VEGF Receptor Inhibitor-Induced Hypertension: Emerging Mechanisms and Clinical Implications

Camarda, Nicholas D.; Travers, Richard; Yang, Vicky; London, Cheryl A.; Jaffe, Iris Z.

doi:10.1007/s11912-022-01224-0

Cited by 43 publications

(32 citation statements)

References 89 publications

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“…Finally, among the potential clinical risks of pharmacological VEGF inhibition, kidney function has been reviewed recently with a special focus on the parallels with the renal damage observed in preeclampsia-like proteinuria. 53 VEGF and its receptors are highly expressed in the kidneys, in particular, in podocytes and in the glomerulus, where they play a critical role in glomerular structure and function. It is conceivable that VEGF inhibition hampers function, growth, and proliferation of glomerular structures.…”

Section: Pharmacology Of Vegf Inhibitorsmentioning

confidence: 99%

VEGF (Vascular Endothelial Growth Factor) Inhibition and Hypertension: Does Microvascular Rarefaction Play a Role?

et al. 2023

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Drugs acting by inhibition of the angiogenic action of VEGF (vascular endothelial growth factor) have become major instruments in the treatment of cancer. The downside of their favorable effects in cancer treatment is their frequent cardiovascular side effects. The most consistent finding thus far on the cardiovascular side effects of VEGF inhibitor is the high incidence of hypertension. In this short review, we discuss the evidence that hypertension during VEGF inhibitor treatment is caused by microvascular rarefaction. After a review of the role of VEGF in microvascular growth and differentiation, we present evidence from studies in experimental models of hypertension as well as clinical studies on the microvascular network changes during and after VEGF inhibitor treatment.

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Section: Pharmacology Of Vegf Inhibitorsmentioning

confidence: 99%

VEGF (Vascular Endothelial Growth Factor) Inhibition and Hypertension: Does Microvascular Rarefaction Play a Role?

et al. 2023

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“…51,61 Predicting VEGFi-induced hypertension has been an identified are of interest, there are currently no proven predictive serum biomarkers available in clinical practice to guide physicians when assessing their patients for these treatments. 62 Exploration has already begun into potential novel biomarkers, such as VEGF-A and VCAM-1 (vascular cell adhesion protein 1), which may be utilized to predict hypertension in VEGFi-treated patients. Most recently a study by Quintanilha et al 63 found lower levels of these markers to be significant predictors of hypertension in colorectal patients treated with Regorafenib.…”

Section: Vascular Endothelial Growth Factor Inhibitorsmentioning

confidence: 99%

“…Recent research interest in the management of VEGFi-induced hypertension and its effective management is evident from the diverse range of recent and ongoing clinical trials (CHA-RISMA [Cancer and Blood Pressure Management; https://www.clinicaltrials.gov; Unique identifiers: NCT04467021, NCT03709771], UNICO [Reporting, Evaluating, Preventing and Treating the Cardiotoxicity Induced by Anticancer Drugs During a Specific Cardio-oncology Consult and Follow up in Routine Care; https://www.clinicaltrials.gov; Unique identifier: NCT03882580] and TITAN [Multidisciplinary Team Interventon in Cardio-Oncology; https://www.clinicaltrials.gov; Unique identifier: NCT01621659]) 62 some of which aim to assess the clinical outcomes of VEGFi treated patients whilst others have been specifically designed to assess the ideal blood pressure (BP) targets for treated patients with cancer to better guide clinical practice. Recent 2022 publication demonstrated in animal models (Wistar rats) treated with Axitinib that losartan, an established angiotensin-receptor blocker, can be used to effectively reduce hypertensive effects without effect on antitumor activity.…”

Section: Vascular Endothelial Growth Factor Inhibitorsmentioning

confidence: 99%

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

et al. 2023

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Cardiovascular disease and cancer are 2 of the leading causes of death worldwide. Although improvements in outcomes have been noted for both disease entities, the success of cancer therapies has come at the cost of at times very impactful adverse events such as cardiovascular events. Hypertension has been noted as both, a side effect as well as a risk factor for the cardiotoxicity of cancer therapies. Some of these dynamics are in keeping with the role of hypertension as a cardiovascular risk factor not only for heart failure, but also for the development of coronary and cerebrovascular disease, and kidney disease and its association with a higher morbidity and mortality overall. Other aspects such as the molecular mechanisms underlying the amplification of acute and long-term cardiotoxicity risk of anthracyclines and increase in blood pressure with various cancer therapeutics remain to be elucidated. In this review, we cover the latest clinical data regarding the risk of hypertension across a spectrum of novel anticancer therapies as well as the underlying known or postulated pathophysiological mechanisms. Furthermore, we review the acute and long-term implications for the amplification of the development of cardiotoxicity with drugs not commonly associated with hypertension such as anthracyclines. An outline of management strategies, including pharmacological and lifestyle interventions as well as models of care aimed to facilitate early detection and more timely management of hypertension in patients with cancer and survivors concludes this review, which overall aims to improve both cardiovascular and cancer-specific outcomes.

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“…Autophagy modulation achievable by a myriad of FDA-approved drugs represents a viable cardioprotective strategy, but approaches exploiting this biology have not yet been translated into the clinical setting [39,40]. While the cardiotoxic effects of doxorubicin are attributed predominantly to direct cardiomyocyte injury, newer targeted therapies such as tyrosine kinase inhibitors may act through vascular cell damage and impact cardiomyocyte autophagy, both of which may lead to systolic dysfunction or heart failure [41][42][43]. The cardiac slice culture addresses such limitations by encompassing the various cell types and tissue architecture, which will allow visualization of protein important in characterizing autophagic flux, such as LC3 and p62, by immunostaining as well as quantification by protein blot in slices while preserving structural and electrophysiological interactions between these cell types [20,24,25,44,45].…”

Section: Plos Onementioning

confidence: 99%

Using cultured canine cardiac slices to model the autophagic flux with doxorubicin

et al. 2023

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Chemotherapy-induced impairment of autophagy is implicated in cardiac toxicity induced by anti-cancer drugs. Imperfect translation from rodent models and lack of in vitro models of toxicity has limited investigation of autophagic flux dysregulation, preventing design of novel cardioprotective strategies based on autophagy control. Development of an adult heart tissue culture technique from a translational model will improve investigation of cardiac toxicity. We aimed to optimize a canine cardiac slice culture system for exploration of cancer therapy impact on intact cardiac tissue, creating a translatable model that maintains autophagy in culture and is amenable to autophagy modulation. Canine cardiac tissue slices (350 μm) were generated from left ventricular free wall collected from euthanized client-owned dogs (n = 7) free of cardiovascular disease at the Foster Hospital for Small Animals at Tufts University. Cell viability and apoptosis were quantified with MTT assay and TUNEL staining. Cardiac slices were challenged with doxorubicin and an autophagy activator (rapamycin) or inhibitor (chloroquine). Autophagic flux components (LC3, p62) were quantified by western blot. Cardiac slices retained high cell viability for >7 days in culture and basal levels of autophagic markers remained unchanged. Doxorubicin treatment resulted in perturbation of the autophagic flux and cell death, while rapamycin co-treatment restored normal autophagic flux and maintained cell survival. We developed an adult canine cardiac slice culture system appropriate for studying the effects of autophagic flux that may be applicable to drug toxicity evaluations.

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VEGF Receptor Inhibitor-Induced Hypertension: Emerging Mechanisms and Clinical Implications

Cited by 43 publications

References 89 publications

VEGF (Vascular Endothelial Growth Factor) Inhibition and Hypertension: Does Microvascular Rarefaction Play a Role?

VEGF (Vascular Endothelial Growth Factor) Inhibition and Hypertension: Does Microvascular Rarefaction Play a Role?

Established and Emerging Cancer Therapies and Cardiovascular System: Focus on Hypertension—Mechanisms and Mitigation

Using cultured canine cardiac slices to model the autophagic flux with doxorubicin

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