Cardiovascular Toxicity Related to Cancer Treatment

Cardiovascular disease is an essential comorbidity in patients with non-small cell lung cancer (NSCLC) and represents an independent risk factor for increased mortality. Therefore, careful monitoring of cardiovascular disease is crucial in the healthcare of NSCLC patients. Inflammatory factors have previously been associated with myocardial damage in NSCLC patients, but it remains unclear whether serum inflammatory factors can be utilized to assess the cardiovascular health status in NSCLC patients. A total of 118 NSCLC patients were enrolled in this cross-sectional study, and their baseline data were collected through a hospital electronic medical record system. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of leukemia inhibitory factor (LIF), interleukin (IL)-18, IL-1β, transforming growth factor-β1 (TGF-β1), and connective tissue growth factor (CTGF). Statistical analysis was performed using the SPSS software. Multivariate and ordinal logistic regression models were constructed. The data revealed an increased serum level of LIF in the group using tyrosine kinase inhibitor (TKI)-targeted drugs compared to non-users (p < 0.001). Furthermore, serum TGF-β1 (area under the curve, AUC: 0.616) and cardiac troponin T (cTnT) (AUC: 0.720) levels were clinically evaluated and found to be correlated with pre-clinical cardiovascular injury in NSCLC patients. Notably, the serum levels of cTnT and TGF-β1 were found to indicate the extent of pre-clinical cardiovascular injury in NSCLC patients. In conclusion, the results suggest that serum LIF, as well as TGFβ1 together with cTnT, are potential serum biomarkers for the assessment of cardiovascular status in NSCLC patients. These findings offer novel insights into the assessment of cardiovascular health and underscore the importance of monitoring cardiovascular health in the management of NSCLC patients. Full article

Aim: COVID-19 pandemic had a big impact on our life, it has revolutionized the practice of cardiology and the organization of hospital and outpatient activities. Thus the aim of our study was to assess the impact of the COVID-19 pandemic on the development of cancer therapy-related cardiac dysfunction (CTRCD). Methods and results: A single center retrospective study was carried out evaluating 96 cancer patients treated with anthracyclines and admitted to our Cardio-Oncology unit from June to August 2019 and 60 patients from June to August 2021. The incidence of CTRCD was assessed performing an echocardiogram at the time of the enrollment. We found a significantly higher incidence of CTRCD in the second period compared to first period (13% vs. 2%, p value 0.0058). In addition we found that fewer yearly visits were performed in our Cardio-oncology unit in 2021 compared to 2019 (300 patients/year in 2019 vs. 144 patients/year in the COVID era). Conclusion: COVID-19 pandemic seems to influence the onset of CTRCD in cancer patients by indirectly reducing hospital access of cancer patients and cardiological checks. In addition our data reflect the impact of the COVID-19 pandemic in the late diagnosis of cancer, in the reduction of hospital admissions and regular medical checks, in the increase of comorbidities and cardiovascular complications. Full article

Aim: Evaluate the influence of doxycycline, an anti-inflammatory and matrix metalloproteinase (MMP) inhibitor, on the attenuation of chronic doxorubicin-induced cardiotoxicity in rats. Methods: We allocated male Wistar rats into four groups: control (C), doxorubicin (D), doxycycline (inhibitor of MMP, IM), and Dox + doxycycline (DIM). Groups IM and DIM received doxycycline (5 mg/kg, IP) once a week for 4 weeks. In addition, 48 h after every doxycycline injection, groups D and DIM received Dox (5 mg/kg, IP). We performed echocardiogram and evaluated TIMP-4 and collagen I protein expression, MMP-2 activity, and oxidative stress and myocardial metabolism. Results: Doxorubicin promotes left atrium (LA) and left ventricle (LV) dilatation and decreases in LV fractional shortening, which was improved by doxycycline. Moreover, doxycycline attenuated the LV cardiomyocyte hypertrophy and collagen type I expression. Doxorubicin increased phosphofructokinase and decreased beta-hydroxyacyl Co-A dehydrogenase, pyruvate dehydrogenase, citrate synthase, and ATP synthase activity, which was partially attenuated by doxycycline. Lastly, doxycycline improved antioxidant enzyme activity in the DIM group. Conclusion: Doxorubicin increases oxidative stress and promotes changes in myocardial energy metabolism, accompanied by structural and functional changes. Doxycycline attenuated the doxorubicin-induced cardiotoxicity, at least in part, through changes in myocardial energy metabolism. Full article

Background: Advances in cancer therapy have dramatically improved outcomes for cancer pa-tients. However, cancer treatment can cause several cardiovascular (CV) complications, increasing cardiac mortality and morbidity in cancer patients and survivors. As a result, a new cardiology subspecialty—cardio-oncology (CO)—has been developed. The goals of CO are to understand the mechanism of the cardiotoxicity (CTX) of cancer therapies and invent the best monitoring and treatment strategies to improve the survival of cancer patients. Methods: We performed a retro-spective observational study reporting on the 6-year experience of the first CO service in Vilnius, Lithuania. Cancer patients were consulted by a single part-time specialist at Vilnius University Hospital. All new patients underwent blood tests, including cardiac biomarkers and advanced transthoracic echocardiogram (TTE) with stress protocol if indicated. During a follow-up, we evaluated the association of patient survival with such variables as age, gender, reasons for re-ferral, cancer location and stage, cardiovascular (CV) risk factors (RF), and rates and stage of CTX and treatment strategies. Results: 447 patients were consulted (70% females), and the median age was 64 years. Cardiovascular (CV) RF was common: 38.5% of patients had hypertension, almost 38% had dyslipidemia, 29% were obese, 10% were smokers, and 9% had diabetes. Nearly 26% of patients had a history of HF. Early biochemical cardiotoxicity was determined in 27%, early functional cardiotoxicity was seen in 17%, and early mixed cardiotoxicity—in 45% of referred patients treated with cardiotoxic cancer therapies. In addition, reduced left ventricular ejection fraction (LVEF) was found in 7% of patients. Beta-blockers (BB) were administered to 61.1% of patients, while angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) to 54.1% of patients. In addition, 18.3% of patients received loop diuretics and almost 12% mineralocorticoid receptor antagonists (MRA), respectively. A total of 143 patients died during the 6-year follow-up period. The leading cause of death was primarily cancer (92.3%). Only in 5.6% of patients, cardiovascular complications were reported as the cause of death, and 2.1% of deaths were due to the COVID–19 infection. We found that age (HR 1.020 [95% CI: (1.005–1.036)] p = 0.009); LV diastolic dysfunction (HR 1.731 [95% CI: 1.115–2.689] p = 0.015; NYHA stage II (HR 2.016 [95% CI: 1.242–3.272] p = 0.005; NYHA stage III (HR 3.545 [95% CI: 1.948–6.450] p < 0.001; kidney dysfunction (HR 2.085 [95% CI: 1.377–3.159] p = 0.001; previous cancer (HR 2.004 [95% CI: 1.219–3.295] p = 0.006); tumor progression (HR 1.853 [95% CI: 1.217–2.823] p = 0.004) and lung cancer (HR 2.907 [95%CI: 1.826–4.627] p < 0.001) were statistically significantly associated with the increased risk of all-cause death. Conclusions: CO is a rapidly growing subspecialty of cardiology that aims to remove cardiac disease as a barrier to effective cancer treatment by preventing and reversing cardiac damage caused by cancer therapies. Establishing a CO service requires a cardiologist with an interest in oncology. Continuous education, medical training, and clinical research are crucial to success. Age, previous cancer, tumor progression, kidney dysfunction, left ventricular diastolic dysfunction, and NYHA stages were associated with increased mortality. Full article

Background: β-caryophyllene (BCP), a natural sesquiterpene, is extensively present in the essential oils of several plants. Cyclophosphamide (CYC) is an anticancer drug. However, its clinical usage is inadequate due to its cardiotoxicity. The aim of this study was to study the effects of BCP on cardiac injury induced by CYC exposure, and to identify the underlying mechanism of action. Methods: Five groups of Wistar rats were allocated. Group I (Normal), II (BCP), and III (CYC) acted as controls. Group IV, V (CYC + BCP) received BCP in two doses (100 and 200 mg/kg, orally, respectively) for 14 days after CYC challenge. CYC groups received 200 mg/kg, i.p. of the drug once on the first day of experiments. Results: CYC group displayed numerous ECG and histological irregularities and cardiac markers elevation. CYC induced lipid peroxidation and oxidative stress intensification, as well as inflammatory and apoptotic markers escalation. Treatment with BCP resulted in modified ECG traces and histological sections. BCP mitigated cardiac markers and lipid peroxidation whereas intensified antioxidant capacity. BCP activated Nrf2, with subsequent HO1 and NQO1 amplification. BCP diminished TLR4/NFκB pathway, which consequently lessened the inflammatory and apoptosis responses. Conclusion: BCP administration was associated with activated Nrf2/HO1/NQO1 and inhibited TLR4/NFκB pathways with subsequent enhanced anti-oxidative capacity and diminished inflammatory and apoptosis responses. Full article

Immune checkpoint inhibitors (ICIs) have now emerged as a mainstay of treatment for various cancers. Along with development of ICIs, immune-related adverse effects (irAEs) have aroused wide attention. The cardiac irAE, one of the rare but potentially fatal effects, have been reported recently. However, the clinical comprehension of cardiac irAEs remains limited and guidelines are inadequate for cardio-oncologists to tackle the problem. In this review, we have summarized current classifications of, manifestations of, potential mechanisms of, and treatment for ICI-related myocardial injury in order to provide some clues for the understanding of cardiac irAEs in clinical work. Full article

Cardiotoxicity is a significant complication of chemotherapeutic agents in cancer patients. Cardiovascular incidents including LV dysfunction, heart failure (HF), severe arrhythmias, arterial hypertension, and death are associated with high morbidity and mortality. Risk stratification of cancer patients prior to initiation of chemotherapy is crucial, especially in high-risk patients for cardiotoxicity. The early identification and management of potential risk factors for cardiovascular side effects seems to contribute to the prevention or minimization of cardiotoxicity. Screening of cancer patients includes biomarkers such as cTnI and natriuretic peptide and imaging measurements such as LV function, global longitudinal strain, and cardiac MRI. Cardioprotective strategies have been investigated over the last two decades. These strategies for either primary or secondary prevention include medical therapy such as ACE inhibitors, ARBs, b-blockers, aldosterone antagonists, statins and dexrazoxane, physical therapy, and reduction of chemotherapeutic dosages. However, data regarding dosages, duration of medical therapy, and potential interactions with chemotherapeutic agents are still limited. Collaboration among oncologists, cardiologists, and cardio-oncologists could establish management cardioprotective strategies and approved follow-up protocols in patients with cancer receiving chemotherapy. Full article

(1) Background: Human health risks and hazards from chemical substances are well regulated internationally. However, cardiotoxicity, is not defined as a stand-alone hazard and therefore there are no defined criteria for the classification of substances as cardiotoxic. Identifying and regulating substances that cause cardiovascular adverse effects would undoubtedly strengthen the national health systems. (2) Methods: To overcome the aforementioned gap, a roadmap is proposed for identifying regulatory criteria from animal studies and endorse legislation in order to classify substances as cardiotoxic. The roadmap consists of: (i) the identification of the appropriate animal species and strains; (ii) the identification of the lines of scientific evidence (e.g., histopathological, biochemical and echocardiographic indices etc.) from animal studies with relevance to humans; (iii) the statistical analysis and meta-analysis for each line of scientific evidence after exposure to well-established cardiotoxicants to humans (e.g., anthracyclines) in order to identify threshold values or range of normal and/ or altered values due to exposure; (iv) validation of the above described lines of evidence in animals exposed to other alleged cardiotoxic substances (e.g., anabolic androgen steroids (AAS) and pesticides); (v) establishment of mechanisms of action based on information of either known or alleged cardiotoxicants; and (vi) introduction of novel indices and in silico methods. (3) Results: Preliminary results in rats indicate a clear distinction from normal values to values measured in rats exposed to anthracyclines regarding left ventricle (LV) fractional shortening (FS) and LV ejection fraction (EF). A distinctive pattern is similarly observed for Creatine Kinase-Myocardial Band isoenzyme (CK-MB) and cardiac tissue glutathione (GSH). These findings are encouraging and indicate that there is room for targeted research to this end, and that these specific indices and biochemical markers should be further investigated in order to be developed to regulatory criteria. (4) Conclusions: Further research should be conducted by both the scientific and regulatory community that aims to clearly define the cardiotoxicity hazard caused by chemicals and develop a full set of scientific criteria. Full article

The therapeutical advances in recent years in the field of oncology treatment have increased survival rates and improved the quality of life of oncology patients, thus turning cancer into a chronic disease. However, most of the new cancer treatments come at the expense of serious cardiovascular adverse events threatening the success story of these patients. The establishment of multidisciplinary medical teams to prevent, monitor, and treat cardiovascular diseases in cancer-treated patients is needed now more than ever. The aim of this narrative review is to demonstrate the existing knowledge and practical approaches on how to establish and maintain a cardio-oncology program for the rising number of patients who need it. Full article

Throughout the last decades, newly developed chemotherapeutic agents and immunotherapies that target signaling pathways have provided patients with better prognoses, improved their quality of life and increased survival rates, thus converting cancer to a stable chronic disease. However, non-anthracycline cancer chemotherapy agents and immunotherapies including human epidermal growth factor receptor 2 (HER2) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, Bcr-Abl tyrosine-kinase inhibitors (TKI), proteasome inhibitors, immune checkpoint inhibitors and chimeric antigen receptor T cells (CAR-T cells) may cause cardiovascular toxicity events and complications that usually interrupt the continuation of an appropriate treatment regimen, which induces life-threatening risks or leads to long-term morbidity. Heart failure, cardiac arrythmias and cardiomyopathies are the most common cardiovascular events related to cardiotoxicity due to chemotherapy. Each patient should be carefully assessed and monitored before, during and after the administration of chemotherapy, to address any predisposing risk factors and the new onset of cardiotoxicity manifestations early and treat them appropriately. The development of novel anticancer agents that cause minimal cardiovascular toxicity events or novel agents that ameliorate the adverse effects of the existing anticancer agents could drastically change the field of cardio-oncology. The aim of this narrative review is to demonstrate new knowledge regarding the screening and diagnosis of non-anthracycline-induced cardiotoxicity and to propose protective measures that could be performed in order to achieve the delivery of optimal care. Full article