A new classification of cardio-oncology syndromes

Abstract

Increasing evidence suggests a multifaceted relationship exists between cancer and cardiovascular disease (CVD). Here, we introduce a 5-tier classification system to categorize cardio-oncology syndromes (COS) that represent the aspects of the relationship between cancer and CVD. COS Type I is characterized by mechanisms whereby the abrupt onset or progression of cancer can lead to cardiovascular dysfunction. COS Type II includes the mechanisms by which cancer therapies can result in acute or chronic CVD. COS Type III is characterized by the pro-oncogenic environment created by the release of cardiokines and high oxidative stress in patients with cardiovascular dysfunction. COS Type IV is comprised of CVD therapies and diagnostic procedures which have been associated with promoting or unmasking cancer. COS Type V is characterized by factors causing systemic and genetic predisposition to both CVD and cancer. The development of this framework may allow for an increased facilitation of cancer care while optimizing cardiovascular health through focused treatment targeting the COS type.

Keywords: Cancer; Cardiac Tumours; Cardio-oncology; Cardiotoxicity; Cardiovascular disease; Heart failure; Immune system; Inflammation; Medical diagnostic radiation; Prevention; Prognostic biomarkers.

Fig. 1

Cardio-Oncology Syndromes in Precision Cardio-Oncology. The five types of Cardio-Oncology Syndromes are listed, along with a description of whether they are direct (black arrows), indirect (grey arrows), or secondary and how they are defined. A few examples are given for each type. CHiP, clonal haematopoiesis of indeterminate potential; COS, Cardio-Oncology Syndromes; CV, cardiovascular; TKI, Tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor

Fig. 2

Relationships between CVD and cancer. This schematic demonstrates the multifaceted relationship that exists between CVD and cancer. While CVD is the leading cause of non-cancer related mortality among cancer survivors, there is also a known increased risk for cancer in patients with CVD. Additionally, CVD and therapies for CVD can have both a direct (curved black arrows) and indirect (curved grey arrows) impact on cancer; while cancer and therapies for cancer can have both a direct (curved black arrows) and indirect (curved grey arrow) impact on cardiac function and health. CVD, cardiovascular disease

Fig. 3

Mechanisms by which the development of cancer can lead to CVD (Cardio-Oncology Syndrome Type I). There are three primary mechanisms demonstrated in this schematic to illustrate COS Type I. Patients with cancer have a higher risk for both venous and arterial thromboembolism. Patients with sudden development of cancer may develop tumour lysis syndrome, whereby hyperuricemia may result in acute kidney injury which may have a deleterious effect on cardiac function, and severe hyperkalaemia may result in arrhythmias. Finally, the inflammatory mediators from cancer cachexia may have a negative impact on cardiac function. CVD, cardiovascular disease

Fig. 4

Cardiovascular toxicities of cancer therapies. Cardiovascular toxicities of a wide spectrum of cancer therapies can affect the heart (center, left, and right of figure) or peripheral vasculature (bottom row of figure). Ab, antibody; CDK, cyclin dependent kinase; HER2, human epidermal growth factor receptor 2; ICI, immune checkpoint inhibitor; MT, microtubule; PI, platinum inhibitor; TKI, tyrosine kinase inhibitor; Tx, Therapy. Used with permission; from Brown [23], Creative Commons Attribution License [CC BY]

Fig. 5

Mechanisms by which anti-neoplastic therapies may result in CVD (Cardio-Oncology Syndrome Type II). There are many examples shown here in which anti-neoplastic therapies may result in acute or chronic CVD [22]. Pharmacotherapies, such as anthracyclines and HER2 receptor antagonists may result in myocardial dysfunction and heart failure. Immunotherapy can also induce cardiotoxicity. Radiation therapy may also result in the development of atherosclerosis, as well as damage to the heart valves or pericardium. CV, cardiovascular; ECM, extracellular matrix; HER2, human epidermal growth factor receptor 2. Adapted with permission; from Brown [23], Creative Commons Attribution License [CC BY]

Fig. 6

Mechanisms by which cardiac scarring and remodelling may promote a pro-oncogenic environment (Cardio-Oncology Syndrome Type III). This schematic demonstrates how a pro-oncogenic environment can result from cardiac dysfunction. With cardiac dysfunction (i.e. development of heart failure after a myocardial infarction), increased central venous congestion can result in hypoperfusion for various end organs, which then release stress signals that may increase tumour growth, angiogenesis, and tumour invasiveness. Increased filling pressures may similarly result in pulmonary congestion and the increase in stress signals. Cardiac dysfunction may also result in release of cardiokines, increased oxidative stress, and pro-inflammatory factors which may result in stimulated tumour growth, angiogenesis, and tumour invasiveness

Fig. 7

Schema illustrating potential mechanisms in which chronic CVD and/or CVD-associated treatments may associate with cancer diagnosis (Cardio-Oncology Syndrome Type IV). Anticoagulation therapy may result in bleeding which unmasks cancer. Cardiovascular diagnostic radiation, including CT scans and cardiac catheterizations, may result in oxidative stress, DNA damage, and subsequent promotion of a cancer state. CT, Computerized Tomography; CV, cardiovascular

Fig. 8

Systemic and genetic conditions may result in concurrent cancer and CVD. Smoking, diabetes, and obesity may increase the risk of both cancer and CVD. Genetic predisposition and somatic mutations may also increase the risk for both disease states. CHiP, clonal haematopoiesis of indeterminate potential; CVD, cardiovascular disease

Fig. 9

Theoretical depiction of a clinical situation with a patient consistent with more than a single classification. However, the application of our classification system depends on which disease is diagnosed first and on the available data regarding systemic and genetic predisposition and risk factors [122, 123]

Fig. 10

Theoretical depiction of how the classification can be useful in the clinical setting