Cardio-oncology: a novel platform for basic and translational cardiovascular investigation driven by clinical need
Year: 2019
Type: editorial
Abstract: Cardio-oncology represents the intersection of cardiology and oncology and has emerged as a new clinical discipline in cardiovascular medicine for several reasons (Figure 1). Traditional, targeted, and immune-based cancer therapies have played a critical role in the current revolution in oncology; rendering previously fatal cancer types into chronic diseases. However, these therapies are associated with cardiovascular and metabolic sequelae, which are increasingly being recognized as novel clinical presentations and disease entities.1 Unlike earlier toxicities reported with anthracyclines and trastuzumab, where systolic cardiac dysfunction was the primary manifestation, novel drugs can cause lead to heterogeneous cardiovascular manifestations including arrhythmias, vascular dysfunction, and metabolic perturbations.2,3 Thus, while initially focused on immediate cardiac toxicity, links between cancer and cardiovascular disease appears much more complex on both pathophysiological and clinical level. For example, it has become clear that a wide range of traditional and novel cancer therapies affect several mechanisms of cardiovascular comorbidities including vascular dysfunction, atherogenesis, epigenetics, and others in a similar manner to classical risk factors of atherosclerosis. As a result, cardiovascular disease represents a clinical challenge in the growing number of cancer survivors (over 16 500 000 Americans in 2019), who are disproportionately at risk of cardiac, vascular, and metabolic diseases.4 Finally, the emerging field of cardio-oncology includes the increasing recognition of common risk factors that predispose to both cancer and cardiovascular disease, by far the leading causes of morbidity and mortality in the world.1 In almost every scenario, the novelty of these cardiovascular issues has required collaboration between oncologists and cardiologists, as well as translational and clinical investigators, who have helped describe these new therapy-associated clinical syndromes. The world of cardio-oncology. The intersection between cancer and cardiovascular disease extends beyond cardiovascular and cardiometabolic toxic effects that are associated with cancer treatment. Besides direct cancer toxicities (e.g. amyloidosis), there is a growing appreciation of common risk factors that predispose patients to both cancer and cardiovascular disease, which are by far the two most common causes of death and complications in industrialized countries. This latter concept may have major implications for public health, including for all cancer survivors (numbering more than 17 million in the United States alone). A simple ‘ABCDE’ approach, which has been proposed to prevent cardiovascular disease in cancer survivors, may have the added benefit of protecting patients from the recurrence of cancer. Figure from Ref.1 Cardio-oncology may also serve as a new platform for basic and translational investigation (Figure 2). Advancement of clinical care for patients in a cardio-oncology clinic, where new clinical entities are often encountered, requires better understanding of underlying pathophysiology and mechanistic delineation. Basic laboratory investigation modelling these toxicities can have immediate relevance to patient care and may formulate new hypotheses about preventive and treatment strategies that can be immediately tested in the practice of a robust cardio-oncology practice. Finally, cardiovascular sequelae of novel therapies that target specific signalling pathways in the cell, as an unexpected side benefit to more effective cancer therapies, may also offer new insights into human cardiovascular and metabolic biology. Like human genetics, cardio-oncology offers an opportunity to start at the cardiovascular phenotype in humans and takes a reductionist approach in preclinical models to understand the cardiovascular and cardiometabolic pathways in the heart and vasculature (Figure 3).5 Bed to bench to bed in cardio-oncology. Mechanistic investigation of cardiovascular sequalae of novel targeted cancer therapies can both have immediate translation for the cardio-oncology population but may also provide insights into human cardiovascular biology. Cardio-Oncology as a platform for investigation. Like genetics, cardio-oncology can serve as a rich vein for mining discovery, in part because the initial observation occurs at a human level. This contrasts with the traditional ‘bottom up’ basic science which starts at the level of a molecule with subsequent experimental models with the hope is that this will ultimately prove relevant to humans. The latter may not be the case for many reasons. CV, cardiovascular. This compendium in Cardiovascular Research highlights some of the many advances in basic and translational research in cardio-oncology in recent years. The growing recognition of common risk factors are captured in three manuscripts. Libby and Kobold6 examine both old and new data implicating inflammation as a common risk factor for heart disease. Patel and Natarajan7 describe clonal haematopoiesis of indeterminate potential, where somatic mutations in specific genes in blood cells can lead to haematological cancers and atherosclerosis. Finally, Meijers and de Boer8 summarize the growing awareness of patients with heart failure and cancer including recent data that suggest that heart failure is associated with increased tumourigenesis. Immunotherapies, specifically immune checkpoint inhibitors (ICIs), harness the immune system in the fight against cancer, and have already changed the natural course of several cancer types, but can cause immune-related adverse events.9 Cardiovascular toxicities may include myocarditis, pericarditis, and vasculitis.10–12 Hu et al.13 discuss these new clinical syndromes while proposing diagnostic, preventive, and treatment strategies. Lichtman et al.14 define the role that immune checkpoints play in normal cardiovascular homoeostasis and the biological plausibility for ICI-associated myocarditis and other toxicities. This is also important as immune checkpoints appear to play a key role in vascular biology as well.15 Arrhythmias can be a side effect of other cancer therapies. Salem et al.16 discuss the role that hormones play in the electrical conductance of the heart and how hormonal therapies, used in breast and prostate cancer, can lead to potential arrhythmias. Roden17 discusses how anti-cancer therapies, such as kinase inhibitors, with QT prolonging liability have defined new pathways whereby drugs can prolong the QT interval. Danser et al.18 focus on angiogenesis, vascular endothelial growth factors inhibitors and associated hypertension, proteinuria, and other cardiovascular toxicities that can occur from these therapies. Chow et al.19 expand on the vast body of knowledge accrued from paediatric survivors of cancer in the cardio-oncology field. Finally, Raber and Asnani20 describe the current state of knowledge regarding cardioprotective strategies, especially with anthracyclines. Mechanistic understanding of cancer and cancer-related toxicities require pre-clinical models. While rodents have been helpful in delineation of some toxicities (e.g. anthracyclines), human based models are clearly needed. The use of human-induced pluripotent stem cells that are then differentiated into cardiomyocytes (iPSC-CM) have the potential to expand these models and bring a personalized approach to the field of cardio-oncology. Two articles, by Burridge et al.21 and Wu et al.,22 complementarily describe the potential for iPSC-CM as well as the current limitations and pitfalls of the technology. Cardio-oncology has clearly emerged as a new frontier in clinical medicine in the past decade. However, with the emergence of new therapies and the growing number of survivors, there is a new dimension to the field every single year. Five years ago, it would have been difficult to predict the prominent role that immunotherapies would play in cardio-oncology. Today, as survivors of metastatic cancers enter their second decade of life, it is upon us to study the long-term effects of immunotherapies on the heart and the cardiovascular perils that may await these patients. The many unanswered questions in the field will require collaboration between basic and translational researchers combined with astute clinicians in a cardio-oncology unit. It may help generate novel and safer drug delivery systems that may be devoid of adverse cardiovascular effects.23 On a larger scale, it will also require input from the many subspecialists in a cardiology division and many experts in science (Figure 4). In the case of ICI-associated myocarditis, for example, input from an immunologist and a myocarditis specialist is critical in better caring for patients. More than a decade ago, cardio-oncology emerged with cardiovascular clinicians in several big cancer centres. Today, a successful cardio-oncology programme needs the backing of a deep and multi-faceted cardiovascular division to advance the field. In this compendium, we introduce the many aspects of the field with the hope that the reader can appreciate the unique position cardio-oncology can play in cardiovascular science. Indeed, the explosion of clinical syndromes being identified along with many unanswered questions in the field, make cardio-oncology a unique opportunity for a physician-scientist. Multi-faceted aspects of a cardio-oncology division. In 2019, a successful cardio-oncology programme will need the backing of a scientifically deep cardiology division and integration with multiple aspects of basic and translational research. Multi-faceted aspects of a cardio-oncology division (example of Vanderbilt Cardio-Oncology Programme). We hope this compendium captures the many advancements in basic, translational, and clinical research in the burgeoning field of cardio-oncology. We thank Dr Jiun-Ruey Hu (Vanderbilt) for critical review of this editorial. Conflict of interest: none declared.
Source: Cardiovascular Research
DOI: 10.1093/cvr/cvz048
Authors: Javid Moslehi, Keigi Fujiwara, Tomasz Guzik
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2924647204