Heart failure (HF) and cancer are tightly linked (1, 2) which is supported by recent studies on epidemiological cohort and case-control, research synopsis and meta-analyses. An increased cancer risk in HF patients was shown by the international cohorts such as America (3–5), Denmark (6), Japan (7), and Korea (8). These studies demonstrate that HF patients have a higher risk to develop cancer, independently of age (9–11). Furthermore, women with HF are at higher risk than men, indicating that gender is an important factor (3). The most common types of cancer in HF patients below age 55 are colorectal (21%), lung (18%), gastrointestinal (20%); prostate (16%) (6).

Cancer patients can develop cardiovascular diseases (CVD) mainly for the three reasons: (1) the anticancer drugs can have direct adverse effect on cardiovascular system (2), soluble factors (secretoms) such as chemokines, hormones, and vesicles released from tumor cells can damage the cardiac cells as a paracrine manner (3), cancer itself or anticancer drugs induce cachexia that leads to cardiac dysfunction (12). As a consequence, approximately 20–30% of cancer patients die from cardiovascular dysfunctions, regardless of the time passed after cancer diagnosis (13). Indeed, 50% of patients with breast, prostate, endometrial, and thyroid cancer die because of CVD (14, 15). In the most aggressive cancer cases such as cancers of the lung, liver, brain, stomach, gallbladder, pancreas, esophagus, ovary, and multiple myeloma, patients die primarily due to cancer (16). However, the CVD -related mortality were higher among the survivals with cancer of bladder (19% of patients), larynx (17%), prostate (17%), uterus (16%), bowel (14%), and breast (12%).

Sturgeon et al. using databases of the Surveillance, Epidemiology and End Results (SEER) found that among the 3,234,256 cancer patients with 28 different types of cancer, 38% of mortality was due to cancer, whereas 11% mortality was from CVDs including hypertension, cerebrovascular disease, arterial diseases, and cardiac ischemia (17). More interestingly, the highest mortality among the younger cancer patients (< 35 years old) 1 year after the cancer diagnosis was due to CVD.

Co-occurrence of both diseases causes a major clinical burden and has a strong outcome on the quality of life and survival rates (10, 18). Early diagnosis and better understanding of bilateral interaction between HF and cancer is critical for an optimal treatment and management strategies, because a one-size-fits-all treatment approach is ineffective for these patients (7, 8).

Here we outline the known common mechanisms and preclinical studies emphasizing the interactions to help mechanistic understanding that may impact on identifying biomarkers and innovative therapeutic strategies targeting both diseases simultaneously.

Any changes in homeostasis by stresses, tissue damage, infection, metabolic alterations induces low-grade inflammation to achieve wound healing and tissue regeneration, and to prevent loss of tissue function (22). However, maladaptive chronic inflammation leads to progressive myocardial injury, development of vascular dysfunction, and reduces cardiac tissue survival. The cytokines chemokines, and lipid mediators are involved in inflammatory signaling. Accordingly, high circulating levels of pro-inflammatory cytokines [e.g., interleukin (IL)-1β, and IL-6] have been found in acute and chronic decompensated HF (23). Many cohort studies (> 50) have showed that both high-sensitive CRP (C-reactive protein) and IL-6 can predict development of myocardial infarction (MI) and stroke (24, 25). However, chronic inflammation predisposes to the development of cancer and affects the tumorigenesis and tumor-permissive state by promoting proinflammatory cytokines and chemokines (26). For example, IL-1β and IL-6 have also been reported as key players in development of cancer (27). Specifically, in the solid malignancies, the infiltration of immune cells and the production of pro-inflammatory mediators play key roles for malignant transformation, via epithelial to mesenchymal transition, and metastasis (28).

In the Whitehall II study cohort, Ridker demonstrated that low level of systemic inflammation detected by increased levels of CRP and IL-6 was associated with prediction of cardiovascular and cancer-related mortality in midlife patients (24). Anti-Inflammatory Thrombosis Outcome Study (CANTOS) has also confirmed this study showing that canakinumab an IL-1β-targeting antibody has beneficial effects on cardiovascular events (29). Moreover, canakinumab significantly decreased incident of mortality in patients with lung cancer.

The role of other inflammatory mediators eicosanoids, such as prostanoids (prostaglandins and prostacyclines) in cancer and CVD has not been extensively investigated yet. For example, prostacyclin has been used to treat pulmonary arterial hypertension (30). Unfortunately, in this condition, the pulmonary cancer incidence has not been studied. In contrary, in mice model prostacyclin prevents lung cancer (31). Unlike prostacyclin, prostaglandin E₂ promotes cancer initiation and lung cancer migration (32) and activates cardiac maladaptive remodeling (33).

All together these studies show that inflammation is one of the shared mechanisms of both HF and cancer. The important question is whether diminishing inflammation can reduce the development rate of CVD and cancer. Use of anti-inflammatory drugs (e.g., low-dose methotrexate, colchicine, and canakinumab) in the large clinical trials should answer this question.

The healthy tissues can derive energy from various circulating substrates. However, metabolic alterations due to accumulation of toxic intermediates and utilization of unbalanced substrates can alter the cardiac cell homeostasis and cancer growth. Indeed, recent studies have shown that onco-metabolic dysregulation can promote cardiac dysfunction (34).

Metabolic reprogramming occurs as an adaptive event in both cancer (35) and cardiac cells (36) in response to pathophysiological insult and stress, indicating that both cells share the same metabolic pathways. In HF and cancer, glucose oxidation and glycolysis are central metabolic pathways to generate energy in the form of adenosine triphosphate (ATP) (37, 38). Cancer cells are dependent on aerobic glycolysis that facilitates the incorporation of nutrients into biomass such as nucleotides, amino acids, and lipids to maintain cancer cell proliferation. Aerobic glycolysis is also needed for the adaptive hypertrophy in cardiomyocytes (39). In cancer cells glutamine is the essential carbon source for aspartate synthesis (40). However, in the damaged heart glycolysis and glucose oxidation are predominant over fatty acid oxidation and are required for pentose phosphate pathway (41).

Because of the upregulated glucose utilization in many solid tumors (42), as well as in the failing heart (43), glucose transporter 1 (GLUT1) becomes an important target for the treatment of cancer and HF. Additionally, it has been shown that sodium glucose co-transporter 2 (SGLT2) inhibition has beneficial effects on the heart as well as in pancreatic and prostate cancers. Thus, inhibition of glucose transports may prevent cardiac hypertrophy (44) and reduce cancer growth (45). However, more extensive researches are required to define their beneficially effects during development and progression of different cancer types and CVDs, before their clinical applications.

De novo lipogenesis leading to lipo-expediency has also emerged as common mechanisms of HF and cancer. Upregulation of fatty acid synthase (FAS), a key enzyme of de novo lipogenesis, has been found in both cancers (46) and HF patients (47). FAS inhibitors have anti-neoplastic properties in solid cancers and represents a potential therapeutic target for HF.

Changes in mitochondrial metabolism is also a common mechanism of HF and cancer development. Inhibition of mitochondrial electron transport chain (ETC) complex I can decrease mitochondrial ATP delivery (48), thereby limiting glucose availability. Additional to ETC inhibitory effects, metformin has been shown to reduce plasma levels of insulin and insulin-like growth factor 1 (IGF-1) to limit glucose availability in the glycolysis-dependent cancer cells (49). In cancer cells (e.g., pancreas cancer), an increased utilization of glutamine, a major substrate for respiration, is required in supporting macromolecule synthesis and maintain the redox homeostasis to contribute cancer growth (50). Thus, inhibitors of glutaminase, a catalyzer of the conversion of glutamine to glutamate, regulate redox balance, and autophagy, induce apoptosis via mTOR signaling, and promote growth arrest. On the other hand, oxidative stress upregulates glutaminase 1 and promotes glutaminolysis in the heart. Inhibition of glutaminase improves maladaptive cardiac remodeling and improves sustain activation of autophagy-mediated reduced cardiac contractility (51).

The common maladaptive metabolism pathways in cancer and HF can provide opportunities to the discovery of new biomarkers, and development of juncture strategies and therapies to battle these diseases, and may anticipate to the metabolic phenotyping of diseases in the precision medicine in the field of cardio-oncology.

Angiogenesis is involved in the pathophysiology of both development of HF (52) and cancer (53). Angiogenesis is crucial for tumor growth and metastasis (54), whereas vascular refraction in the maladaptive sustained pressure overload contributes to the transition from compensated hypertrophy to HF (55). Because of increased oxygen demand in tumor or ischemic hearts, hypoxia upregulates HIF1a that promotes expression of angiogenic factors, such as vascular endothelial growth factor (VEGF) (56), angiopoietin-1 and -2 (57), and prokineticin (58, 59) to stimulate microvascular expansion.

The pharmacological or genetic inhibition of VEGF, and other key angiogenic signaling pathways accelerate the transition from adaptive cardiac remodeling to HF (60), while anti-angiogenic therapy beneficial to cancer (e.g., metastatic colon cancer, non-small cell lung cancer, breast cancer). However, cancer cells develop adaptive resistance to the anti-angiogenic therapy as well as severe cardiotoxicity, leading to development of ischemic CVD and HF (61). Thus, angiogenesis delineates an auspicious substrate for both cancer and HF.

Genetic assets leading to hematologic malignancies such as somatic mutations in hematopoietic stem cells are the potent risk factors for CVD and cancer (62). The mutation on the genes encode for key epigenetic regulators of hematopoiesis leads to the abnormal expansion of clonally derived hematopoietic stem cells (63). A higher frequency of accumulation of hematopoietic mutations in DNA methyltransferase 3 alpha (DNMT3α), Ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) (64) have been found in individuals with lymphoid or solid tumors who are exposure to genotoxic stress (65). Hematopoietic mutations in DNMT3a, TET2, and JAK2^V671F, can accelerate atherosclerosis and the increase risk of CVD by generating a pool of myeloid cells with an augmented proinflammatory profile (66). These mutations are associated with worse outcomes in patients with ischemic HF (67, 68).

Identification of the mechanisms linking somatic mutation-driven clonal hematopoiesis to CVDs is off interest specifically in personalized medicine. There are some questions needs to be addressed such as whether clonal hematopoiesis also contribute to CVD in cancer survivors (69) and whether these mutations can be predictive markers of cardiovascular risk and therapeutic responsiveness.

Recent studies have demonstrated that 50% of non-ischemic cardiomyopathies caused by more than gene variants encoding for cytoskeleton, ion channels, nuclear envelope, intercellular junctions sarcolemma and sarcomeric proteins (70). A genetic predisposition to therapy-induced cardiomyopathy has been observed in families with history of hypertrophic, dilated and arrhythmogenic cardiomyopathies (71). Patients with cardiomyopathy or asymptomatic carriers of inherited cardiac diseases have a potential increased risk for cardiotoxicity induced by anticancer treatment (72).

Interestingly, several of these genes associated with familial cardiomyopathies harbor relevant genetic variants in somatic cancer cells. A high prevalence of somatic mutations in Titin (TTN), Dystrophin (DMD), and Desmoglein 2 (DSG2) have been associated with different stages of carcinogenesis process.

The KEGG (Kyoto Encyclopedia of Genes and Genomes terms) analyses have identified the total of 33 genes and 25 links with 17 metabolic pathways that can be implicated in interaction between genetic cardiomyopathies and molecular pathways of cancer. The genes involved in both cardiomyopathy and carcinogenesis include Protein tyrosine phosphatase, non-receptor 11 (PTPN11) and LMNA, another 12 genes from sarcomeric (thin and thick filament), desmosomal (PKG/JUP), metabolic (PRKAG2, LAMP2, GLA), and calcium handling (PLN) (73). For example, the RAS family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) plays a key role in intracellular signal transduction required for normal cardiac growth, development of hypertrophic cardiomyopathy and HF as well as cancer (74). RASopathies are single-gene inheritance disorder caused by germline mutations in genes that encode constituents or regulators of the RAS/mitogen-activated protein kinase (MAPK) pathway. RASopathies are accompanied with the higher risk of hematologic or solid cancer and congenital CVD (75). For example, hypertrophic cardiomyopathy development during childhood can be triggered by genetic mutations in PTPN11, KRAS, Son of sevenless homolog 1 (SOS1), a RAS effector (RAF1), genes which are also involved in cancer developments (73).

The signaling pathway of wingless-related integration site (Wnt) controls proliferation and differentiation processes in different types of cancer. Indeed, in patients with desmosomal mutations on the Wnt pathway exhibit the histological fibro-adipose differentiation, a characteristic of arrhythmogenic cardiomyocardiopathy (76).

Additional mechanistic studies on damaging gene variants in CVD and cancer can unravel prognostic biomarkers and new treatment strategies for both disorders.

Cancer or anti-cancer drug-mediated cachexia and cancer-secretoms, adverse effects of anticancer drugs may induce several organ dysfunctions and HF as outlined in Figure 3.