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The Role of Cardiovascular Imaging and Serum Biomarkers in Identifying Cardiotoxicity Related to Cancer Therapeutics.

Methodist Debakey Cardiovasc J. 2019 Oct-Dec;15(4):258-266

Authors: Agha A, Zarifa A, Kim P, Iliescu C, Gladish G, Hassan S, Palaskas N, Durand JB, Lu Y, Lopez-Mattei J

Abstract

Innovations and discoveries in cancer therapeutics have improved survival rates in patients with various types of malignancies. At the same time, physicians are identifying an increased number of patients with treatment-related cardiotoxicity. It is imperative that physicians recognize early treatment-related adverse effects to determine the safest therapeutic options for patients with cancer. This manuscript evaluates the role of cardiovascular imaging and biomarkers in identifying cardiotoxicity trigged by various chemotherapeutic agents and summarizes expert consensus statements regarding cardiotoxicity monitoring.

PMID: 31988686 [PubMed - in process]

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pubmed: tutte cardiotoxicity...

Heart Failure in Relation to Tumor-Targeted Therapies and Immunotherapies.

Methodist Debakey Cardiovasc J. 2019 Oct-Dec;15(4):250-257

Authors: Agunbiade TA, Zaghlol RY, Barac A

Abstract

Tumor-targeted therapies such as trastuzumab have led to significant improvements in survival of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, these therapies have also been associated with significant left ventricular dysfunction. The incidence of trastuzumab-induced heart failure has decreased significantly since the initial reports, in large part due to improved screening, closer monitoring for early changes in left ventricular function, and a significant decrease in the concurrent administration of anthracyclines. The mechanism of trastuzumab cardiotoxicity is still not well understood, but current knowledge suggests that ErbB2 inhibition in cardiac myocytes plays a key role. In addition to trastuzumab and other HER2-targeted agents, vascular endothelial growth factor inhibitors, proteasome inhibitors, and immune checkpoint inhibitors are all additional classes of drugs used with great success in the treatment of solid tumors and hematologic malignancies. Yet these, too, have been associated with cardiac toxicity that ranges from a mild asymptomatic decrease in ejection fraction to fulminant myocarditis. In this review, we summarize the cardiotoxic effects of tumor-targeted and immunotherapies with a focus on HER2 antagonists.

PMID: 31988685 [PubMed - in process]

30 January 2020

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Cardiotoxicity News

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MMP inhibitors attenuate doxorubicin cardiotoxicity by preventing intracellular and extracellular matrix remodeling.

Cardiovasc Res. 2020 Jan 29;:

Authors: Chan BYH, Roczkowsky A, Cho WJ, Poirier M, Sergi C, Keschrumrus V, Churko JM, Granzier H, Schulz R

Abstract

AIMS: Heart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin. Doxorubicin enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against doxorubicin cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodeling the extracellular matrix.

METHODS AND RESULTS: 8-week old male C57BL/6J mice were treated with doxorubicin weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodeling before and after treatment. MMP inhibitors ameliorated doxorubicin-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E'/A'. MMP inhibitors attenuated adverse left ventricular remodeling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. Doxorubicin increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that doxorubicin elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. Doxorubicin-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. Doxorubicin also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817.

CONCLUSIONS: MMP-2 activation is an early event in doxorubicin cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated doxorubicin cardiotoxicity by attenuating intracellular and extracellular matrix remodeling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.

TRANSLATIONAL PERSPECTIVE: Heart failure is the primary chronic toxicity of anthracycline chemotherapy. Anthracyclines such as doxorubicin cause left ventricular remodeling and loss of myofilament proteins. We determined in mice whether matrix metalloproteinase-2, an intracellular and extracellular protease in the heart, contributes to doxorubicin cardiotoxicity. Doxorubicin activated myocardial MMP-2 in mouse hearts and human cardiomyocytes, including de novo expression of an N-terminal truncated MMP-2 isoform which is exclusively expressed by increased oxidative stress. Increased MMP-2 levels and activity in the heart contributed to left ventricular remodeling, interstitial fibrosis, and titin proteolysis in doxorubicin cardiotoxicity. These adverse effects on the heart were prevented by two orally available MMP inhibitors, demonstrating the potential benefits of MMP inhibition in the prophylaxis of doxorubicin cardiotoxicity.

PMID: 31995179 [PubMed - as supplied by publisher]

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Anthracycline-induced cardiotoxicity prevention with angiotensin-converting enzyme inhibitor ramipril in low-risk breast cancer women: results of a prospective randomized study.

Kardiol Pol. 2020 Jan 29;:

Authors: Słowik A, Jagielski P, Potocki P, Streb J, Ochenduszko S, Wysocki P, Gajos G, Konduracka E

Abstract

BACKGROUND: Anthracycline-induced cardiotoxicity (AIC) remains the main long-term and irreversible side effect in malignancy survivors. Cardiotoxicity prevention is one of most reasonable attitudes.

AIM: To verify whether ramipril is able to protect from early-onset AIC in prospective randomized open-label study.

METHODS: Women with breast cancer (BC) were randomized to ramipril (RA) or control arm (CA). Data from 96 women, median age 47 years, without significant cardiovascular diseases, post-breast surgery and eligible for adjuvant anthracyclines, was analyzed. Cardiotoxicity was estimated with repeated echocardiography, troponin I and NT-proBNP levels over one-year follow-up. AIC was defined as a decrease in left ventricular ejection fraction (LVEF) and/or biomarkers elevation and/or occurrence of heart failure (HF) or cardiac death.

RESULTS: LVEF decrease ˃10 percent points occurred in 6.3% in RA vs 18.5% in controls (P = 0.15). No cases of HF, cardiac death or LVEF decline below ˂50% were reported. Percentage of patients with NT-proBNP elevation increased with time in CA (P = 0.003), whereas it remained unchanged in RA. At the end of observation, more patients in CA showed NTproBNP increase and fewer NT-proBNP decline (P = 0.01). No significant difference in troponin levels was found between the study arms. Ramipril was well tolerated in normotensive women.

CONCLUSIONS: In relatively young BC women without serious co-morbidities, who underwent anthracycline therapy, one year treatment with ramipril exerts potentially protective effect on the cardiotoxicty assessed with NT-proBNP, however its efficacy in long-term follow-up needs further investigations.

PMID: 31995035 [PubMed - as supplied by publisher]

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Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort.

//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-bmj_full.gif //www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-bmjjournals_open_access.gif Related Articles

Major cardiac events for adult survivors of childhood cancer diagnosed between 1970 and 1999: report from the Childhood Cancer Survivor Study cohort.

BMJ. 2020 01 15;368:l6794

Authors: Mulrooney DA, Hyun G, Ness KK, Ehrhardt MJ, Yasui Y, Duprez D, Howell RM, Leisenring WM, Constine LS, Tonorezos E, Gibson TM, Robison LL, Oeffinger KC, Hudson MM, Armstrong GT