Prevention of liver cancer cachexia-induced cardiac wasting and heart failure

Abstract

Aims: Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130).

Methods and results: Tumour-bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated.

Conclusion: Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV-dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the β-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer.

Keywords: Cancer cachexia; Cardiac wasting; Heart failure; Intervention; Survival.

Figure 1

Alterations in weight, body composition, and cardiac function in the timeline experiment. (A) Loss of body weight, lean mass (=skeletal muscle), and fat mass as the cancer progressed. Tumour-bearing rats had a decreased food intake and the overall weight of the heart was progressively reduced. (B) The left-ventricular ejection fraction and fractional shortening were reduced starting Day 11 after tumour inoculation. A progressive loss of LV end-diastolic diameter (LVEDD) was seen and the stroke volume as well as the cardiac output was already reduced on Day 7, when the clinical definition of cachexia was met. LVmass was progressively lost compared with baseline, reaching its maximum of 58% loss at Day 13. LV end-systolic pressure (LVESP) was reduced on Days 11 and 13, while the end-diastolic pressure (LVEDP) was reduced starting Day 9 compared with sham. The contractility given as delta pressure/delta time (dP/dt) was affected starting Day 11. Time constant of relaxation (tau) was prolonged on Days 11 and 13, and heart rate was lower starting Day 7. *P < 0.05, **P < 0.01, ***P < 0.001 vs. sham.

Figure 2

Survival proportions. Only the best dose for each compound is shown (for complete survival analysis, see Supplementary material online, Figure S4). Rats were treated with 5 mg/kg/day (n = 23) of bisoprolol, 50 mg/kg/day (n = 16) of spironolactone, 0.4 mg/kg/day (n = 9) of Imidapril or placebo (n = 73). A high mortality was observed in the placebo group (87%), which was significantly reduced bisoprolol or spironolactone, see hazard ratios (HR) below the Kaplan–Meier curves.

Figure 3

(A) Spironolactone reduced activity of caspase-3. (B) A lower trypsin-like activity of the proteasome was seen in groups treated with bisoprolol or spironolactone, while imidapril enhanced proteasome activity. (C) Imidapril-induced expression of FOXO3 and also its phosphorylation, possibly contributing to increased expression of MuRF-1. MAFbx is induced by cancer cachexia, and not regulated by bisoprolol or spironolactone. While there was no change in the reduction of p62 by treatment, an increase in LC-3 II /LC-3 I ratio was observed in the imidapril-treated group, suggesting increased autophagy. (D) Cancer cachexia caused loss of myosin heavy chain in myocardium, which was prevented by bisoprolol and spironolactone, while imidapril had no effect. Toponin-T was only reduced in the imidapril group and tropomyosin was not affected by cancer cachexia. ND, not done due to lack of material. *P < 0.05, **P < 0.01, ***P < 0.001 vs. placebo.

Figure 4

Effect of treatment on signalling. (A) Anabolism in the hearts of tumour-bearing rats was increased by treatment with bisoprolol or spironolactone, which can be seen in the higher Akt phosphorylation, while imidapril failed to excerpt positive effects on anabolic signalling. (B) The negative growth regulator myostatin was induced in tumour-bearing animals and its levels were reduced to normal by bisoprolol or spironolactone treatment. *P < 0.05, **P < 0.01, ***P < 0.001 vs. placebo.

Figure 5

(A) Incubation of neonatal rat cardiomyocytes with isoproterenol (Iso) reduced mRNA expression of α- and β-MHC, which was rescued by bisoprolol (Biso), metoprolol (Meto), or the GSK3-inhibitor SB 425286. Aldosterone (Aldo) and spironolactone (Spiro) had no effect on α- and β-MHC-expression. (B) The ratio of phospho-GSK3 to GSK3 was somewhat shifted to pGSK by bisoprolol and to a lesser extent by metoprolol.

Figure 6

(A) Rat aldosterone (aldo) plasma level in sham (open bars) and tumour-bearing animals (solid bars). (B) Cardiac fibrosis is occurring as early as 7 days after tumour inoculation. Scale bar: 100 µm. (C) Aldosterone and cortisol plasma levels were elevated in rats with cancer cachexia (reduced by spironolactone and to a lesser extent by bisoprolol), possible by both RAS-dependent and -independent mechanisms, as suggested by adrenal gland hypertrophy and evaluated renin levels. (D) Noradrenalin was induced by cancer cachexia, which was reduced by spironolactone. (E) Hydroxyproline (HP) as a marker of fibrosis, spironolactone reduced HP-expression compared with placebo. *P < 0.05, **P < 0.01, ***P < 0.001 vs. placebo cancer cachexia.

Figure 7

(A) Human cadaver heart weights and wall thickness (WT) of the posterior left (LV) and right ventricle (RV) wall of controls (open bar n = 11), cancer (grey bars, n = 12), and cancer cachexia (black bar, n = 14). (B) Representative sections of the LV posterior wall (top panels AZAN stain, lower panels Sirius Red stain). Fibrosis and perivascular fibrosis was seen in patients who died of cancer with or without cachexia. (C) Plasma aldosterone (aldo), cortisol, renin, and BNP levels in a second set of patients with cancer (n = 34), cancer cachexia (n = 20), and controls (n = 22). Scale bar 50 µm *P < 0.05, **P < 0.01 vs. control/sham, ^##P < 0.01 vs. cancer.