Megestrol acetate improves cardiac function in a model of cancer cachexia‐induced cardiomyopathy by autophagic modulation

Musolino, Vincenzo; Palus, Sandra; Tschirner, Anika; Drescher, Cathleen; Gliozzi, Micaela; Carresi, Cristina; Vitale, Cristiana; Muscoli, Carolina; Doehner, Wolfram; Haehling, Stephan von; Anker, Stefan D.; Mollace, Vincenzo; Springer, Jochen

doi:10.1002/jcsm.12116

Cited by 56 publications

(64 citation statements)

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“…A suppression of myostatin expression in knockout mice has shown significant increased muscle mass, an effect that can also be found in spontaneous, natural gene deletions in Belgian Blue cattle, whippets, and in a rare case, humans. 123 Espindolol, the s-enantiomer of pindolol, is another multifactorial drug. 112 Myostatin released from the myocardium has been reported to be causal for skeletal muscle atrophy in a CHF mouse model.…”

Section: Chronic Heart Failure and Muscle Maintenancementioning

confidence: 99%

Skeletal muscle wasting in chronic heart failure

2018

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Patients suffering from chronic heart failure (CHF) show an increased prevalence (~20% in elderly CHF patients) of loss of muscle mass and muscle function (i.e. sarcopenia) compared with healthy elderly people. Sarcopenia, which can also occur in obese patients, is considered a strong predictor of frailty, disability, and mortality in older persons and is present in 5–13% of elderly persons aged 60–70 years and up to 50% of all octogenarians. In a CHF study, sarcopenia was associated with lower strength, reduced peak oxygen consumption (peak VO2, 1173 ± 433 vs. 1622 ± 456 mL/min), and lower exercise time (7.7 ± 3.8 vs. 10.22 ± 3.0 min, both P < 0.001). Unfortunately, there are only very limited therapy options. Currently, the main intervention remains resistance exercise. Specialized nutritional support may aid the effects of resistance training. Testosterone has significant positive effects on muscle mass and function, and low endogenous testosterone has been described as an independent risk factor in CHF in a study with 618 men (hazard ratio 0.929, P = 0.042). However, the use of testosterone is controversial because of possible side effects. Selective androgen receptor modulators have been developed to overcome these side effects but are not yet available on the market. Further investigational drugs include growth hormone, insulin‐like growth factor 1, and several compounds that target the myostatin pathway. The continuing development of new treatment strategies and compounds for sarcopenia, muscle wasting regardless of CHF, and cardiac cachexia makes this a stimulating research area.

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Section: Chronic Heart Failure and Muscle Maintenancementioning

confidence: 99%

Skeletal muscle wasting in chronic heart failure

2018

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“…4 Echocardiography Echocardiography was performed using the high-resolution Vevo 770 system (VisualSonics Inc., Toronto, Canada), as 90 V. Musolino et al 4 Echocardiography Echocardiography was performed using the high-resolution Vevo 770 system (VisualSonics Inc., Toronto, Canada), as 90 V. Musolino et al…”

Section: Body Compositionmentioning

confidence: 99%

“…4 Briefly, rats were anaesthetized with 1.5% isoflurane and laid in supine position on a heated surface to maintain body temperature and with all legs taped to electrocardiogram electrodes. 4 Briefly, rats were anaesthetized with 1.5% isoflurane and laid in supine position on a heated surface to maintain body temperature and with all legs taped to electrocardiogram electrodes.…”

Section: Body Compositionmentioning

confidence: 99%

“…4 Approximately 50 mg of heart was homogenized in 500 μL ice-cold lysis buffer [ 4 Approximately 50 mg of heart was homogenized in 500 μL ice-cold lysis buffer [ …”

Section: Protein Extraction and Sodium Dodecyl Sulfate Polyacrylamidementioning

confidence: 99%

“…1 Cachexia is characterized by an involuntary weight loss due to the atrophy of skeletal muscle with or without loss of adipose tissue 2 affecting~50-80% of patients with cancer and is the direct cause of 30% of cancer deaths. [4][5][6][7] Although several inflammatory, hormonal, and oxidative stress molecules have been suggested as markers of prognosis in cachexia, 8 there are no universally accepted specific biomarkers for this condition. Although impaired cardiac function in cancer patients is usually attributed to cardiotoxicity of anti-neoplastic therapies, the effects of cancer cachexia (CC) on cardiac atrophy and function have given rise to the hypothesis that CC itself results in cardiac atrophy and cardiac dysfunction, which lead to heart failure (HF), which is well supported by several pre-clinical studies.…”

Section: Introductionmentioning

confidence: 99%

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Cardiac expression of neutrophil gelatinase‐associated lipocalin in a model of cancer cachexia‐induced cardiomyopathy

et al. 2018

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AimsCachexia is a severe consequence of cancer. Although cancer‐induced heart atrophy leads to cardiac dysfunction and heart failure (HF), biomarkers for their diagnosis have not been identified. Neutrophil gelatinase‐associated lipocalin (NGAL) is an aldosterone‐responsive gene increased in HF. We studied NGAL and its association with aldosterone levels in a model of cancer cachexia‐induced cardiomyopathy.Methods and resultsRats were injected with Yoshida 108 AH‐130 hepatoma cells to induce tumour. Cachectic rats were treated daily, for 16 days, with placebo or with 5 or 50 mg/kg/day of spironolactone. Cardiac function was analysed by echocardiography at baseline and at Day 11. Weight loss and atrophy of lean body and fat mass of cachectic rats were significantly attenuated by spironolactone. Cardiac dysfunction of tumour‐bearing rats was improved by spironolactone. Plasma aldosterone was up‐regulated from 337 ± 7 pg/mL in sham animals to 591 ± 31 pg/mL in the cachectic rats (P < 0.001 vs. sham). Treatment with 50 or 5 mg/kg/day of spironolactone reduced plasma aldosterone to 396 ± 22 and 391 ± 25 pg/mL (P < 0.01 vs. placebo). Plasma levels of NGAL were also increased in cachectic rats (1.462 ± 0.3603 μg/mL) than in controls (0.0936 ± 6 μg/mL, P < 0.001). Spironolactone treatment (50 mg/kg/day) significantly reduced cardiac mRNA and protein NGAL levels (P < 0.05 and P < 0.001 vs. placebo, respectively). NGAL mRNA and protein levels were overexpressed in cachectic animal hearts treated with placebo, compared with control (P < 0.05 and P < 0.01 vs. sham). Spironolactone treatment at 50 mg/kg/day reduced significantly cardiac NGAL (P < 0.05 and P < 0.001 vs. placebo).ConclusionsCancer cachexia induced increased levels of aldosterone and NGAL, contributing to worsening cardiac damage in cancer cachexia‐induced cardiomyopathy. Spironolactone treatment may greatly attenuate cardiac dysfunction and lean mass atrophy associated with cancer cachexia.

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The pathophysiology of cancer‐mediated cardiac cachexia and novel treatment strategies: A narrative review

Tichy,

Parry

2023

Cancer Medicine

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SignificanceTwo of the leading causes of death worldwide are cancer and cardiovascular diseases. Most cancer patients suffer from a metabolic wasting syndrome known as cancer‐induced cardiac cachexia, resulting in death in up to 30% of cancer patients. Main symptoms of this disease are severe cardiac muscle wasting, cardiac remodeling, and cardiac dysfunction. Metabolic alterations, increased inflammation, and imbalance of protein homeostasis contribute to the progression of this multifactorial syndrome, ultimately resulting in heart failure and death. Cancer‐induced cardiac cachexia is associated with decreased quality of life, increased fatiguability, and decreased tolerance to therapeutic interventions.Recent advancesWhile molecular mechanisms of this disease are not fully understood, researchers have identified different stages of progression of this disease, as well as potential biomarkers to detect and monitor the development. Preclinical and clinical studies have shown positive results when implementing certain pharmacological and non‐pharmacological therapy interventions.Critical issuesThere are still no clear diagnostic criteria for cancer‐mediated cardiac cachexia and the condition remains untreated, leaving cancer patients with irreversible effects of this syndrome. While traditional cardiovascular therapy interventions, such as beta‐blockers, have shown some positive results in preclinical and clinical research studies, recent preclinical studies have shown more successful results with certain non‐traditional treatment options that have not been further evaluated yet. There is still no clinical standard of care or approved FDA drug to aid in the prevention or treatment of cancer‐induced cardiac cachexia. This review aims to revisit the still not fully understood pathophysiological mechanisms of cancer‐induced cardiac cachexia and explore recent studies using novel treatment strategies.Future directionsWhile research has progressed, further investigations might provide novel diagnostic techniques, potential biomarkers to monitor the progression of the disease, as well as viable pharmacological and non‐pharmacological treatment options to increase quality of life and reduce cancer‐induced cardiac cachexia‐related mortality.

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Megestrol acetate improves cardiac function in a model of cancer cachexia‐induced cardiomyopathy by autophagic modulation

Cited by 56 publications

References 58 publications

Skeletal muscle wasting in chronic heart failure

Skeletal muscle wasting in chronic heart failure

Cardiac expression of neutrophil gelatinase‐associated lipocalin in a model of cancer cachexia‐induced cardiomyopathy

The pathophysiology of cancer‐mediated cardiac cachexia and novel treatment strategies: A narrative review

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