The special issue discusses the currently known cardiovascular effects of anticancer therapies, focusing on the putative mechanisms of cardiotoxicity (CTX), role of biomarkers, and potential methods of preventing and minimizing cardiovascular complications.
The advancement of cancer therapy in the past 2 decades has allowed the recovery and long-term survival of millions of people around the world, and this population is expected to grow.1
Unfortunately, almost every effective therapeutic treatment is accompanied by undesirable side-effects. In the case of anticancer drugs, the side-effects include cardiovascular adverse events, such as left ventricular (LV) failure, myocardial ischaemia, QT prolongation, arrhythmias, pericarditis, myocarditis, hypertension, and thromboembolism.2
There are at least two links between the cardiovascular system and cancer: in many cases, cardiovascular disease (CVD) and carcinogenicity share the same risk factors, especially smoking and obesity; in addition, the antineoplastic agents are capable of immediately producing short and long-term cardiovascular events. Lastly, because of an increase in the aging population of developed countries, it is increasingly likely that a patient may suffer from both cancer and CVD.3
Heart and vessels are, therefore, targets of the activities of powerful anticancer classes; indeed, a prolonged follow-up of cancer survivors reveals that, while approximately half of them died because of the original disease, more than one-third died from a CVD.4
Because anticancer therapy is intended to save human lives, it is unacceptable that a patient, who is often very young, can survive cancer but gets sick and dies because of an iatrogenic cardiomyopathy.
Measures that address early the detection of potential cardiovascular damage, personalized monitoring of patients in chemotherapy, and development of cardioprotective strategies require greater attention.
LV failure caused by anthracyclines has historically been the most common form of antineoplastic drug-induced CTX, defined as type I toxicity, with generally irreversible myocardial ultrastructural damage.5 However, because of their target pathways, new biological drugs, and targeted therapies may affect the cardiovascular system and may play a role in cardiac homeostasis, especially when the heart is overloaded, as it is in hypertension or hypertrophy. Accordingly, human epidermal growth factor receptor 2 and angiogenesis inhibitors are able to influence metabolism and the cardiac contractile proteins. CTX caused by these drugs, called type II LV dysfunction, does not occur with cardiomyocyte rearrangements and is usually reversible on discontinuation of treatment. However, these two forms of CTX can overlap, and trastuzumab, an anti-ErbB2, can lead to irreversible myocardial damage in patients who were previously treated with anthracyclines.6
The special issue also aims to describe the molecular mechanisms of CTX induced by the main classes of antineoplastic agents and preview the new oncological and cardiological therapeutic proposals that prevent or mitigate CTX.
Monitoring techniques represent indispensable support for paying prompt attention to the patient and therapeutic scenario, with the aim of intercepting any minimum anticipatory sign of a cardiovascular insult. To this end, we have developed a proven biological approach that is based on markers that are sensitive to cardiomyocyte damage or functional stress. In particular, the cardiac troponin and natriuretic peptide dosages have proven to be adequate to detect CTX in patients undergoing chemotherapy in a variety of clinical settings.
Because of the still limited knowledge regarding the cardiovascular impact of current anticancer therapies, alternative mechanisms of CTX and their related biological markers are being actively investigated. Among these, the genomic markers, epigenetic factors, redox signaling, stem cells, and autologous cardiac progenitors have shown to be promising features for the identification of early markers of CTX and the development of cardioprotective agents.7 Although these results are not yet applicable in clinical settings, they form the basis for the development of personalized medicine in the prevention of CTX. The usefulness, applicability, and limitations of their use in clinical practice will be extensively discussed hereafter.
Cardiovascular imaging is critical in the evaluation of CTX in patients undergoing cancer treatment. It enables the early detection of LV dysfunction and risk stratification of heart failure, leading to a better management of cancer therapy and, eventually, cardiac therapy. This issue includes an extensive discussion of conventional measurements, new echocardiographic techniques, integration of imaging tools, importance of a comprehensive cardiac evaluation, and positions of the international scientific societies on these topics.
Although echocardiography is the first-line imaging method and the most widely used diagnostic tool to monitor the cardiovascular effects of anticancer drugs, there is a need for greater reliability, reproducibility, and accuracy in detecting the early signs of CTX. This has prompted the introduction of second-line advanced imaging modalities, such as cardiac magnetic resonance (CMR) and nuclear techniques.
Therefore, a section dedicated to the new imaging techniques, a description of traditional and new parameters to detect CTX, and a comparison between traditional and CMR/nuclear imaging techniques is included in this issue.
The timing, dose, and mode of administration of chemotherapy are important factors in the development of acute or late myocardial dysfunction. In accordance with these concepts and taking into account the better-known pathophysiological aspects of anticancer drug-induced CTX, different cardioprotective strategies have been established, ranging from classes of drugs that are traditionally used in heart failure – such as β-blockers and renin–angiotensin–aldosterone system antagonists – to nutritional supplementation and physical workout. On the other hand, despite these proposals, most likely because there are too limited and sporadic studies available, little consensus has been generated around a common and shared clinical practice. However, the effort of containing CTX should start from the identification and containment of cardiovascular risk factors.
In any event, a simultaneous or sequential management of cancer therapy and cardiovascular protection should be more attentive and personalized. This is because clinical CTX is typically preceded by asymptomatic systolic and/or diastolic dysfunction; anthracyclines can cause cardiovascular events on treatment, as well as years or decades after treatments ends; some patients have a higher predisposition to cardiac events; comorbidities and cardiovascular risk factors are particularly common in the elderly and require more stringent measures to prevent primary and secondary cardiovascular events.
The special issue will also discuss the possible role in the prevention of cancer drug-induced myocardial injury of some drugs that have been previously used or are being investigated for use in other contexts of cardiac protection (e.g. statins, ranolazine, and sildenafil).
The cardiologist is responsible for preventing or minimizing CTX as well as managing the potential cardiovascular side-effects of the anticancer treatment. However, a shared consensus between cardiologists and oncologists on methods to identify the onset of CTX and manage its potential progression toward cardiomyopathy has not been reached.
In the last two articles of this issue, members of the Working Group on Drug CTX and Cardioprotection of the Italian Society of Cardiology examine potential strategies to prevent or minimize CTX induced by the three major classes of chemotherapeutic drugs. They propose a practical approach to the clinical management of cancer-related CTX based on the collaborative efforts of onco-cardiology teams.
The increasing collaboration between cardiologists – who are aware of the cardiovascular risks of cancer treatment – and oncologists – who are knowledgeable about cancer management – has led to the rapid growth of a new discipline: the cardioncology.
In our opinion, the field of cardioncology will evolve from encouraging oncologists and cardiologists to work cooperatively into a pharmacology-oriented translational discipline that is aimed at monitoring the cardiovascular safety of anticancer therapies.
The concerted efforts of oncologists and cardiologists in the design of new, predictive models of CTX will prevent the detrimental side-effects induced by the novel-targeted cancer drugs on cardiomyocytes. This integrated approach will ensure that the cancer survivors have a better quality of life and reduce their risk of life threatening cardiovascular events.
1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin
2. Colombo A, Cipolla C, Beggiato M, Cardinale D. Cardiac toxicity of anticancer agents. Curr Cardiol Rep
3. Eyre H, Kahn R, Robertson RM, et al. Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association. Circulation
4. Vejpongsa P, Yeh ET. Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol
5. Octavia Y, Tocchetti CG, Gabrielson KL, et al. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol
6. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol
7. Madonna R, Cadeddu C, Deidda M, et al. Improving the preclinical models for the study of chemotherapy-induced cardiotoxicity: a Position Paper of the Italian Working Group on Drug Cardiotoxicity and Cardioprotection. Heart Fail Rev