Cardio-onco-metabolism: metabolic remodelling in cardiovascular disease and cancer

Abstract

Cardiovascular disease and cancer are the two leading causes of morbidity and mortality in the world. The emerging field of cardio-oncology has revealed that these seemingly disparate disease processes are intertwined, owing to the cardiovascular sequelae of anticancer therapies, shared risk factors that predispose individuals to both cardiovascular disease and cancer, as well the possible potentiation of cancer growth by cardiac dysfunction. As a result, interest has increased in understanding the fundamental biological mechanisms that are central to the relationship between cardiovascular disease and cancer. Metabolism, appropriate regulation of energy, energy substrate utilization, and macromolecular synthesis and breakdown are fundamental processes for cellular and organismal survival. In this Review, we explore the emerging data identifying metabolic dysregulation as an important theme in cardio-oncology. We discuss the growing recognition of metabolic reprogramming in cardiovascular disease and cancer and view the novel area of cardio-oncology through the lens of metabolism.

Fig. 1 |. The central role of metabolic remodelling in cardiovascular disease and cancer.

a | An overview of the metabolic consequences of stressors to the heart, which initially might be compensated for, but in the long term lead to dysfunction of the heart. b | In adult cardiomyocytes (left), the main source of fuel under normal physiological conditions is fatty acids. Stress initiates a shift in nutrient utilization away from fatty acid oxidation (dashed line) and towards glucose, ketone bodies or amino acids (such as glutamine) as sources of energy. These dynamic changes ensure continued ATP provision and maintenance of cardiac contractile function. In cancer cells (right), metabolic reprogramming supports successful adaptation to acquired mutations during tumorigenesis. Both catabolic and anabolic processes are maintained to ensure ATP provision and macromolecule synthesis during tumour growth. c | Post-translational modifications of proteins are linked to energy substrate metabolism and have a key role in the regulation of signalling, gene expression, protein stability and interactions, and enzyme kinetics. Ac, acetyl; α-KG, α-ketoglutarate; Me, methyl; O-GlcNAc, O-linked β-N-acetylglucosamine; P, phosphate.

Fig. 2 |. Metabolism bridges cancer and cardiovascular disease.

Several metabolic stressors and perturbations, including obesity and cachexia, prompt the production and release of metabolic and inflammatory signal peptides and molecules. These systemic effects are accompanied by distinct differences as well as shared features in cardiac tissue and in cancer cells.

Fig. 3 |. Putative mechanisms of cardio-onco-metabolic remodelling.

The presence of cancer and/or the use of anticancer therapies can provoke changes in the organism, such as remodelling of immune cells, that affect the heart. Furthermore, specific oncometa bolites, such d-2-hydroxyglutarate and succinate, can affect the heart tissue directly. Metabolic risk factors can cause cardiovascular disease as well as exacerbate tumour proliferation and cancer progression.

Fig. 4 |. Accumulation of somatic mutations changes the metabolic profile of tumours and influences the cardiovascular system.

Variants (indicated by red stars) in IDH1 or IDH2, encoding cytosolic isocitrate dehydrogenase [NADP] (IDH1) and mitochondrial isocitrate dehydrogenase [NADP] (IDH2), cause increased production and release of the oncometabolite d-2-hydroxyglutarate (D2-HG). D2-HG promotes epigenetic modifications and tumorigenesis. Variants in VHL, encoding von Hippel–Lindau disease tumour suppressor (VHL), are associated with vascular tumours by interference with the hypoxia-inducible factor 1α (HIF1α)–vascular endothelial growth factor (VEGF) pathway. Likewise, variants in succinate dehydrogenase (SDH)-encoding genes increase malignant remodelling and affect transcriptional regulation. α-KG, α-ketoglutarate; AKT, RACα serine/threonine-protein kinase; FH, mitochondrial fumarate hydratase; GLUT1, glucose transporter type 1; KRAS, GTPase KRas; mTOR, mechanistic target of rapamycin; MYC, MYC proto-oncogene protein; p53, cellular tumour antigen p53; PDH, pyruvate dehydrogenase; PI3K, phosphoinositide 3-kinase.

Fig. 5 |. Metabolic targets and interventions in cardiovascular disease and cancer.

a | Inhibitors targeting variant forms of cytosolic isocitrate dehydrogenase [NADP] (IDH1) or mitochondrial isocitrate dehydrogenase [NADP] (IDH2) are efficacious in patients with acute myeloid leukaemia. b | Inhibitors of the phosphoinositide 3-kinase (PI3K) pathway or of fatty acid synthase (FASN), ATP–citrate synthase (ACLY) or stearoyl-CoA desaturase 1 (SCD1) lower plasma levels of glucose or fatty acids and might have beneficial effects in patients with cardiovascular disease or cancer. c | Caloric restriction has beneficial effects in patients with cardiovascular disease or cancer via its pleiotropic effects on various metabolic and inflammatory components. CCL2, C-C motif chemokine 2; IGF1, insulin-like growth factor 1; TNF, tumour necrosis factor.