Abstract

The field of cardio-oncology has traditionally focused on the impact of cancer and its therapies on cardiovascular health. However, growing clinical and preclinical evidence suggests that the reverse may also be true: cardiovascular disease (CVD) can influence tumor growth and metastasis.

Several epidemiological studies have reported that individuals with existing cardiovascular disease have a higher incidence of cancer. These findings suggest a possible bidirectional relationship between the two conditions.

Preclinical research further supports this concept. Mouse models of myocardial infarction, heart failure, and cardiac remodeling demonstrate that cardiovascular disorders can accelerate the growth of solid tumors and promote metastasis.

These discoveries have led to the emergence of a new and expanding field known as reverse cardio-oncology. This area of research investigates how cardiovascular disease pathophysiology contributes to cancer development and progression.

Recent studies have begun to clarify the mechanisms underlying this connection. Proposed pathways include shared risk factors, immune system reprogramming, altered gene expression, and the release of cardiac-derived factors that create a tumor-promoting environment.

In this review, we examine the evidence linking cardiovascular disease and cancer, explore the mechanistic pathways connecting them, and discuss the clinical implications for patient care.

Graphical Abstract

Highlights

• Cancer and cardiovascular disease share risk factors, including advanced age, hypercholesterolemia, obesity, and diabetes, as well as common pathophysiological pathways such as oxidative stress and inflammation.
• While studies show that cancer patients experience higher rates of cardiovascular disease due to oncological therapies, evidence increasingly suggests that the relationship between these two diagnoses is bidirectional.
• Recent observational studies indicate that patients with cardiovascular diagnoses, such as heart failure and myocardial infarction, develop cancer more frequently than the general population.
• Mechanistic inquiries have elucidated several modalities by which incident cardiovascular events can directly impact tumor growth, including cardiac-derived factors, extracellular vesicles, and immune reprogramming.
• Strategies to modify cardiovascular risk factors may also beneficially impact cancer incidence. Pending investigation in clinical trials, existing therapeutics could potentially decrease cancer incidence in patients with cardiovascular disease.

Cancer and cardiovascular disease (CVD) are two leading causes of death worldwide. Despite major improvements over the past three decades in detection, treatment, and prevention, mortality from both conditions continues to rise globally. Together, they account for nearly 30 million deaths each year.

Although historically considered separate diseases, researchers increasingly recognize that cancer and CVD share common risk factors and pathophysiological pathways.
Researchers first identified this connection among cancer survivors, noting that they face a significantly higher risk of developing CVD compared with the general population.

Researchers later attributed much of this increased risk to the harmful cardiovascular effects of cancer therapies, including radiation and certain chemotherapies such as anthracyclines.

More recently, studies have shown that cancer itself acts as an independent risk factor for CVD, suggesting that the two diseases may share underlying biological mechanisms.
In addition, while immune checkpoint inhibitors have revolutionized cancer treatment, researchers have observed that they can cause cardiovascular complications.

These include myocarditis, atherosclerosis, pericardial disease, and arrhythmias.

Please see www.ahajournals.org/atvb/atvb-focus for all articles published in this series.

Understanding the relationship between cancer and CVD is increasingly urgent. Cancer patients now survive longer due to effective therapies, many of which carry frequent cardiovascular complications. In addition, an aging population faces risk for both diseases.
Retrospective and prospective cohort studies show that individuals with prior CVD, such as heart failure (HF) or myocardial infarction (MI), have higher rates of cancer. These findings provide strong evidence of a bidirectional relationship, especially for lung, breast, and colorectal cancers. Shared risk factors may partly explain this link.

Preclinical studies use orthotopic mouse models of lung and breast cancer and genetically modified models of breast and colorectal cancer with MI, HF, or cardiac remodeling. These studies show that cardiovascular conditions trigger additional pathological pathways. These pathways promote cancer growth and metastasis.

In this brief review, we outline the interactions of risk factors, immune responses, and cardiac-derived signaling mechanisms that lead to CVD-induced cancer pathology, as well as the epidemiological and preclinical studies illuminating the oncogenic impact of CVD.

Shared Risk Factors Between CVD and Cancer

Nearly 50% of Americans over the age of 20 years have evidence of CVD. In fact, CVD-related deaths recently increased in the United States, reversing a decades-long trend of decline. Similarly, incidences of many malignancies, including lung, breast, and colorectal cancer, have increased in people under 50 years of age. These rates are predicted to remain elevated. CVD and cancer share several common risk factors, including advanced age, smoking, hyperlipidemia, obesity, diabetes, and hypertension. These associations indicate shared pathogenic drivers in CVD and cancer, and evidence shows that patients with multiple traditional cardiovascular risk factors face a higher risk of developing cancer.

Aging

Aging is a risk factor for CVD as well as most cancers. As cells enter senescence, or cell cycle arrest, they release substances such as matrix metalloproteinases and cytokines. These molecules trigger nuclear changes and promote the expression of altered molecular markers. The resulting inflamed environment damages cardiovascular tissues. It causes vascular endothelial dysfunction and fibrosis, cardiac hypertrophy, and loss of arterial elasticity. These physiological alterations cause stroke, HF, atrial fibrillation, MI, and hypertension, among other clinical concerns. 

The senescence-associated secretory phenotype contributes to cancer. Inflammatory mediators create an oncogenic environment. They promote cellular accumulation and activate antiapoptotic pathways. These changes combine with declining immune defenses to drive tumor growth and proliferation. The effect intensifies in the presence of genomic instability, epigenetic alterations, or prolonged exposure to metabolic and environmental stressors.

Smoking

Smoking has long been recognized as a leading cause of both CVD and cancer. Chemicals in tobacco smoke adversely affect the cardiovascular system via physical damage to vascular endothelial cells as well as induction of vessel remodeling, inflammation, and a procoagulatory environment. These insults subsequently potentiate aneurysm, thrombosis, and plaque formation. This oxidative stress also causes direct damage to DNA, increasing the mutational burden and inducing tumorigenesis as these alterations compound over time. Additionally, epigenetic changes instigated by tobacco smoke have been shown to influence tumor aggression and responsiveness to medical therapies.

Hyperlipidemia

Hyperlipidemia is commonly implicated in MI, stroke, and peripheral atherosclerosis as well as malignancies. In a hyperlipidemic state, plaque accumulates in arteries, decreasing blood flow to the point of eventually inducing acute ischemia. Although researchers have not fully established the link between hyperlipidemia and cancer, recent studies show that elevated blood lipids raise angiotensin II levels. Angiotensin II then stimulates VEGF (vascular endothelial growth factor), a protein that promotes tumor growth.angiogenesis. Furthermore, evidence increasingly suggests that malignant cells rely upon cholesterol to facilitate rapid growth. Statins and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors lower cholesterol levels. They can help prevent multiple cancers, including esophageal, hematologic, colorectal, pancreatic, and hepatic malignancies.

Obesity

Obesity also leads to CVD secondary to widespread inflammation causing thrombosis and syndromes of vascular endothelial dysfunction, including the acceleration of intra-arterial plaque deposition. Some of these cellular adaptations also favor tumor initiation and progression secondary to alterations in nutrient metabolism. Data suggest, for instance, that shifts in cholesterol metabolism can cause reprogramming of T cells to suppress antitumoral immune capabilities. Finally, obese patients have elevated total blood volume due to greater perfusion requirements of adipose tissue. Increased blood volume in turn increases cardiac output, eventually causing myocardial adaptations that lead to diastolic dysfunction and HF.

Diabetes

CVD remains the leading cause of morbidity and mortality in patients with diabetes. Insulin resistance disrupts vascular signaling and responses. Elevated blood sugar damages endothelial cells and nerves, promotes plaque buildup, and impairs autonomic control of the vascular system and myocardium.

 Chronic inflammation and oxidative stress incurred secondary to these states may drive microenvironmental changes that favor tumor growth and proliferation. Additionally, high blood glucose fuels tumorigenesis by supporting aerobic glycolysis, the primary energy-generating mechanism for malignant cells, also known as the Warburg effect.

Hypertension

Extensive evidence shows that hypertension both causes and results from CVD. Prolonged high blood pressure can lead to myocardial hypertrophy and HF, in addition to intimal vascular injury that promotes atherosclerosis. In contrast, the mechanistic connection between hypertension and cancer is less defined. Researchers have found that high blood pressure associates with multiple cancer types, including renal, pancreatic, lung, skin, and genitourinary malignancies. Hemodynamic impairment and elevated neurohumoral, inflammatory, or cytokine protumorigenic factors likely drive this link.

Reverse Cardio-Oncology

The risk factors outlined above propose commonly correlated hallmarks of CVD and cancer, including inflammation, genomic instability, cellular metabolism, and oxidative cellular stress. Of course, mutual determinants do not necessarily prove the influence of one disease state over another. A growing body of research, however, has shown that incident cardiovascular events (eg, HF and MI) can directly impact tumor growth, indicating potentially shared causative mechanisms (Figure).

Hasin et al were among the first to document this finding in 2013 after comparing can… Read More