Mechanisms shared between cancer, heart failure, and targeted anti-cancer therapies

Abstract

Heart failure (HF) and cancer are the leading causes of death worldwide and accumulating evidence demonstrates that HF and cancer affect one another in a bidirectional way. Patients with HF are at increased risk for developing cancer, and HF is associated with accelerated tumour growth. The presence of malignancy may induce systemic metabolic, inflammatory, and microbial alterations resulting in impaired cardiac function. In addition to pathophysiologic mechanisms that are shared between cancer and HF, overlaps also exist between pathways required for normal cardiac physiology and for tumour growth. Therefore, these overlaps may also explain the increased risk for cardiotoxicity and HF as a result of targeted anti-cancer therapies. This review provides an overview of mechanisms involved in the bidirectional connection between HF and cancer, specifically focusing upon current 'hot-topics' in these shared mechanisms. It subsequently describes targeted anti-cancer therapies with cardiotoxic potential as a result of overlap between their anti-cancer targets and pathways required for normal cardiac function.

Keywords: Cancer; Cardiotoxic drugs; Heart failure; Mechanisms.

Graphical Abstract

Figure 1

Metabolic alterations in heart failure and cancer. Heart failure and cancer are characterized by several overlapping changes in metabolic pathways. Both diseases are characterized by an increase in glycolysis and a decrease in oxidative respiration. Glycolytic intermediates are redirected into branch pathways for nucleotide and lipid synthesis. Alternative fuel sources are used for the Krebs cycle, a mechanism called anaplerosis, to compensate for the decreased acetyl-CoA levels for ATP production. Adjusted from DeBerardinis et al. and Garcia-Ropero et al.

Figure 2

The overlapping effects of microbial dysbiosis in HF and cancer. Overgrowth of pathogenic bacteria and decreased SCFA levels can induce intestinal inflammation, resulting in increased circulating PAMPs, which can induce cardiac fibrosis and dysfunction. Increased circulating levels of microbial metabolite TMAO can induce atherosclerotic plaque formation and HF. In cancer increased TMAO and pathogenic bacteria can directly promote tumour growth by activating immune cells. In addition, pathogenic bacteria can directly promote tumourigenesis by activating Wnt/β-catenin signalling. Decreased SCFA levels are favourable for tumourigenesis and tumour cells actively inhibit SCFA uptake.