The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity

Bordun, Kimberly-Ann; Premecz, Sheena; daSilva, Megan; Mandal, Soma; Goyal, Vineet; Glavinovic, Tamara; Cheung, Matthew C.; Cheung, David; White, Christopher W.; Chaudhary, Rakesh; Freed, Darren H.; Villarraga, Hector R.; Herrmann, Joerg; Kohli, Manish; Ravandi, Amir; Thliveris, James A.; Pitz, Marshall; Singal, Pawan K.; Mulvagh, Sharon L.; Jassal, Davinder S.

doi:10.1152/ajpheart.00172.2015

Cited by 46 publications

(22 citation statements)

References 63 publications

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“…However, our data challenge the development of such therapeutic approach because the immediate cardiovascular impact could be disastrous similar to the cardiotoxic effects of antiangiogenic drugs, such as bevacizumab and sunitinib used in cancer therapy. 39 • In this study, we showed that besides its role in the differentiation of vascular smooth muscle cells and in the vascular tone, Notch3 signaling is necessary for the vascular adaptation to hypertension. The consequence of Notch3 signaling impairment is a severe dilated cardiomyopathy that can progress to heart failure.…”

Section: Perspectivesmentioning

confidence: 76%

Loss of Notch3 Signaling in Vascular Smooth Muscle Cells Promotes Severe Heart Failure Upon Hypertension

et al. 2016

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Hypertension, which is a risk factor of heart failure, provokes adaptive changes at the vasculature and cardiac levels. Notch3 signaling plays an important role in resistance arteries by controlling the maturation of vascular smooth muscle cells. Notch3 deletion is protective in pulmonary hypertension while deleterious in arterial hypertension. Although this latter phenotype was attributed to renal and cardiac alterations, the underlying mechanisms remained unknown. To investigate the role of Notch3 signaling in the cardiac adaptation to hypertension, we used mice with either constitutive Notch3 or smooth muscle cell-specific conditional RBPJκ knockout. At baseline, both genotypes exhibited a cardiac arteriolar rarefaction associated with oxidative stress. In response to angiotensin II-induced hypertension, the heart of Notch3 knockout and SM-RBPJκ knockout mice did not adapt to pressure overload and developed heart failure, which could lead to an early and fatal acute decompensation of heart failure. This cardiac maladaptation was characterized by an absence of media hypertrophy of the media arteries, the transition of smooth muscle cells toward a synthetic phenotype, and an alteration of angiogenic pathways. A subset of mice exhibited an early fatal acute decompensated heart failure, in which the same alterations were observed, although in a more rapid timeframe. Altogether, these observations indicate that Notch3 plays a major role in coronary adaptation to pressure overload. These data also show that the hypertrophy of coronary arterial media on pressure overload is mandatory to initially maintain a normal cardiac function and is regulated by the Notch3/RBPJκ pathway.

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Section: Perspectivesmentioning

confidence: 76%

Loss of Notch3 Signaling in Vascular Smooth Muscle Cells Promotes Severe Heart Failure Upon Hypertension

et al. 2016

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“…We have recently shown in patients with lymphoma [51], breast cancer (mainly anthracycline based chemotherapy) [52], and those undergoing treatment with VEGFi [53] that GLS measured by 2D-STE can detect early cardiac damage before a decrease in LVEF is identified. The method has been widely used to monitor cancer patients undergoing chemotherapy [20,[50][51][52][53][54][55][56].…”

Section: Baseline and Monitoring Evaluation Of Oncology Patientsmentioning

confidence: 99%

Rationale for setting up a cardio-oncology unit: our experience at Mayo Clinic

et al. 2016

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Background: The diagnosis and management of cardiovascular complications have become a clinical concern for oncologists, cardiologists, surgeons, interventional radiologists, radiation therapy physicians, internists, nurses, pharmacists, administrators, and all the stakeholders involved in the care of cancer patients. Anticancer therapies have extended the lives of patients with cancer, but for some this benefit is attenuated by adverse cardiovascular effects.Methods: This review article aims to provide an overview of the rationale of setting up a cardio-oncology unit and reflect on our own experience establishing this service, and conclude with some fundamental aspects of consideration for evaluation and management of patients with cancer and cardiovascular diseases. Results: Cardiotoxicity can lead to congestive heart failure and cardiac death. In fact, chemotherapy-related cardiac dysfunction may carry one of the worst prognoses of all types of cardiomyopathies, and has a profound impact on morbidity and mortality in oncology patients. Other complex clinical situations involve cancer patients who might benefit from a highly curative drug in terms of cancer survival but face limitations of its administration because of concomitant cardiovascular diseases. Indeed, the balance between the benefits and risks of the cancer therapy regimen in the context of the cardiovascular status of the individual patient can sometimes be extraordinarily challenging. A subspecialty with a multidisciplinary integrative approach between oncologists, hematologists, cardiologists, among others has thus emerged to address these issues, termed cardio-oncology. Cardio-oncology addresses the spectrum of prevention, detection, monitoring and treatment of cancer patients with cardiovascular diseases, or at risk for cardiotoxicity, in a multidisciplinary manner. In this field, cardiologists assist oncologists and hematologists with cardiovascular recommendations. This can be mediated through e-consultations or face-to-face evaluations. Conclusion: Cardio-oncology is a subspecialty that assists in the overall care of cancer patients with and without cardiovascular disease in an interdisciplinary fashion. We believe that this partnership of sharing responsibilities and experiences among health-care team members can potentially decrease cancer therapeutics-related cardiovascular complications and improve clinical outcomes.

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“…Hence, dysfunctional autophagy is a key player involved in the etiology and/or progression of several cognitive deficitassociated neurodegenerative diseases (Ghavami, et al, 2014). Others and we have previously shown that sunitinib had both positive and negative effects on autophagic status in cancer cells (Abdel-Aziz, et al, 2014, Bordun, et al, 2015, Lopergolo, et al, 2014, Santoni, et al, 2013. In spite of this, the effects of sunitinib on both apoptotic and autophagic machineries within a "neurocognitive" frame have not been addressed yet.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Indeed, cognitive deficits associated with several neurodegenerative diseases as Alzheimer's disease as well as exposure to neurotoxic insults triggered by chemotherapeutics and traumatic brain injury were shown to be mediated via activation of the "executioner" apoptotic machinery ultimately resulting in synaptic malfunction and neuronal cell loss (Walker and Tesco, 2013). In this context, the cyotoxic effects of sunitinib in both cancer and non-cancerous cells as cardiomyocytes is mediated via inducing apoptosis (Abdel- Aziz, et al, 2014, Bordun, et al, 2015. Autophagy (or self-eating) is an evolutionarily conserved recycling process.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries

Abdel-Aziz

Mantawy

Said

et al. 2016

Experimental Neurology

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The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity

Cited by 46 publications

References 63 publications

Loss of Notch3 Signaling in Vascular Smooth Muscle Cells Promotes Severe Heart Failure Upon Hypertension

Loss of Notch3 Signaling in Vascular Smooth Muscle Cells Promotes Severe Heart Failure Upon Hypertension

Rationale for setting up a cardio-oncology unit: our experience at Mayo Clinic

The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries

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