may be associated with fluid overload, limiting its diagnostic and prognostic role. Elevated BNP levels have been found at baseline in patients with malignancies and without HF and/or sepsis; it is likely that tumor-related mechanisms and oxidative stress contribute to increasing this biomarker [88].

In patients with multiple myeloma receiving proteasome inhibitors, baseline high levels of BNP (>100 pg/mL) and NT-proBNP (>125 pg/mL) predicted cardiovascular adverse events associated with worse overall outcomes [89]. It is recommended to monitor NP at baseline, before starting proteosome inhibitors, and during treatment, especially in the setting of cardiac amyloidosis [39]. Regarding a biomarker-guided cardioprotective strategy, the recently published multicenter prospective Cardiac Care trial failed to demonstrate a cardioprotective effect of a troponin-measurement-guided strategy in patients receiving anthracycline-based chemotherapy [90]. Certainly, the use of cardiac biomarkers shows advantages compared to imaging in the management of cancer patients and, in particular, they are easier to obtain by oncologists and more reproducible than imaging; they are also less time-consuming for patients. However, many problems still limit their implementation in clinical practice, such as the lack of standardization in trial methodologies evaluating biomarkers, the wide heterogeneity in terms of malignancy types, cancer treatment schedules and the definition of cardiotoxicity across the trials.

This entry is adapted from the peer-reviewed paper 10.3390/biom14020199

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