Sorafenib Cardiotoxicity Increases Mortality After Myocardial Infarction

Duran, Jason; Makarewich, Catherine A.; Trappanese, Danielle M.; Gross, Polina; Husain, Sharmeen; Dunn, Jonathan; Lal, Hind; Sharp, Thomas E; Starosta, Timothy; Vagnozzi, Ronald J.; Berretta, Remus; Barbe, Mary F.; Yu, Daohai; Gao, Erhe; Kubo, Hajime; Force, Thomas; Houser, Steven R.

doi:10.1161/circresaha.114.303200

Cited by 78 publications

(63 citation statements)

References 65 publications

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“…Our laboratories have studied myocyte regeneration in multiple small and large animal cardiac injury models, including continuous ISO infusion via osmotic minipumps 5 , myocardial infarction 14 , myocardial infarction in the presence of cardiotoxic agents 15 , and myocardial infarction with exogenous implantation of CSCs 14 . All of these studies have shown low rates (< 1%) of new myocyte formation.…”

Section: Introductionmentioning

confidence: 99%

Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration

Wallner

Duran

Mohsin

et al. 2016

Circulation Research

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Rationale Catecholamines increase cardiac contractility, but exposure to high concentrations or prolonged exposures can cause cardiac injury. A recent study demonstrated that a single subcutaneous injection of isoproterenol (ISO; 200 mg/kg) in mice causes acute myocyte death (8-10%) with complete cardiac repair within a month. Cardiac regeneration was via endogenous cKit+ cardiac stem cell (CSC)-mediated new myocyte formation. Objective Our goal was to validate this simple injury/regeneration system and use it to study the biology of newly forming adult cardiac myocytes. Methods and Results C57BL/6 mice (n=173) were treated with single injections of vehicle, 200mg/kg or 300mg/kg ISO, or with two daily doses of 200mg/kg ISO for 6 days. Echocardiography revealed transiently increased systolic function and unaltered diastolic function 1 day after single ISO injection. Single ISO injections also caused membrane injury in about 10% of myocytes but few of these myocytes appeared to be necrotic. Circulating troponin I levels after ISO were elevated, further documenting myocyte damage. However, myocyte apoptosis was not increased after ISO injury. Heart weight to body weight ratio and fibrosis were also not altered 28 days after ISO injection. Single or multiple dose ISO injury was not associated with an increase in the percentage of 5-ethynyl-2’-deoxyuridine (EdU)-labeled myocytes. Furthermore, ISO injections did not increase new myocytes in cKit+/Cre × R-GFP transgenic mice. Conclusions A single dose of ISO causes injury in about 10% of the cardiomyocytes. However, most of these myocytes appear to recover and do not elicit cKit+ cardiac stem cell (CSC)-derived myocyte regeneration.

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Section: Introductionmentioning

confidence: 99%

Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration

Wallner

Duran

Mohsin

et al. 2016

Circulation Research

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“…Among these cardiovascular toxicities, hypertension and bleeding are most frequent adverse events associated with sorafenib therapy (18). Although there have been reports of cardiotoxicity from the long-term sorafenib therapy of patients with renal cell cancer and lung cancer, the present case is the first report of cardiotoxicity caused by long-term sorafenib therapy in a patient with advanced HCC; this adverse effect has been underestimated by phase III studies due to the relatively short-term treatment (19,20). The present case encourages the clinician to monitor cardiac toxicity during sorafenib therapy, particularly in elderly patients with underlying cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 79%

Long-term follow-up of complete remission of advanced hepatocellular carcinoma following sorafenib therapy: A case report

et al. 2017

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Abstract. Sorafenib is a tyrosine kinase inhibitor that has been demonstrated to improve the overall survival time of patients with advanced hepatocellular carcinoma (HCC). Although there have been a number of reports of patients achieving complete remission (CR) following sorafenib therapy, the long-term clinical outcomes of these patients have yet to be ascertained. A 72-year-old male patient with chronic hepatitis C, diabetes, hypertension and an old cerebral infarction was referred for the evaluation of a liver mass identified on an abdominal ultrasound. Abdominal computed tomography (CT) demonstrated a 13-cm mass replacing the right lobe of the liver, with portal vein thrombosis. HCC was confirmed by a percutaneous needle biopsy and treated with sorafenib. At 4 months, a follow-up CT demonstrated no enhancing viable lesions in the tumor and recanalization of the portal vein. Sorafenib therapy was continued for 48 months until the patient experienced dyspnea due to congestive heart failure, with pleural effusion. Following the discontinuation of sorafenib, the patient's symptoms improved. The patient followed up without recurrence for 52 months. Subsequent to achieving CR through treatment with sorafenib, long-term sorafenib therapy may be an option and efforts should be made to monitor cardiac toxicity during sorafenib therapy, particularly in high-risk patients.

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“…Moreover, bevacizumab given after acute myelogenous leukemia chemotherapy resulted in an increase in cardiovascular toxicity, although the mechanisms for this toxicity remain unknown [73]. Sorafenib has also been demonstrated to cause cardiotoxicity in mice due to myocyte necrosis [74]. Table 2.…”

Section: Side Efects Of Anti-vegf Medicationsmentioning

confidence: 99%

Anti-VEGF Therapy in Cancer: A Double-Edged Sword

Gardner¹,

Madu²,

Lü³

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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Vascular endothelial growth factor (VEGF) is a mitogen that plays a crucial role in angiogenesis and lymphangiogenesis. It is involved in tumor survival through inducing tumor angiogenesis and by increasing chemoresistance through autocrine signaling. Because of its importance in tumor formation and survival, several medications have been developed to inhibit VEGF and reduce blood vessel formation in cancer. Although these medications have proven to be efective for late-stage and metastatic cancers, they have been shown to cause side efects such as hypertension, artery clots, complications in wound healing, and, more rarely, gastrointestinal perforation and istulas. Current research in using anti-VEGF medication as a part of cancer treatments is focusing on elucidating the mechanisms of tumor resistance to VEGF medication, developing predictive biomarkers that assess whether a patient will respond to VEGF therapy and creating novel treatments and techniques that increase the eicacy of antiangiogenic medication. This chapter aims to review the role of VEGF in tumor angiogenesis and metastasis, the structure and function of VEGF and its receptors, and VEGF's role in cancer are discussed. Furthermore, tumor therapies targeting VEGF along with their side efects are presented and, inally, new directions in anti-VEGF therapy are considered along with the challenges.

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Sorafenib Cardiotoxicity Increases Mortality After Myocardial Infarction

Cited by 78 publications

References 65 publications

Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration

Acute Catecholamine Exposure Causes Reversible Myocyte Injury Without Cardiac Regeneration

Long-term follow-up of complete remission of advanced hepatocellular carcinoma following sorafenib therapy: A case report

Anti-VEGF Therapy in Cancer: A Double-Edged Sword

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