Background Doxorubicin-mediated adverse cardiovascular events are among the leading causes of mor... more Background Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction (HFrEF), conditions that commonly coexist and are interrelated pathophysiologically. Purpose We hypothesized that Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100)...
Introduction: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed... more Introduction: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation for cancer therapy, opening to advantages in cancer outcomes. However, several ICIs-induced side effects emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. Hypothesis: We analyzed the differential vasculo and cardiotoxicity of Pembrolizumab, Nivolumab and Ipilimumab in preclinical models highlighting on the molecular pathways involved. Methods: C57 female mice were treated with Ipilimumab, Pembrolizumab or Nivolumab (15 mg/kg) through intraperitoneal injection for 10 days. pAMPK expression and vascular p65/NF-kB was analyzed through Immunohistochemistry. Cardiac and systemic levels of IL-1α, IL-1β, IL-2, IL-6 and IL-10 were quantified through ELISA method Results: In preclinical models, all ICIs increased p65/NF-kB expression in vascular endothelial cells of mice compared to saline group. IHC analysis indicates that ICIs reduced pAMPK expression in myocardial cells. Notably, tissue levels of IL-1α, IL-1β, IL-2, IL-6 were strongly increased in ICIs group vs saline (p<0.05 vs saline). On the other hand, levels of the anti-inflammatory cytokine IL-10 were strongly reduced ( overall reduction of 43.3-54.5 % vs saline) Conclusions: In preclinical models, a short treatment with ICIs is sufficient to confer a pro-inflammatory phenotype in the heart of mice. Furthermore, reductions in pAMPK indicate the inhibition of mitochondrial metabolism after ICIs. Furthermore ICIs induce chemokines involved in fibrosis, myocarditis and vascultitis. These results could indicate new therapeutic candidates aimed to prevent myocardial and vascular damages in cancer patients treated with ICIs
Introduction: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer... more Introduction: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. Dapagliflozin is a SGLT2i with cardio-renal benefits. In DAPA-HF trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin decreased the risk of worsening HF events and cardiovascular death in patients with HF and reduced ejection fraction. Berberine is a nutraceutical compound characterized by multiple metabolic effects in patients with/without cardiovascular diseases. Hypothesis: To investigate on the potential cardioprotective properties of Berberine associated to SGLT2i Dapagliflozin against HER-2 blocking agent-induced cardiotoxicity Methods: Human fetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of trastuzumab (200 nM) alone or co-incubated with Berberine (200 mM) or Dapagliflozin (50 nM) or both in combination for 48 h. After the incubation period, we performed the following tests: cell viability, apoptosis, expression of NLRP3 inflammasome, methylglyoxal and leukotrienes-B4. Expression of pAMPK was analyzed through western blot. Moreover, quantification of IL-6 was performed Results: Berberine and Dapagliflozin increased significantly the cell viability of cardiomyocytes exposed to Trastuzumab. When combined, Berberine and Dapagliflozin increased synergistically cell viability of cardiac cells (p<0.001 vs Trastuzumab). Cell apoptosis was reduced of 32.5, 41.8 and 72.7% for berberine, dapagliflozin and both combined (vs trastuzumab group). Methylglyoxal,a marker of AGEs, was strongly reduced compared to untreated cells. Western blot analysis clearly demonstrate that pAMPK was induced by berberine and Dapagliflozin, improving mitochondrial metabolism. No significant changes in Leukotriene B4 expression were seen. Intracellular levels of IL-6 were reduced of 46.3, 62.7 and 86.3% for berberine, dapagliflozin and both combined (vs trastuzumab group). Conclusions: Berberine and Dapagliflozin in combination induces an anti-inflammatory phenotype to myocardial cells through the reduction of biomarkers involved in heart failure and apoptosis.
Introduction: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of ... more Introduction: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction (HFrEF), conditions that commonly coexist and are interrelated pathophysiologically. Hypothesis: Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods: Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100) , pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods. Results: DAPA improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-DAPA group compared to DOXO mice (p<0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in DAPA-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in DAPA-DOXO group vs DOXO (p<0.005). Hystology evaluation indicate reduction in hypertrophy, fibrosis and cardiac necrosis in DOXO-DAPA vs DOXO. Conclusions: DAPA is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. The overall picture of the study pushes the use of DAPA in prevention of cardiomyopathies induced by anthracyclines in cancer patients.
G ITAL CARDIOL | VOL 19 | GIUGNO 2018 termine, a volte oltre i 6 mesi. Infine il loro utilizzo è ... more G ITAL CARDIOL | VOL 19 | GIUGNO 2018 termine, a volte oltre i 6 mesi. Infine il loro utilizzo è limitato o controindicato nei pazienti con severa insufficienza renale. D’altro canto nei pazienti oncologici l’uso degli antagonisti della vitamina K è complicato dallo scarso controllo terapeutico e dalla difficoltà di mantenere un adeguato international normalized ratio (INR) a causa delle interazioni con farmaci, dell’imprevedibile biodisponibilità per vomito, della malnutrizione o diarrea; inoltre, la necessità di ripetuti controlli di laboratorio ha un impatto negativo sulla qualità di vita di questi pazienti, e la gestione di eventuali procedure invasive può risultare molto complessa.
Patients with cancer may have several kinds of arrhythmias either as an independent comorbidity o... more Patients with cancer may have several kinds of arrhythmias either as an independent comorbidity or as a consequence of the cancer itself or of the antineoplastic therapies.
Background Doxorubicin-mediated adverse cardiovascular events are among the leading causes of mor... more Background Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction (HFrEF), conditions that commonly coexist and are interrelated pathophysiologically. Purpose We hypothesized that Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100)...
Introduction: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed... more Introduction: Several strategies based on immune checkpoint inhibitors (ICIs) have been developed or are under investigation for cancer therapy, opening to advantages in cancer outcomes. However, several ICIs-induced side effects emerged in these patients, especially a rare but clinically significant cardiotoxicity with high rate of mortality. Hypothesis: We analyzed the differential vasculo and cardiotoxicity of Pembrolizumab, Nivolumab and Ipilimumab in preclinical models highlighting on the molecular pathways involved. Methods: C57 female mice were treated with Ipilimumab, Pembrolizumab or Nivolumab (15 mg/kg) through intraperitoneal injection for 10 days. pAMPK expression and vascular p65/NF-kB was analyzed through Immunohistochemistry. Cardiac and systemic levels of IL-1α, IL-1β, IL-2, IL-6 and IL-10 were quantified through ELISA method Results: In preclinical models, all ICIs increased p65/NF-kB expression in vascular endothelial cells of mice compared to saline group. IHC analysis indicates that ICIs reduced pAMPK expression in myocardial cells. Notably, tissue levels of IL-1α, IL-1β, IL-2, IL-6 were strongly increased in ICIs group vs saline (p<0.05 vs saline). On the other hand, levels of the anti-inflammatory cytokine IL-10 were strongly reduced ( overall reduction of 43.3-54.5 % vs saline) Conclusions: In preclinical models, a short treatment with ICIs is sufficient to confer a pro-inflammatory phenotype in the heart of mice. Furthermore, reductions in pAMPK indicate the inhibition of mitochondrial metabolism after ICIs. Furthermore ICIs induce chemokines involved in fibrosis, myocarditis and vascultitis. These results could indicate new therapeutic candidates aimed to prevent myocardial and vascular damages in cancer patients treated with ICIs
Introduction: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer... more Introduction: Trastuzumab has improved the prognosis in patients with HER2-positive breast cancer, but it can induce left ventricular dysfunction with reduced ejection fraction or HF during treatment. Dapagliflozin is a SGLT2i with cardio-renal benefits. In DAPA-HF trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin decreased the risk of worsening HF events and cardiovascular death in patients with HF and reduced ejection fraction. Berberine is a nutraceutical compound characterized by multiple metabolic effects in patients with/without cardiovascular diseases. Hypothesis: To investigate on the potential cardioprotective properties of Berberine associated to SGLT2i Dapagliflozin against HER-2 blocking agent-induced cardiotoxicity Methods: Human fetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of trastuzumab (200 nM) alone or co-incubated with Berberine (200 mM) or Dapagliflozin (50 nM) or both in combination for 48 h. After the incubation period, we performed the following tests: cell viability, apoptosis, expression of NLRP3 inflammasome, methylglyoxal and leukotrienes-B4. Expression of pAMPK was analyzed through western blot. Moreover, quantification of IL-6 was performed Results: Berberine and Dapagliflozin increased significantly the cell viability of cardiomyocytes exposed to Trastuzumab. When combined, Berberine and Dapagliflozin increased synergistically cell viability of cardiac cells (p<0.001 vs Trastuzumab). Cell apoptosis was reduced of 32.5, 41.8 and 72.7% for berberine, dapagliflozin and both combined (vs trastuzumab group). Methylglyoxal,a marker of AGEs, was strongly reduced compared to untreated cells. Western blot analysis clearly demonstrate that pAMPK was induced by berberine and Dapagliflozin, improving mitochondrial metabolism. No significant changes in Leukotriene B4 expression were seen. Intracellular levels of IL-6 were reduced of 46.3, 62.7 and 86.3% for berberine, dapagliflozin and both combined (vs trastuzumab group). Conclusions: Berberine and Dapagliflozin in combination induces an anti-inflammatory phenotype to myocardial cells through the reduction of biomarkers involved in heart failure and apoptosis.
Introduction: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of ... more Introduction: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to be of therapeutic value in patients with type 2 diabetes, chronic kidney disease, and heart failure with reduced ejection fraction (HFrEF), conditions that commonly coexist and are interrelated pathophysiologically. Hypothesis: Dapagliflozin (an SGLT2i), administered during doxorubicin, could improve cardiac function in preclinical models Methods: Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), DAPA at 12 mg/kg (DAPA, n=6) or doxorubicin combined to DAPA (DOXO-DAPA, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100) , pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods. Results: DAPA improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-DAPA group compared to DOXO mice (p<0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with DAPA indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in DAPA-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in DAPA-DOXO group vs DOXO (p<0.005). Hystology evaluation indicate reduction in hypertrophy, fibrosis and cardiac necrosis in DOXO-DAPA vs DOXO. Conclusions: DAPA is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. The overall picture of the study pushes the use of DAPA in prevention of cardiomyopathies induced by anthracyclines in cancer patients.
G ITAL CARDIOL | VOL 19 | GIUGNO 2018 termine, a volte oltre i 6 mesi. Infine il loro utilizzo è ... more G ITAL CARDIOL | VOL 19 | GIUGNO 2018 termine, a volte oltre i 6 mesi. Infine il loro utilizzo è limitato o controindicato nei pazienti con severa insufficienza renale. D’altro canto nei pazienti oncologici l’uso degli antagonisti della vitamina K è complicato dallo scarso controllo terapeutico e dalla difficoltà di mantenere un adeguato international normalized ratio (INR) a causa delle interazioni con farmaci, dell’imprevedibile biodisponibilità per vomito, della malnutrizione o diarrea; inoltre, la necessità di ripetuti controlli di laboratorio ha un impatto negativo sulla qualità di vita di questi pazienti, e la gestione di eventuali procedure invasive può risultare molto complessa.
Patients with cancer may have several kinds of arrhythmias either as an independent comorbidity o... more Patients with cancer may have several kinds of arrhythmias either as an independent comorbidity or as a consequence of the cancer itself or of the antineoplastic therapies.
Uploads
Papers by irma bisceglia