Cardiotoxicity with vascular endothelial growth factor inhibitor therapy

Abstract

Angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway (VSP) have been important additions in the therapy of various cancers, especially renal cell carcinoma and colorectal cancer. Bevazicumab, the first VSP to receive FDA approval in 2004 targeting all circulating isoforms of VEGF-A, has become one of the best-selling drugs of all times. The second wave of tyrosine kinase inhibitors (TKIs), which target the intracellular site of VEGF receptor kinases, began with the approval of sorafenib in 2005 and sunitinib in 2006. Heart failure was subsequently noted, in 2-4% of patients on bevacizumab and in 3-8% of patients on VSP-TKIs. The very fact that the single-targeted monoclonal antibody bevacizumab can induce cardiotoxicity supports a pathomechanistic role for the VSP and the postulate of the "vascular" nature of VSP inhibitor cardiotoxicity. In this review we will outline this scenario in greater detail, reflecting on hypertension and coronary artery disease as risk factors for VSP inhibitor cardiotoxicity, but also similarities with peripartum and diabetic cardiomyopathy. This leads to the concept that any preexisting or coexisting condition that reduces the vascular reserve or utilizes the vascular reserve for compensatory purposes may pose a risk factor for cardiotoxicity with VSP inhibitors. These conditions need to be carefully considered in cancer patients who are to undergo VSP inhibitor therapy. Such vigilance is not to exclude patients from such prognostically extremely important therapy but to understand the continuum and to recognize and react to any cardiotoxicity dynamics early on for superior overall outcomes.

Fig. 1

Hypertension and heart failure with sunitinib. Percentage of renal cell cancer patients free of hypertension and with various grades of hypertension (a) or heart failure (b) after initiation of sunitinib therapy. Modified from ref.

Fig. 2

Myocardial hypertrophy and angiogenesis. Illustration of the VEGF-mediated, angiogenesis response to hypertrophic stimuli. Modified from ref.

Fig. 3

Pericyte–endothelial–myocardial coupling. Illustration of pericyte–endothelial–myocardial coupling. None of these cells exists in isolation in the myocardium, but there is interaction on multiple levels. Accordingly, cardiomyocytes can be affected by an initial action on endothelial/pericyte level. This has been shown for sunitnib, although it has been reported to affect all three outlined cell types

Fig. 4

Conceptual outline of the vascular nature of VSP inhibitor cardiotoxicity. Outline of the concept of absolute or relative and structural or functional coronary microvascular deficit and cardiomyopathy with VSP inhibitor therapy

Fig. 5

Comorbidities contributing to the vascular nature of VSP inhibitor cardiotoxicity. Illustration of the comorbidities to consider and to screen for in patients who are considered for VSP therapy matching the pathophysiological concept introduced in Fig. 4