Investigation of the mechanism of hypertension caused by BTKi in the treatment of hematologic diseases.

in Frontiers in pharmacology by Jiayi Xu, Junling Lin, Haojian Gan, Qingjian He, WenJuan Wang, Yuanhua Liu

TLDR

  • BTKis cause hypertension by disrupting the BCR signaling cascade and impacting downstream signaling pathways, leading to endothelial dysfunction, oxidative stress, and vascular constriction.
  • Careful monitoring of blood pressure, individualized antihypertensive treatment, and possible modifications of the dosing of BTKis are essential for managing BTKi-induced hypertension.
  • Future research should focus on identifying the molecular mechanisms underlying BTKi-induced hypertension and the effects of various antihypertensive regimens on patient outcomes

Abstract

Bruton's tyrosine kinase inhibitors (BTKis) have made substantial impacts on the treatment of B-cell malignancies like chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Therapeutic benefits aside, the clinical use of BTKis comes with several side effects, of which hypertension (HTN) is quite common and serious and of significant clinical concern. The present article will discuss the mechanisms by which the use of BTKis causes hypertension and outline strategies for managing the condition within the clinic. Studies indicate that using BTKis interferes with BTK's central role within the B-cell receptor (BCR) signaling cascade and impacts multiple downstream signaling pathways like PI3K/Akt, MAPK, and NF-κB. These changes contribute to endothelial dysfunction, increased oxidative stress, and vascular constriction, all of which are implicated in the development of hypertension. Of special concern is that oxidative stress (OS) is directly related to decreased endothelial nitric oxide (NO) production, a finding that becomes particularly relevant during the initiation of BTKi therapy. Also, BTKis affect vascular development and tone regulation by activating the Notch and RhoA/ROCK pathways, leading to increased vasoconstriction and the advancement of hypertension. In light of the possibility that BTKi-induced hypertension might jeopardize treatment tolerability and patient outcomes, this review proposes a multimodal management of the condition, including careful monitoring of blood pressure, individualized antihypertensive treatment, and possible modifications of the dosing of BTKis. Future investigations should look into the specific molecular mechanisms underpinning the development of hypertension due to BTKis as well as the effects of various antihypertensive regimens on the improvement of the cardiovascular profile of affected individuals.

Overview

  • The study focuses on understanding the mechanisms by which Bruton's tyrosine kinase inhibitors (BTKis) cause hypertension and outlines strategies for managing the condition within the clinic.
  • The study examines the impact of BTKis on the B-cell receptor (BCR) signaling cascade, multiple downstream signaling pathways, and their relationship to endothelial dysfunction, oxidative stress, and vascular constriction.
  • The primary objective of the study is to identify the specific molecular mechanisms underlying BTKi-induced hypertension and the effects of various antihypertensive regimens on the cardiovascular profile of affected individuals.

Comparative Analysis & Findings

  • The study finds that BTKis interfere with BTK's central role in the BCR signaling cascade, impacting multiple downstream signaling pathways, including PI3K/Akt, MAPK, and NF-κB.
  • Changes in these signaling pathways contribute to endothelial dysfunction, increased oxidative stress, and vascular constriction, leading to the development of hypertension.
  • BTKis also affect vascular development and tone regulation by activating the Notch and RhoA/ROCK pathways, leading to increased vasoconstriction and adverse hypertension

Implications and Future Directions

  • The study highlights the importance of careful monitoring of blood pressure, individualized antihypertensive treatment, and possible modifications of the dosing of BTKis to manage BTKi-induced hypertension.
  • Future investigations should focus on identifying the specific molecular mechanisms underlying BTKi-induced hypertension and the effects of various antihypertensive regimens on the cardiovascular profile of affected individuals.
  • Understanding the mechanisms of BTKi-induced hypertension can inform the development of more effective therapeutic strategies and improve patient outcomes
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