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. 2023 Sep 27;75(6):398–402. doi: 10.1016/j.ihj.2023.09.004

Reverse cardio-oncology: A budding concept

Chhabi Satpathy a, Trinath Kumar Mishra a,∗, Subhasish Singh a, Anshu Kumar Jha b
PMCID: PMC10774571  PMID: 37774949

Abstract

Having established the significance of cardiovascular side-effects of anti-neoplastic drugs, present day cardio-oncology has forayed into newer territories buoyed by research into the multiple connections that exist between cardiovascular disease and cancer. An emerging concept of reverse cardio-oncology focuses on the heightened risk of cancer in patients with cardiovascular disease. Common mechanistics of cancer and heart failure (HF) like chronic inflammation and clonal haematopoesis as well as common predisposing factors like obesity and diabetes underline the relation between both cardiovascular disease and various cancers.This review discusses the potential magnitude of the problem, the underlying pathophysiological mechanisms and classification of this novel subject.

Keywords: Cardio-oncology, Cancer, Cardiovascular disease, Anti cancer treatment

1. Introduction

The total estimated number of incident cases of cancer in India in the year 2022 was found to be 1.4 million which is estimated to increase by 12.8% by the time we reach 2025.1 However, cancer treatment has advanced significantly in recent years, offering improved survival rates and better quality of life for patients. But this also increases the number of patients surviving with cancer. In United States alone there would be 22 million such patients by 2030.2 A few years back cancer and cardiac diseases were considered as two different entities and the only common point between them was the adverse effects on the cardiovascular system (CVS) caused by cancer therapies, including chemotherapy and radiation which lead to cardiovascular toxicity and an increased risk of heart-related complications. This section was basically dealt by the cardiologists who took special interest in treating patients with cardiovascular diseases (CVD) due to anticancer treatment (cardio-oncologists). This emerging field of research led to the foundation of cardio-oncology which aims to better understand and manage the cardiovascular complications in cancer patients. In recent times, a new approach known as "reverse cardio-oncology" has gained attention among researchers and clinicians. Reverse cardio-oncology basically focuses on a reciprocal approach of CVD influencing the cancer pathogenesis. It has been observed that patients with CVD are more prone to develop cancer when compared to general population.3,4 Also, there are substantial evidence from the pre-clinical studies done by Meijers et al and Avraham et al which show cancer cell proliferation and metastasis in animal models of heart failure and cardiac remodelling. Whether this has a causal relationship or is just a finding due to common risk factors like alcohol, smoking, pro inflammatory states like atherosclerosis, hypoxia or obesity, diabetes, etc still remains in question.5 This review will try to elaborate the common risk factors and their association to both CVD and cancer. Further, we discuss the mechanisms that conciliate the cross talk between CVD and cancer. In addition to it we shall also discuss the newly proposed classification of cardio-oncology syndromes.

2. Interplay between cardiovascular disease and cancer

2.1. Shared risk factors and co-morbidities

Both CVD and cancer share various mutual risk factors which somewhat explains their simultaneous manifestation. Hypertension is seen to be associated with higher incidence of cancer in men as proven by a prospective study spanning over 12 years done by Stock et al. Also, it was found that there exists a positive correlation between cancer mortality, with hazard ratio per 10-mmHg increment of 1.12 (95% CI: 1.08–1.15) for men and 1.06 (95% CI: 1.02–1.11) for women.6 Various meta-analysis showed that hypertensive patients were also at risk of developing renal cell carcinoma and may be at higher risk of colorectal, breast, endometrial and prostate cancer.7 Having said that, the research work also hinted at careful interpretation of data as most meta-analysis had taken studies with mild to moderate relative risk with high chance of residual confounding. As far as treatment of hypertension is concerned, in the landmark ALLHAT trial cancer was the main cause of non cardiovascular death.8 There is a meta-analysis of 70 Randomised Control Trials (RCT) were the result neither supported that any of the blood pressure lowering drug promotes cancer, nor that any of these strategies protect against cancer.9 Thus this area remains a field of active research due to much disparity in the results of the published data.

Type 2 diabetes mellitus is a well established risk factor for CVD having both macro as well a micro vascular complication. In 2010 American Diabetic Association released a consensus report which suggested that cancer incidence is associated with diabetes.10 Diabetes is a risk factor for certain solid malignancies, such as pancreatic (especially type 3c), liver, colon, breast, and endometrial cancer.11 Anti diabetic drugs like pioglitazone have a well established relationship with bladder cancer.12 Conversely metformin and SGLT2 inhibitors, latter being used for CVD even in absence of diabetes, have shown to have anticancer properties.13

Obesity is a CVD risk factor which has been shown to create a microenvironment for cell growth, proliferation and survival by altering the growth factor and signalling pathway due to various mutagenic reactive oxygen species.14 A prospective study of 16 years follow up done by Calle et al reported that in patients with Body Mass Index (BMI) of >40 in men, the relative risk of cancer related death was 1.52 (95 percent confidence interval, 1.13 to 2.05) for men and 1.62 (95 percent confidence interval, 1.40 to 1.87) for women.15 Also, it has been found that for every 5% increase in BMI the risk of cancer increases by 10%.16

Pooled analysis of various prospective studies consisting of 1.44 million adults suggest that physical inactivity increases the risk of 13 types of cancer.17 A dose–response effect of physical activity on cancer mortality was inferred from findings from 71 prospective cohort studies which showed that 2.5 h/week of moderate–intensity activity resulted in 13% reduction in cancer mortality. Apart from that the study also suggested physical activity after a cancer diagnosis may result in significant protection among cancer survivors.18 Various mechanisms via which physical inactivity leads to cancer incidence and progression have been explained further in this article.

Dyslipidemia is one of the leading cause of CVD and has now been found to have links with development and progression of cancer though the results are mixed.19 In mice model it has been well proven that hypercholesterolemia has a role to play in development of breast cancer.20 Tumor-induced hyperlipidemia creates a feed-forward loop which reprograms hepatic lipoprotein homeostasis where LDL cholesterol supports tumour growth.21 On the other hand there are reports of retrospective longitudinal cohort study from the UK Algorithm for Co-morbidity, Associations, Length of stay and Mortality (ACALM) registry which say that patients with a diagnosis of hyperlipidemia have a reduced risk of developing breast cancer.22 Zahao J et al showed that hypercholesterolemia is an associated risk factor for differentiated thyroid cancer.23 Looking at the ambiguity of the data further researches are required to know the association of dyslipidemia and cancer.

2.2. Effect of anticancer treatment on cardiovascular system

Treatment of cancer by means of either chemotherapy, radiotherapy, immunotherapy or targeted therapy have show to negative impact on the CVS. Though the data with the novel immunotherapy and targeted therapies are limited but chemo and radiotherapy are a major cause of morbidity as well as mortality in people living with or surviving with cancer.24 Most well studied anticancer therapy drug with respect to cardio toxicity is the anthracycline group. They ensue their cardiotoxic effect via reactive oxygen species (ROS) production, which is one of their chief mechanism to destroy tumour cells. But these ROS cause mitochondrial swelling in the cardiomyocytes and increasing their permeability. Following this Cytochrome c is released and the apoptotic pathway is activated.25,26 The effect on Calcium regulation is significant. There is inactivation of ATP dependent Calcium channel, Sodium Calcium exchange pump and Ryanodine receptor 2 protein.27 Anthracyclines also lead to modifications at the epigenetic levels. They interfere with DNA methylation due to post-transcriptional modification of sirtuins and histone deacetylase proteins.28 Role of this mechanism affecting the cardiac myocytes are well established.29

Talking about platinum group of anticancer drugs, the p38-mitogen-activated protein kinase and Janus kinase pathway are their main target for inducing apoptosis in tumor cells. But this also kills the cardiac cells.30 Apart from this, it has been found that the serum level of Platinum in the treated patients is higher. This leads to endothelial damage, increase in t-PA (tissue plasminogen activator), fibrinogen, vWF (von Willibrand factor).31

Alkylating agents like Cyclophosphamide have shown to cause heart failure and conduction blocks.32 Apart from causing oxidative stress it also causes nitrative stress due to its metabolic byproduct acrolein.33 These lead to degeneration and vacuolisation of myocardial cells.

Antimetabolites are commonly used for leukaemia, lymphoma, lung cancer, breast cancer, etc. But apart from that, its cardiotoxic side effects are well documented. Various pathways which lead to damage and death of cardiac myocytes are, decrease expression of Bcl-2 protein, increase p53 expression and CD68.34 Leakage of Potassium occurs leading to arrhythmia which causes increase oxygen depletion. This causes accumulation of 2,3-bisphosphoglycerate thus decreasing ATP level leading to ischemia.35

Radiotherapy is one of the important modalities to treat various cancer like thyroid, prostate, breast, etc. Their main mechanism of action is by causing breakage of the DNA strands which leads to lysis of the tumour cells. But this action leads to simultaneous cardio toxicity and it is dose dependent. At 1–4 Gy the atherosclerotic process and various other inflammatory process are accelerated. Between 4 and 5 Gy chances of myocardial infarction and angina are increased. Above 8 Gy exposure fibrosis of cardiomyocytes occurs.36

Targeted therapy which include monoclonal antibodies have brought a storming change in treatment of cancers like breast cancer, lung cancer, various leukemias and bladder cancer to name a few. Their main mechanism to cause cardio toxicity is by interfering with intracellular signalling pathway. This causes oxidative stress, endoplasmic reticular stress and apoptosis, finally ending up with cardiac injury.37

The latest target for treatment of cancer is the immunotherapy which causes checkpoint inhibition of cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1). Inhibition of CTLA-4 expression in heart increases CD8 T cells and thus activation of cytokine release syndrome. This ends up with heart failure, arrhythmia and myocarditis.37

3. The connecting link between cardiovascular disease and cancer

A simplified diagram of this new concept has been shown in Fig. 1. Study done by Libby et al showed that inflammation is the main culprit which leads to both initiation and progression of cancer and cardiovascular disease.38 When myocardial infarction occurs, it stimulates a chain of signalling molecules like mitogen activated protein kinases and NF-κB. Eventually pro inflammatory genes are activated and the tissue surrounding at microscopic level is altered which forms a niche for malignancy.39 The CANTOS study (Canakinumab Anti-inflammatory Thrombosis Outcome Study) revealed the role of Canakinumab, an IL-1β antibody as a potential target in myocardial infarction. The beneficial effects were also seen extending to the cancer group (especially lung cancer) where the total mortality was less as compared to placebo.40 Apart from this, another evidence in support of inflammatory link between these two diseases came from the work done by Meijers et al where they corroborated the fact that ⍺-1-antichymotrypsin, a well known systemic inflammatory marker, leads to proliferation of HT-29 cell of colorectal cancer via the protein kinase B pathway.41

Fig. 1.

Fig. 1

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The vicious cycle of reverse cardio-oncology (on the left) and cardio-oncology (on the right) PDGF - Platelet Derived Growth factor, VEGF - Vascular Endothelial Growth Factor, HIF-1 - Hypoxia-Inducible Factor 1.

Clonal hematopoiesis is the latest concept which acts as a crossroad between CVD and hematological cancers. With age there are some somatic mutations which occur in the hematopoietic cells. Some of the important genes are TET2 (Ten-Eleven Translocation-2), DNMT3-⍺ (DNA Methyltransferase 3A), ASXL1 (Additional Sex Combs Like 1), JAK2 (Janus Kinase 2) and TP53 (Tumour Protein 53).42 Though these mutations don't cause cancer but instead they cause “Clonal hematpoiesis of indeterminate significance”. TET2 and DNMT3-⍺ mutations are linked to atherosclerotic CVD, thrombosis and heart failure. DNMT3-⍺, TET2, ASXL1 and JAK2 are the potential cross connections between heart failure with preserved ejection fraction and reduced ejection fraction, atherosclerosis, thrombosis and haematological malignancy.43

There are various other molecules which have common association between CVD and cancer. A few of them are discussed here. Hypoxia-inducible factor 1 (HIF-1) is released whenever a cell doesn't get enough oxygen and this is a common pathology in CVD. This HIF-1 is involved in development of atherosclerosis, induces angiogenesis, helps in tumour growth by inciting antiapoptotic factors.44 In conditions like heart failure various cardiokines are secreted which may be either pro-inflammatory, cardioprotective or cardiotoxic. The interplay between these lead to growth and proliferation of tumour cells. Apelin is a member of adipokines family which are bioactive mediators released by adipose tissue. Their levels have been found to be elevated in various cardiac conditions. Several possible mechanisms have been proposed which blame Apelin as an important factor leading to migration of cancer cells. p-21 activated kinase (PAK1)/cofilin signaling pathway, mitogen-activated protein kinase (MAPK) signalling pathway, AMP-activated protein kinase pathway, phosphatidyl inositol 3-kinase/protein kinase B (PI3K/Akt), and peroxisome proliferator-activated receptor (PPAR) pathways in lung adenocarcinoma, gastric cancer, oral squamous cell carcinoma, ovarian cancer.45 Currently researches have focussed on the various micro RNAs (miRNAs) which act as common link between CVD and cancer. miR-17∼92 cluster is involved in tumorigenesis and tumor vascularisation. Similarly there are various domains of miRNAs which contribute to fibrosis and immune response of cardiac myocytes and survival of tumour cells.46 These links give us a chance to target on those areas which are common to both CVD and cancer so that we kill two birds in one shot.

Reverse cardio-oncology in cases of heart failure - There are plenty of data from animal studies to community based cohort studies to suggest a link between heart failure and cancer. Study by Meijers et al took into account NT-proBNP levels to diagnose heart failure and surprisingly found that NT-proBNP levels correlate well with the incidence of cancer.41 Another proof of cancer inducing/promoting effect of heart failure was demonstrated in an animal model. In this study, the mice with heart failure showed increased proliferation of polyps in colon and was supported by increase in Ki67 plasma levels suggestive of colon cancer. Also, this study proved that the chances of cancer was equal for both heart failure with reduced ejection fraction and preserved ejection fraction.41

Reverse cardio-oncology in cases of atrial fibrillation - The most common cardiac arrhythmia is AF. The index case report of AF leading to cancer was published in 1994. Since then, various studies have supported the temporal association of AF with cancer. Two of them with most significant associations are - Women Health Study group, in which cancer developed in 10% of patients with new onset AF.47 Second is a published report of Danish registry which proved that after being diagnosed of AF, a time period of as less as 3 months was sufficient to develop cancer with absolute risk of 2.5%.48

Reverse cardio-oncology following myocardial infarction - Animal studies done on mice model by Koelwyn et al showed that MI could alter the progression of cancer cell proliferation. In this study the mice being studied developed spontaneous breast cancer and the cancer cell proliferated mainly due to increased level of monocytes.49 High plasma levels of circulating monocytes have been well documented to worsen the cancer outcomes. A meta-analysis of 221,994 patients from various studies showed that incidence of cancer post MI was more common in females than males and out of all cancers, lung cancer had the highest incidence rate.50

4. Proposed classification of cardio-oncology syndrome

De Boer and team, in their research article have tried to categorise Cardio-Oncology Syndrome (COS) into 5 types. COS type 1 - Progressive development of cancer leading to CVD, COS type 2 - Treatment of cancer causing CVD, COS type 3 - Progressive remodelling of heart creating a pro-oncogenic microenvironment, COS type 4 - CVD associated treatment leading to pro-oncogenic environment and COS type 5 - Systemic and genetic condition causing both CVD and cancer. Classifying COS into these sub-categories shall help us to better focus on treatment. Instead of having one medicine for all types of patient more specialised treatment will give better outcome. Though this is just a proposal, but then it will be requiring modifications from time to time as our understanding of COS improves. Currently the category of patient depends heavily on which disease is being diagnosed first, CVD or cancer.16

5. The future of reverse cardiac oncology

Reverse cardio-oncology is an upcoming area of research. A lot has been done and a lot is still unexplored. Our knowledge regarding this subject at the molecular level has started to unearth itself and with this background knowledge we should try to transfer our skill from laboratory to bedside clinics. Previously it was thought that CVD can only arise due to cancer or its treatment until recently this concept was found to be true other way around also. Both cardiologists and oncologist need to pay special attention to this sub-population of patients and involve as many as cardiac patients in the cancer trials and as many as cancer patients in cardiac trials to better understand the interplay between these two systems. Though we have much clarity of cardiac oncology, the understanding of reverse cardiac oncology is blurred as clinical trials, cohort studies, reviews and meta-analysis give inconclusive results. Absence of any strict guideline to diagnose patients with reverse cardiac oncology, lack of multicentric randomised trials and trained specialist dealing with this reverse concept are the pitfalls which needs to be addressed. Detailed phenotyping and pinpoint genotyping of the disease shall help the clinicians develop a treatment algorithm focussing this newer concept of “reverse cardiac oncology”.

Source of funding

None.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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