Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.

A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated patients with cancer at different sites with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. All patients underwent conventional echocardiography, as well as tissue Doppler imaging (TDI) with strain (Σ) and strain rate (SR), a very accurate technique for detecting minimal changes in cardiac left ventricular (LV) function. Moreover, echocardiographic changes identified during epirubicin treatment were compared with those of a series of biochemical markers of both myocardial damage and inflammation/oxidative stress. Sixteen patients (male-to-female ratio, 3:13; mean age ± standard deviation, 56 ±3 years; range, 27–75 years) with histologically confirmed tumors at different sites, scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled in the study. A significant impairment in systolic LV function was observed after 200 mg/m² of epirubicin; this was shown by a lower SR peak compared with baseline (1.82 ± 0.57/second versus 1.45 ± 0.44/second), whereas Σ remained unchanged. The following significant changes in LV diastolic function occurred only after 300 mg/m² of epirubicin: a decrease in conventional early/late diastolic (E/A) velocities (1.16 ± 0.31 versus 0.93 ± 0.24) and a reduction in both the E_m wave in the basal portion of the interventricular septum (8.86 ± 1.73 cm/second versus 7.51 ± 2.30 cm/second) and in the E_m/A_m ratio (1.09 ± 0.51 versus 0.83 ± 0.51), as measured using the TDI technique. No significant changes in LV ejection fraction were observed. Baseline values of brain natriuretic peptide, troponin I, myoglobin, and creatine kinase-myocardial subfraction were within the normal range and no significant changes were observed throughout the study. Levels of interleukin (IL)-6 and its soluble receptor (sIL-6R) and reactive oxygen species increased significantly, whereas glutathione peroxidase (GPx) levels decreased significantly, after 200 mg/m² of epirubicin. Significant correlations between the reduction in the SR peak (ΔSR) after 200 mg/m² of epirubicin and the increase in IL-6 and ROS and decrease in GPx were observed. The multiple regression analysis showed that the only independent predictive variable for ΔSR was ROS level. Our data show that: (a) subtle cardiac abnormalities may occur at epirubicin doses significantly below those known to be potentially clinically harmful and (b) the earliest myocardial impairment affects LV systolic rather than diastolic function. Early contractility impairment during epirubicin treatment was associated with high levels of ROS and markers of inflammation. The clinical meaningfulness of our findings warrants further investigations in a larger number of patients for a longer period of follow-up.

The risk and mechanism of chemotherapy-induced cardiotoxicity (CTX) vary depending on the type and intensity of the anticancer regimen. Myriad chemotherapeutic drugs produce adverse cardiovascular effects such as arterial hypertension, heart failure, and thromboembolic events. Among the numerous classes of these drugs, anthracyclines have been studied most extensively because of their overt cardiovascular effects and the high associated incidence of heart failure. However, CTX might also be caused by other types of chemotherapeutic agents, including alkylating agents (cyclophosphamide, ifosfamide), platinum agents, antimetabolites (5-fluorouracil, capecitabine), antibiotics (mitoxantrone, mitomycin, bleomycin), and antimicrotubule agents (taxanes). Here, we review the incidence, clinical impact, and potential mechanisms of CTX associated with nonanthracycline chemotherapy used for cancer patients. The published data support a marked increase in CTX risk, particularly with certain drugs such as 5-fluorouracil and cisplatin. Each anticancer regimen is associated with distinct modes of heart damage, both symptomatic and asymptomatic. However, the underlying mechanisms of CTX have been established only in a few cases, and only few nonanthracycline chemotherapeutics (mitoxantrone, mitomycin, ifosfamide) act through a recognizable mechanism and show a predictable dose dependence. Lastly, nonanthracycline chemotherapy can induce both chronic lesions, such as systolic dysfunction, and acute lesions, such as the ischemia that occurs within hours or days after treatment. An increased understanding of the incidence, mechanisms, and potential therapeutic targets of CTX induced by various nonanthracycline chemotherapeutic agents is clearly required.

Metabolic syndrome (Mets) is a clinical condition characterized by a cluster of major risk factors for cardiovascular disease (CVD) and type 2 diabetes: proatherogenic dyslipidemia, elevated blood pressure, dysglycemia, and abdominal obesity. Each risk factor has an independent effect, but, when aggregated, they become synergistic, doubling the risk of developing cardiovascular diseases and causing a 1.5-fold increase in all-cause mortality. We will highlight gender differences in the epidemiology, etiology, pathophysiology, and clinical expression of the aforementioned Mets components. Moreover, we will discuss gender differences in new biochemical markers of metabolic syndrome and cardiovascular risk.