Cardiac Cachexia: Unaddressed Aspect in Cancer Patients

Abstract

Tumor-derived cachectic factors such as proinflammatory cytokines and neuromodulators not only affect skeletal muscle but also affect other organs, including the heart, in the form of cardiac muscle atrophy, fibrosis, and eventual cardiac dysfunction, resulting in poor quality of life and reduced survival. This article reviews the holistic approaches of existing diagnostic, pathophysiological, and multimodal therapeutic interventions targeting the molecular mechanisms that are responsible for cancer-induced cardiac cachexia. The major drivers of cardiac muscle wasting in cancer patients are autophagy activation by the cytokine-NFkB, TGF β-SMAD³, and angiotensin II-SOCE-STIM-Ca²⁺ pathways. A lack of diagnostic markers and standard treatment protocols hinder the early diagnosis of cardiac dysfunction and the initiation of preventive measures. However, some novel therapeutic strategies, including the use of Withaferin A, have shown promising results in experimental models, but Withaferin A's effectiveness in human remains to be verified. The combined efforts of cardiologists and oncologists would help to identify cost effective and feasible solutions to restore cardiac function and to increase the survival potential of cancer patients.

Keywords: angiotensin II; autophagy; cancer; cardiac cachexia; chemotherapy; proinflammatory cytokines; withaferin A.

Figure 1

Cancer-induced cachexia involves multiple organs, including the heart and is a systemic phenomenon. GLUT: glucose transporter, APR: acute phase response, PPAR: peroxisome proliferator-activated receptors, EF: ejection fraction, FS: fractional shortening, TDF: tumor-derived factor. “↑” denotes increase. “↓” denotes decrease. Redrawn with modification from ref [5].

Figure 2

Schematic diagram showing the molecular mechanisms underlying cardiac cachexia in cancer patients. Some pathways, such as the cytokine, myostatin, activin, and leptin-mediated signalling pathways, are involved in both skeletal and cardiac muscle wasting. IL: interleukin, ROS: reactive oxygen species, NFkB: nuclear factor kappa B, IGF1: insulin-like growth factor 1, TNF: tumor necrosis factor, TGF: transforming growth factor, ERK: extracellular signal-regulated kinases, ActRIIA: activin type II receptors A, Foxo: forkhead transcription factors, MuRF 1: muscle ring finger protein-1, LC3: microtubule-associated protein 1A/1B-light chain 3, mTOR: mammalian target of rapamycin, NLRP3: NLR family pyrin domain containing 3, TLR: Toll-like receptor, miRNA: micro RNA, JNK: c-Jun N-terminal kinase, ECM: extra-cellular matrix. “↑” denotes increase. “↓” denotes decrease. Redrawn with modification from reference [27].

Figure 3

Diagram showing different sources of reactive oxygen species (ROS) and its probable mechanism for the induction of cardiac atrophy in cancer patients. NOX: NADPH oxidase, cyt b: cytochrome b, GPX-3, 7: glutathione peroxidase 3 and glutathione peroxidase 7, HIF1α: hypoxia inducible factor, PINK1: PTEN induced kinase1. “↑” denotes increase. “↓” denotes decrease. Redrawn with modification from ref [37] under Attribution License (CC BY 4.0).

Figure 4

Molecular mechanisms associated with angiotensin II-mediated cardiac dysfunction. CH₂₅H: cholesterol 25 hydroxylase, TGFβ: transforming growth factor, CF: cardiac fibroblast, MF: myofibroblast, SMA: smooth muscle actin, SIRT3: sirtuin 3, FOXO: forkhead transcription factors, JMJD1C: Jumonji domain containing 1c; histone demethylase, FOXF1: forkhead box protein F1, LKB1: liver kinase B1, AMPK: AMP activated protein kinase, ROS: reactive oxygen species, SOCE: store-operated calcium entry, STIM: stromal interaction molecule, TIMP: tissue inhibitor of metalloproteinases, R: receptor, COL: collagen, ROS: reactive oxygen species. “↑” denotes increase. “↓” denotes decrease.

Figure 5

Effect of Withaferin A (WFA) on the reversal of cardiac cachexia induced by cancer. Reversal of cardiac systolic functions by Withaferin A in the form of reversal of heart weight, left ventricular heart rate, fractional shortening, cardiac output and left ventricular mass, cross-sectional area of cardiomyocytes (not shown), and partial reversal of diastolic function (E/A ratio, E/e’ ratio, IVRT: isovolumetric relaxation time), and shift in MHC isoforms) through the decrease in angiotensin II and proinflammatory cytokines levels in an NSG mice tumor model. *** p < 0.001; **** p < 0.0001 indicates a significant difference from the corresponding value of the tumor-free vehicle-treated group by two-way ANOVA followed by Tukey’s multiple comparison test, #### p < 0.0001 indicates a significant difference from the corresponding value of the tumor-free WFA 2 mg/kg group, αααα p < 0.0001 indicates a significant difference from the corresponding value of the tumor-free WFA 4 mg/kg group. ¥¥¥¥ p < 0.0001 indicates a significant difference from the corresponding value of the tumor-bearing vehicle-treated group. Adopted from reference [18]. Reproduced under Attribution License (CC BY 4.0).