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

Abstract

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.

Keywords: blood pressure; cardiovascular diseases; epidemiology; hypertension; neoplasms; risk factor; treatment.

Figure 1.. Pathophysiological changes associated with hypertension induced by new and emerging anti-cancer agents.

BRAF - B1 homolog v-raf murine sarcoma viral kinase oncogene; BTK - Bruton tyrosine kinase; ENaC -; MEK - mitogen-activated protein kinase; NO – nitric oxide; PARP - Poly(ADP-ribose) polymerases; PI3K - phosphatidylinositol 3-kinase; VEGF - Vascular endothelial growth factor.

Figure 2.. Potential mechanisms involved in the onset of hypertension by established and emerging cancer therapies.

Schematic representations of major pathways affected by cancer therapies (orange boxes): Proteasome inhibitors (PI), RET inhibitors (RETi), BRAF-MEK inhibitors (BRAF-MEKi), Vascular endothelial growth factor inhibitors (VEGFi), Phosphatidylinositol 3-kinase inhibitors (PI3Ki), Bruton tyrosine kinase inhibitors (BTKi), and Poly (ADP Ribose) Polymerase inhibitors (PARPi). Lines with arrowheads and flatheads at the end represent “activation” and “inhibition,” respectively. Dashed line represents a plausible pathway. The red circles are key signalling molecules whilst green circles are potential anti-hypertensive therapeutic targets. The grey boxes represent the major mechanisms whilst the blue boxes indicate the common pathogenesis underpinning the onset of elevated blood pressure and, consequently, the development of hypertension. ERK = extracellular signal–regulated kinases; AKT = Protein Kinase B; ROCK = Rho-associated protein kinase; PI3K = Phosphoinositide 3-kinases; DYRK1A = Dual-specificity tyrosine phosphorylation-regulated kinase; eNOS = endothelial nitric oxide synthase; NO = nitric oxide; Y-27632 = ROCK Inhibitor; PP2A = Protein phosphatase 2; NOX = NADPH Oxidase; AMPKα = AMP-activated protein kinase; L-arg = L-arginine; GSK-3β = Glycogen synthase kinase-3 beta; CAT-1 = Cationic amino acid transporter-1; sFlt-1 = Soluble fms-like tyrosine kinase-1; and CRY2 = Cryptochrome circadian regulator 2.

Figure 3.

Avenues for the detection and management of hypertension in cancer patients