Cardiac effects of deferasirox in transfusion-dependent patients with myelodysplastic syndromes: TELESTO study.

Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.

Management of cancer patients at high and very-high risk of cardiotoxicity: Main questions and answers.

In recent years, important advances have been made in the field of Cardio-Oncology. The 2022 ESC Guidelines on Cardio-Oncology proposed a baseline cardiovascular risk stratification for cancer patients and preventive strategies in patients at high and very-high risk of cardiotoxicity. Cardiovascular toxic effects of anti-cancer drugs are being extensively studied; surveillance programs have been proposed, based on the baseline cardiovascular risk. On the other hand, there is little data on Cardio-Oncological management of patients at high and very-high cardiovascular risk with previous cardiovascular diseases. For example, little is known about management of cancer patients with heart failure with reduced ejection fraction (HFrEF), patients with a recent myocardial infarction or other cardiovascular diseases; when to resume anti-cancer drugs after a cardiovascular toxic event. Collaboration between Cardiologists and Oncologists and multidisciplinary team evaluations are certainly essential to decide the best therapeutic strategy for cancer patients, to treat cancer while saving the heart. Therefore, in the present review, we attempt to provide a useful guide to clinicians in treating patients with high and very-high risk of cardiotoxicity by enucleating main questions and answering them based on the evidence available as well as expert opinion and our clinical experience.

Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: Clinical Relevance, Impact on Outcome, Preventive Measures and Treatment Strategies.

OPINION STATEMENT: The introduction of TKIs into the therapeutic armamentarium of CML has changed the disease paradigm, increasing long-term survival from 20% to over 80%, with a life expectancy now approaching that of the general population. Although highly effective, TKIs also have a toxicity profile that is often mild to moderate, but sometimes severe, with multiple kinases involved in the development of adverse events (AEs). Among others, cardiovascular AEs observed in TKI-treated CML patients may represent a significant cause of morbidity and mortality, and their pathogenesis is still only partially understood. In view of the recent introduction into daily clinical practice of new TKIs, namely the STAMP inhibitor asciminib, with a distinct safety profile, hematologists now more than ever have the opportunity to select the most suitable TKI for each patient, an aspect that will be fundamental in terms of personalized preventive and therapeutic strategies. Furthermore, physicians should be aware of the feasibility of TKI dose modifications at all stages of the patients' treatment journey, both at diagnosis for frail or elderly subjects or with multiple comorbidities, and during follow-up for those patients who experience toxicity, as well as to prevent it, with the main objective of reducing side effects while maintaining the response. Consequently, preserving the cardiovascular health of CML patients will likely be a more urgent topic in the near future, with specific measures aimed at controlling cardiovascular risk factors through a multidisciplinary approach involving a panel of healthcare professionals together with the hematologist.

Direct Oral Anticoagulants for Cancer-Associated Venous Thromboembolism.

PURPOSE OF REVIEW: To present the randomized controlled trial (RCT) evidence and highlight the areas of uncertainty regarding direct oral anticoagulants (DOAC) for cancer-associated venous thromboembolism (CAT). RECENT FINDINGS: In the last years, four RCTs have shown that rivaroxaban, edoxaban, and apixaban are at least as effective as low-molecular-weight heparin (LMWH) for the treatment of both incidental and symptomatic CAT. On the other hand, these drugs increase the risk of major gastrointestinal bleeding in patients with cancer at this site. Another two RCTs have demonstrated that apixaban and rivaroxaban also prevent CAT in subjects at intermediate-to-high risk commencing chemotherapy, albeit at the price of higher likelihood of bleeding. By contrast, data are limited about the use DOAC in individuals with intracranial tumors or concomitant thrombocytopenia. It is also possible that some anticancer agents heighten the effects of DOAC via pharmacokinetic interactions, up to making their effectiveness-safety profile unfavorable. Leveraging the results of the aforementioned RCTS, current guidelines recommend DOAC as the anticoagulants of choice for CAT treatment and, in selected cases, prevention. However, the benefit of DOAC is less defined in specific patient subgroups, in which the choice of DOAC over LMWH should be carefully pondered.

Cardiotoxicity in children with cancer treated with anthracyclines: A position statement on dexrazoxane.

Cardiovascular disease is the leading cause of non-malignant morbidity and mortality in childhood cancer survivors (CCSs). Anthracyclines are included in many treatment regimens for paediatric cancer, but unfortunately, these compounds are cardiotoxic. One in 10 CCSs who has received an anthracycline will develop a symptomatic cardiac event over time. Given the crucial need to mitigate anthracycline-related cardiotoxicity (ARC), the authors critically examined published data to identify effective cardioprotective strategies. Based on their expert analysis of contemporary literature data, it was concluded that consideration should be given for routine use of dexrazoxane in children with cancer who are at risk of ARC.

Cardiovascular Effects of Immune Checkpoint Inhibitors: More Than Just Myocarditis.

PURPOSE OF REVIEW: Immune checkpoint inhibitors have reshaped the treatment of cancer, but they are characterized by peculiar toxicity consisting of immune-related adverse events that may potentially affect any organ or system. In this review, we summarize data on clinical presentation, diagnosis, pathogenesis, and management of the main immune-related cardiovascular toxicities of immune checkpoint inhibitors. RECENT FINDINGS: The most relevant immune-related cardiovascular toxicity is myocarditis, but other non-negligible reported events include non-inflammatory heart failure, conduction abnormalities, pericardial disease, and vasculitis. More recently, growing evidence suggests a role for immune checkpoint inhibitors in accelerating atherosclerosis and promoting plaque inflammation, thus leading to myocardial infarction. Immune checkpoint inhibitors are associated with several forms of cardiovascular toxicity; thus, an accurate cardiovascular baseline evaluation and periodical monitoring are required. Furthermore, the optimization of cardiovascular risk factors before, during, and after treatment may contribute to mitigating both short-term and long-term cardiovascular toxicity of these drugs.

Role of Arterial Hypertension and Hypertension-Mediated Organ Damage in Cardiotoxicity of Anticancer Therapies.

PURPOSE OF THE REVIEW: Arterial hypertension (AH) is the most common cardiovascular (CV) risk factor in the community and in oncologic patients. It also represents the most important CV condition predisposing to anticancer treatment-related cardiotoxicity. This risk is heightened in the presence of cardiac AH-mediated organ damage (HMOD). Influence of AH and HMOD on the development of cardiotoxicity will be reviewed, with a focus on specific scenarios and implications for management of oncologic patients. RECENT FINDINGS: Not adequately controlled AH before or during anticancer treatments and/or development of AH during or after completion of such therapies have detrimental effects on the clinical course of oncologic patients, particularly if HMOD is present. As overlooking CV health can jeopardize the success of anticancer treatments, the goal for clinicians caring for the oncologic patient should include the treatment of AH and HMOD.

A contemporary update on cancer and takotsubo syndrome.

Takotsubo syndrome (TTS) is characterized by a transient left ventricular systolic dysfunction, burdened by significant acute and long-term mortality and morbidity. The prognosis of TTS, especially in the long-term, is influenced by both non-cardiovascular (non-CV) and CV comorbidities, among which cancer is one of the most common. The presence of a malignancy is proven to be associated with higher mortality in TTS. Moreover, a number of anticancer treatments has been reported to possibly cause TTS as a form of cardiotoxicity, even though clearcut associations are lacking. The aim of this narrative review is to sum up contemporary knowledge on the association of cancer and TTS, addressing unmet needs and practical implications. The importance of a close collaboration between cardiologists and oncologists is herein highlighted, both to allow an adequate management of the acute TTS phase, and to actively and safely return to the oncologic management once the acute setting is resolved.

Exploring the influence of takotsubo syndrome on oncologic patients' mortality.

It has been reported that patients affected by takotsubo syndrome (TTS) with a concurrent diagnosis of cancer suffer from greater mortality as compared to their non-cancer counterpart. It remains unclear whether TTS worsens the prognosis of cancer patients as well. Aim of this study was to compare outcomes of cancer patients with and without TTS. We combined data from two independent cohorts: one consisted of a prospective multicentre TTS registry; the second cohort consisted of all oncologic patients from two Cardio-Oncology Outpatient Clinics, who did not have cardiovascular conditions at the time of the cardio-oncologic visit. From the TTS registry, we selected patients with cancer (cancer-TTS patients). Next, we matched these patients with those from the cardio-oncologic cohort (cancer non-TTS patients) in a 1:2 fashion by age, sex, and type and cancer staging. Study endpoint was all-cause mortality. Among 318 TTS patients, 42 (13%) had a concurrent diagnosis of cancer. Characteristics of cancer-TTS patients and of the 84 matched cancer non-TTS subjects were comparable with the exception of diabetes mellitus, which was more common in cancer non-TTS patients. All-cause mortality was similar between cancer-TTS and cancer non-TTS patients. At Cox regression analysis TTS was not associated with mortality (OR 1.4, 95% CI 0.6-3.3, p = 0.43). Our findings show that even in the presence of acute heart failure due to TTS, the prognosis of oncologic patients is driven by the malignancy itself. Our results may prove useful for integrated management of cardio-oncologic patients.

Baseline cardio-oncologic risk assessment in breast cancer women and occurrence of cardiovascular events: The HFA/ICOS risk tool in real-world practice.

BACKGROUND: the European Society of Cardiology Heart Failure Association (HFA) together with the International Cardio-Oncology Society (ICOS) proposed charts for baseline CV risk assessment of cancer patients scheduled to receive anthracyclines and anti-human epidermal growth factor receptor-2 (HER2) agents. METHODS: We investigated HFA/ICOS risk stratification, prescriptions of cardioactive drugs, and occurrence of CV events in a multicentric breast cancer (BC) cohort from 3 Italian Outpatient Cardio-Oncology Clinics. RESULTS: 373 BC patients who underwent a baseline Cardio-Oncologic evaluation were included, of whom 202 scheduled to receive anthracyclines and 171 anti-HER2. Mean age was 60 ± 12 years and 49% of BC patients had ≥2 CV risk factors. In the anthracyclines group, 51% were at low-risk, 43% at medium-risk and 6% at high-risk; while in the anti-HER2 group, 27% patients were at low-risk, 58% at medium-risk and 15% at high-risk. In both groups, a medium-to-high risk was associated with use of cardioactive therapies (p < 0.0001). There were no LVD events in anthracycline recipients, and 16 LVD among anti-HER2 patients. A medium-to-high risk was not associated with LVD occurrence (p = 0.17). CONCLUSIONS: Patients with medium-to-high HFA/ICOS risk were more likely to receive cardioactive therapies, possibly explaining the lack of association of risk categories with LVD occurrence.

Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC.

BACKGROUND: High circulating levels of cellular adhesion molecules (CAMs) in non-small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre-treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC. MATERIALS AND METHODS: Seventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow-up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival ≥2 years or absence of disease progression at the end of the follow-up, and the overall survival. RESULTS: Composite outcome and overall survival were positively associated with VCAM-1 baseline levels and with the reduction of VCAM-1 during the treatment. After adjustment for potential confounders, the change in VCAM-1 serum levels during the treatment was an independent predictor of overall survival. CONCLUSIONS: High baseline serum levels of VCAM-1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy.

Diversity of Cardiologic Issues in a Contemporary Cohort of Women With Breast Cancer.

Background: Women with breast cancer (BC) represent a special population particularly exposed to cardiovascular disease (CVD) risk. However, cardiologic assessment in BC is mostly limited to detection of left ventricular dysfunction cardiotoxicity (LVD-CTX) due to anticancer treatments. Our aim was to comprehensively investigate CV profile and events in a contemporary BC cohort. Methods and Results: Records of BC patients referred for a Cardio-Oncologic evaluation before starting anticancer treatments, between 2016 and 2019, were retrospectively reviewed (n = 508). Information regarding prevalence and control of CV risk factors, and novel CVD diagnoses were extracted. Occurrence of LVD-CTX, CV events other than LVD-CTX and mortality was assessed. Mean age of study population was 64 ± 13 years; 287 patients were scheduled to receive anthracycline and 165 anti-HER2 therapy. Overall, 53% of BC women had ≥2 CV risk factors, and 67% had at least one of arterial hypertension, dyslipidaemia or diabetes mellitus not adequately controlled. Eighteen (4%) patients were diagnosed a previously unknown CVD. Over a mean follow-up of 2.5 ± 1 years, 3% of BC patients developed LVD-CTX, 2% suffered from other CV events and 11% died. CV risk factors were not associated with LVD-CTX, except for family history of CAD. On the contrary, patients with other CV events exhibited a worse CV profile. Those who died more commonly experienced CV events other than LVD-CTX (p = 0.02). Conclusions: BC women show a suboptimal CV risk profile and are at risk of CV events not limited to LVD-CTX. A baseline Cardio-Oncologic evaluation was instrumental to implement CV prevention and to optimize CV therapies.

Cancer Patient With Unusual Dyspnea in the COVID-19 Era: Challenging Management of a Rare Cardiac Tumor.

Heart failure symptoms, in particular dyspnea, may be difficult to frame in a patient with cancer. We report the case of an oncological patient whose dyspnea could have been attributable to various causes and whose management was challenging in the context of the coronavirus disease-2019 pandemic. (Level of Difficulty: Beginner.).

Cardiovascular safety of the tyrosine kinase inhibitor nintedanib.

The intracellular tyrosine kinase inhibitor nintedanib has shown great efficacy for the treatment of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases. However, the incidence rate of myocardial infarction (MI) among participants in landmark IPF trials was remarkable, peaking at 3/100 patient-years. Although subjects with IPF often have a high cardiovascular (CV) risk profile, the occurrence of MI in nintedanib-treated patients may not be fully explained by clustering of CV risk factors. Nintedanib inhibits the vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor pathways, which play important roles in the biology of the atherosclerotic plaque and in the response of the heart to ischaemia. Hence, unwanted CV effects may partly account for nintedanib-related MI. We review the evidence supporting this hypothesis and discuss possible actions for a safe implementation of nintedanib in clinical practice, building on the experience with tyrosine kinase inhibitors acquired in cardio-oncology.

Anthracyclines and regional myocardial damage in breast cancer patients. A multicentre study from the Working Group on Drug Cardiotoxicity and Cardioprotection, Italian Society of Cardiology (SIC).

AIMS: In breast cancer (BC) patients treated with anthracyclines-based therapies, we aim at assessing whether adjuvant drugs impact cardiac function differently and whether their cardiotoxicity has a regional pattern. METHODS AND RESULTS: In a multicentre study, 146 BC patients (56 ± 11 years) were prospectively enrolled and divided into three groups according to the received treatments: AC/EC-Group (doxorubicin or epirubicin + cyclophosphamide), AC/EC/Tax-Group (AC/EC + taxanes), FEC/Tax-Group (fluorouracil + EC + taxanes). Fifty-six patients of the total cohort also received trastuzumab. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were calculated before starting chemotherapy (T0), at 3 months (T3), at 6 (T6), and 12 months (T12). A ≥10% drop of EF, while remaining within the normal range, was reached at T6 in 25.3% of patients from the whole cohort with an early decrease only in FEC/Tax-Group (P = 0.04). A ≥15% GLS reduction was observed in many more (61.6%) patients. GLS decreased early both in the whole population (P < 0.001) and in the subgroups. The FEC-Tax Group showed the worst GLS at T6. Trastuzumab further worsened GLS at T12 (P = 0.031). A significant reduction of GLS was observed in all LV segments and was more relevant in the anterior septum and apex. CONCLUSIONS: The decrease of GLS is more precocious and pronounced in BC patients who received FEC + taxanes. Cardiac function further worsens after 6 months of adjuvant trastuzumab. All LV segments are damaged, with the anterior septum and the apex showing the greatest impairments.

Redox Imbalances in Ageing and Metabolic Alterations: Implications in Cancer and Cardiac Diseases. An Overview from the Working Group of Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology (SIC).

Metabolic syndrome (MetS) is a well established risk factor for cardiovascular (CV) diseases. In addition, several studies indicate that MetS correlates with the increased risk of cancer in adults. The mechanisms linking MetS and cancer are not fully understood. Several risk factors involved in MetS are also cancer risk factors, such as the consumption of high calorie-food or high fat intake, low fibre intake, and sedentary lifestyle. Other common aspects of both cancer and MetS are oxidative stress and inflammation. In addition, some anticancer treatments can induce cardiotoxicity, including, for instance, left ventricular (LV) dysfunction and heart failure (HF), endothelial dysfunction and hypertension. In this review, we analyse several aspects of MetS, cancer and cardiotoxicity from anticancer drugs. In particular, we focus on oxidative stress in ageing, cancer and CV diseases, and we analyse the connections among CV risk factors, cancer and cardiotoxicity from anticancer drugs.