Detrimental effects of chemotherapy on human coronary microvascular function

Hader, Shelby N.; Zinkevich, Natalya S.; Toro, Laura E. Norwood; Kriegel, Alison J.; Kong, Amanda L.; Freed, Julie K.; Gutterman, David D.; Beyer, Andreas

doi:10.1152/ajpheart.00370.2019

Cited by 34 publications

(22 citation statements)

References 31 publications

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“…Cardiac mass showed a significant decrease (p < 0.05) following 4 months of treatment, and echocardiographic metrics also showed that after the 4 month treatment, there was a significant (p < 0.05) decrease in the ventricular septum thickness in treated compared to untreated mice. Recent clinical studies have indicated that reduced myocardial capillary density (microvascular rarefaction) with reduced coronary flow reserve (maximum increase in blood flow through the coronary arteries above the normal resting volume) contributes substantially to diastolic dysfunction in HFpEF patients [28,29]. The observation of subclinical cardiotoxicity in DOX/TRZ treated mice is consistent with the observation that cardiac ECs, in addition to cardiomyocytes became damaged during the combination treatment.…”

Section: Discussionsupporting

confidence: 71%

Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity

et al. 2021

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Background Breast cancer is the most common female cancer worldwide. Effective therapies including doxorubicin and trastuzumab have improved survival, but are associated with a substantial risk of cardiovascular disease. Mechanisms underlying cancer treatment-induced cardiotoxicity (CTC) are poorly understood and have largely focused on cardiomyocyte damage, although other cellular populations in the heart such as the cardiac endothelium, may play an important role in cardiac damage. We treated a breast tumor-bearing mouse model with doxorubicin and trastuzumab to investigate the role of the cardiac endothelium in the development of CTC. Methods Immune compromised mice were inoculated in the 4th mammary fat pad with human breast cancer cells overexpressing HER2 (BT474). When tumors were palpable, mice were treated weekly with doxorubicin (5 mg/kg) and trastuzumab (4 mg/kg). The cardiac phenotype of mice was assessed by echocardiography and histological evaluation of the heart. Cardiac vascular damage was assayed by in vivo permeability assays and primary cultures of murine cardiac endothelial cells were used to assay doxorubicin toxicity in vitro. Results The growth of BT474 breast tumors in Balb/c Nude mice was suppressed upon treatment with doxorubicin and trastuzumab. Mice treated for 4 months with doxorubicin and trastuzumab maintained body weights, but demonstrated an echocardiographic phenotype consistent with preserved left ventricular (LV) ejection fraction, decreased LV mass and increased filling pressures (E/e’). Histological staining with Masson’s trichrome and Picrosirius red showed extensive fibrosis and increased collagen deposition in the ventricular myocardium surrounding blood vessels of treated mice compared to untreated mice. Evans blue permeability assays demonstrated increased cardiac vasculature permeability while primary cardiac endothelial cells exposed to doxorubicin in vitro showed increased cell death as compared to lung or liver endothelial cells. Conclusions An orthotopic mouse model of human breast cancer in Nude mice treated with doxorubicin and trastuzumab resulted in a cardiac vascular defect accompanied by preserved LV ejection fraction, decreased LV mass, suggesting mild diastolic dysfunction and cardiac remodeling consistent with subclinical cardiotoxicity. Our data suggest that cardiac endothelium is more sensitive to doxorubicin therapy as compared to other organ endothelium and cardiac endothelial damage may correlate with breast cancer treatment-induced cardiotoxicity.

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Section: Discussionsupporting

confidence: 71%

Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity

et al. 2021

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“…[31] This finding highlights that MVN functionality, even in healthy vessels, is altered during and following successive rounds of treatment, which can recapitulate the adverse effects of chemotherapy often inferred, [32] and directly shown recently in ex vivo microvasculature. [33] Next, we compared drug delivery between a simple spheroid model and our system. Taxol was used to treat TSs alone and within vascular networks (TS-MVN) ( Figure 4C-G).…”

Section: Vascular Transport Of Chemotherapeutics In 3dmentioning

confidence: 99%

Endothelial Regulation of Drug Transport in a 3D Vascularized Tumor Model

Haase

Offeddu

Gillrie

et al. 2020

Adv Funct Materials

106

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Drug discovery and efficacy in cancer treatments are limited by the inability of pre-clinical models to predict successful outcomes in humans. Limitations remain partly due to their lack of a physiologic tumor microenvironment (TME), which plays a considerable role in drug delivery and tumor response to therapy. Chemotherapeutics and immunotherapies rely on transport through the vasculature, via the smallest capillaries and stroma to the tumor, where passive and active transport processes are at play. Here, a 3D vascularized tumor on-chip is used to examine drug delivery in a relevant TME within a large bed of perfusable vasculature. This system demonstrates highly localized pathophysiological effects of two tumor spheroids (Skov3 and A549), which cause significant changes in vessel density and barrier function. Paclitaxel (Taxol) uptake is examined through diffusivity measurements, functional efflux assays, and accumulation of the fluorescent-conjugated drug within the TME. Due to vascular and stromal contributions, differences in the response of vascularized tumors to Taxol (shrinkage and CD44 expression) are apparent compared with simpler models. This model specifically allows for examination of spatially resolved tumor-associated endothelial dysfunction, likely improving the representation of in vivo drug distribution, and has potential for development into a more predictable model of drug delivery.

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“…(reviewed by Armenian et al 19 ). Our recent study showing that anthracycline exposure causes a loss of endothelial dilator function in the human coronary circulation further amplifies the negative impact of different cancer therapies on vascular function 20 …”

Section: Discussionmentioning

confidence: 82%

BCR‐ABL tyrosine kinase inhibitors promote pathological changes in dilator phenotype in the human microvasculature

et al. 2020

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Objective Treatment with BCR‐ABL tyrosine kinase inhibitors (TKIs) is the standard of care for patients with chronic myeloid leukemia, however evidence indicates these compounds may have cardiovascular side‐effects. This study sought to determine if ex vivo exposure of human adipose arterioles to the BCR‐ABL TKIs imatinib and nilotinib causes endothelial dysfunction. Methods Human adipose arterioles were incubated overnight in cell culture media containing vehicle (PBS), imatinib (10 µmol/L) or nilotinib (100 µmol/L). Arterioles were cannulated onto glass pipettes and flow mediated dilation (FMD) was assessed via video microscopy. To determine the mechanism of vasodilation, FMD was re‐assessed in the presence of either the nitric oxide synthase inhibitor L‐NAME (100 µmol/L) or the H2O2 scavenger PEG‐Catalase (500 U/mL). Results Neither imatinib nor nilotinib affected the magnitude of FMD (max dilation = 78±17% vehicle, 80 ± 24% nilotinib, 73 ± 13% imatinib). FMD was decreased by L‐NAME in vehicle‐treated arterioles (max dilation = 47±29%). Conversely, L‐NAME had no effect on FMD in imatinib‐ or nilotinib‐treated vessels (max dilation = 79±14% and 80 ± 24%, respectively), rather FMD was inhibited by PEG‐Catalase (max dilation = 29±11% and 29 ± 14%, respectively). Conclusion Incubating human arterioles with imatinib or nilotinib switches the mediator of FMD from vasoprotective nitric oxide to pro‐inflammatory H2O2.

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Detrimental effects of chemotherapy on human coronary microvascular function

Cited by 34 publications

References 31 publications

Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity

Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity

Endothelial Regulation of Drug Transport in a 3D Vascularized Tumor Model

BCR‐ABL tyrosine kinase inhibitors promote pathological changes in dilator phenotype in the human microvasculature

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