Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression

Thackeray, James T.; Pietzsch, Stefan; Stapel, Britta; Ricke‐Hoch, Melanie; Lee, Chun-Wei; Bankstahl, Jens P.; Scherr, Michaela; Heineke, Jörg; Scharf, Gesine M.; Haghikia, Arash; Bengel, Frank M.; Hilfiker‐Kleiner, Denise

doi:10.1172/jci.insight.93098

Cited by 37 publications

(69 citation statements)

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“…5 However, in our patient cohort, we did not observe metabolic changes in patients with malignant melanoma. 5 However, in our patient cohort, we did not observe metabolic changes in patients with malignant melanoma.…”

Section: Discussioncontrasting

confidence: 59%

“…Recent preclinical findings showed differences in cardiac glucose metabolism in mice inoculated with colon cancer and melanoma cells. 5 However, in our patient cohort, we did not observe metabolic changes in patients with malignant melanoma. This could be possibly explained by different factors (tumour burden, melanoma subtype, patient characteristics, and cohort size).…”

Section: Discussioncontrasting

confidence: 59%

“…1 Additionally, preclinical studies postulate a potential direct crosstalk between cancer cells and cardiomyocytes. 5 In humans, there are currently no data available for metabolic cardiac changes in cancer patients suffering from different tumour entitites. [2][3][4] Furthermore, in vivo animal data on colon cancer and malignant melanoma linked systemic insulin depletion to a dysregulation of the cardiac glucose metabolism, visualized by 2-deoxy-2-( 18 F)fluoro-D-glucose (FDG) positron emission tomography in combination with a low-dose computed tomography (PET-CT) scans.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4] Furthermore, in vivo animal data on colon cancer and malignant melanoma linked systemic insulin depletion to a dysregulation of the cardiac glucose metabolism, visualized by 2-deoxy-2-( 18 F)fluoro-D-glucose (FDG) positron emission tomography in combination with a low-dose computed tomography (PET-CT) scans. 5 In humans, there are currently no data available for metabolic cardiac changes in cancer patients suffering from different tumour entitites.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

et al. 2019

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Aims Our aim was to investigate the glucose uptake in cancer patients suffering from different entities, using 18F‐FDG positron emission tomography–computed tomography scans. We further aimed at identifying potential variables altering cardiac and skeletal muscle glucose metabolism. Methods and results In a retrospective cohort study, we analysed cardiac and skeletal muscle 18F‐FDG uptake in onco‐positron emission tomography–computed tomography scans in adult patients suffering from Hodgkin's lymphoma, non‐Hodgkin's lymphoma, and non‐lymphatic cancer including patients suffering from thyroid cancer, bronchial carcinoma, and malignant melanoma. Univariate logistic regression models were created for increased cardiac and skeletal muscle 18F‐FDG uptake using cancer entity, sex, age, previous radiation, previous chemotherapy, diabetes, obesity, serum glucose levels, renal function, and thyroid function as parameters. Multivariate models were created by selecting variables according to Akaike's information criterion in a step‐down approach. Between 2014 and 2018, a total of 337 consecutive patients suffering from Hodgkin's lymphoma (n = 52), non‐Hodgkin's lymphoma (n = 57), and non‐lymphatic cancer (n = 228) were included in the analysis. Univariate logistic regression models showed high serum glucose levels to be associated with lower absorption rates in both cardiac and skeletal muscle (odds ratio [OR] 0.38 [0.23, 0.60, 95% confidence interval—CI], P < 0.0001, and 0.52 [0.33, 0.82, 95% CI], P < 0.005, respectively). Hodgkin's lymphoma was associated with an increase in cardiac uptake (OR 2.4 [1.3, 4.5, 95% CI], P < 0.005). Decreased skeletal muscle 18F‐FDG uptake was noted in elderly and obese patients. In our multivariate analysis, Hodgkin's lymphoma patients showed higher cardiac 18F‐FDG uptake, while non‐Hodgkin's lymphoma patients did not differ significantly from non‐lymphatic cancer patients (OR 1.6 [0.7, 3.3, 95% CI], P = 0.24). High serum glucose levels and prior chemotherapy were both associated with a significantly decreased cardiac 18F‐FDG uptake (OR 0.40 [0.24, 0.65, 95% CI], P < 0.0005, and 0.50 [0.27, 0.90, 95% CI], P < 0.05, respectively). Notably, prior chemotherapy did not influence FDG uptake in skeletal muscle to the same extent. Obesity and older age were both significantly associated with decreased gluteal 18F‐FDG uptake (OR 0.49 [0.27, 0.89, 95% CI], P < 0.05, and 0.47 [0.25, 0.87, 95% CI], P < 0.05). Conclusions Our data provide evidence for metabolic alterations in patients with Hodgkin's lymphoma related to cardiac glucose uptake in humans. This effect was independent from skeletal muscle metabolism.

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Section: Discussioncontrasting

confidence: 59%

Section: Discussioncontrasting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

et al. 2019

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“…Murine adult primary cardiomyocytes were isolated and cultivated as described previously (60) from 3-month-old WT and CKO mice. Supernatants of adult primary cardiomyocytes were collected after 48 h, centrifuged at 300×g for 10 min to deplete cell fragments and stored at −80 °C.…”

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confidence: 99%

Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

Stelling

Ricke‐Hoch

Erschow

et al. 2020

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31 Cardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline 32 with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency (CKO) 33 display premature age-related heart failure associated with reduced cardiac capillary density.34 In the present study isolated male and female CKO-cardiomyocytes exhibit increased 35 prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading 36 hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male 37 cardiomyocytes, which is associated with increased PGD 2 secretion from isolated male but not 38 female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from 39 impaired androgen-receptor-(AR)-signaling due to loss of its co-factor STAT3. Elevated PGD 2 40 secretion in males is associated with increased white adipocyte accumulation in aged male 41 but not female hearts. Adipocyte differentiation is enhanced in isolated SCA-1 + -cardiac-42 progenitor-cells (CPC) from young male CKO-mice compared to the adipocyte differentiation 43 of male wildtype (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly 44 isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and 45 hypomethylation in the white adipocyte differentiation gene Zfp423 associated with 46 upregulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation 47 compared to WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in 48 male CKO-CPC compared to male WT-CPC whereas no differences in the EZH2 expression 49 in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells 50 or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is 51 sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD 2 52 stimulation reduces the expression of EZH2 thereby upregulating ZFP423 expression and 53 promoting white adipocyte differentiation.54 Thus, cardiomyocyte STAT3-deficiency leads to age-related and sex-specific cardiac 55 remodeling and failure in part due to sex-specific alterations in PGD 2 secretion and subsequent 56 epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired 3 57 AR signaling in absence of STAT3, which reduces the expression of the PG degrading enzyme 58 HPGD. 59 4 60 Introduction 61 Men and women experience quite different cardiovascular disease susceptibility profiles and 62 outcome, a feature that is poorly understood. Further, the effects of biologic sex on health, 63 disease susceptibility and mortality are vastly understudied (1, 2). Recent studies showed that 64 genetics contribute to sex-specific differences in fat tissue and cardiovascular and metabolic 65 diseases (3). Pathophysiologically enhanced cardiac fat content is frequently observed in 66 patients with heart failure, in arrhythmogenic right ventricular dysplasia (ARVD), and after 67 ...

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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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Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression

Cited by 37 publications

References 37 publications

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

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

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Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression

Cited by 37 publications

References 37 publications

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

Increased prostaglandin-D2 in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation

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

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Increased prostaglandin-D₂ in male but not female STAT3-deficient hearts shifts cardiac progenitor cells from endothelial to white adipocyte differentiation