Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies

Abstract

The cardiovascular care of cancer patients (“Cardio-Oncology”) has emerged as a new discipline in clinical medicine given recent advances in cancer therapy, and is driven by the cardiovascular complications that occur as a direct result of cancer therapy. Traditional therapies, such as anthracyclines and radiation, have been recognized for years to have cardiovascular complications. Less expected were the cardiovascular effects of “targeted” cancer therapies, which were initially felt to be specific to cancer cells and would spare any adverse effects on the heart. Cancers are typically driven by mutations, translocations, and/or over-expression of protein kinases. The majority of these mutated kinases are tyrosine kinases, though serine/threonine kinases also play key roles in some malignancies. Several agents were developed to target these kinases, but many more are in development. Major successes have been largely restricted to agents targeting Her2 (mutated or over-expressed in breast cancer), BCR-ABL (CML and some cases of ALL),and c-Kit (gastrointestinal stromal tumor).Other agents targeting more complex malignancies such as advanced solid tumors have had successes, but have not extended life to the degree seen with CML. Years before the first targeted therapeutic, Judah Folkman correctly proposed that to address solid tumors, one had to target the inherent neo-angiogenesis. Unfortunately, emerging evidence confirms that angiogenesis inhibitors cause cardiac complications, including hypertension, thrombosis, and heart failure. And therein lies the Catch 22. On the other hand, cardiomyopathies that arise unexpectedly from such targeted therapies can provide key insights into the normal function of the heart.

Aerobic Exercise Training as a Potential Cardioprotective Strategy to Attenuate Doxorubicin-Induced Cardiotoxicity

“…These studies further suggest that the chronic manifestations of DOXinduced cardiotoxicity may result from myocardial injuries associated with acute DOX exposure [18]. Thus far multiple mechanisms of DOX-induced cardiotoxicity have been proposed in the literature [19][20][21][22][23][24][25][26]. Among the proposed mechanisms, DOXinduced generation of reactive oxygen species (ROS) is the central mediator of numerous direct and indirect cardiac adverse consequences.…”

Evaluation of the Cardiotoxicity of Evodiamine <em>In Vitro</em> and<em> In Vivo</em>

“…The redox environment of the cell is extremely important to control either apoptosis or autophagy. One of the most widely cited and accepted mechanisms underlying cardiotoxicity involves the formation of ROS, leading to oxidative stress [31][32][33][34]. A previous study reported that ROS and nitric oxide (NO) generation was induced by evodiamine time-dependently in human cervical carcinoma HeLa cells [25].…”

Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond

“…ErbB2 is a transmembrane glycoprotein receptor which plays a key role in cell growth, including myocyte growth, and inhibition of apoptosis [7][8][9]42]. Cardiac endothelial cells produce the growth factor NRG1, which activates the Her-2/Her-4 complex, thus triggering cascades of ERK-MAPK and PI3K-Akt signaling pathways, promoting cell survival [43].…”

“…Such molecules are characterized by a targeted action [1] on well-known proteins with important roles in cancer biology [2]. However, despite their selective action, they can still cause cardiovascular complications such as arterial hypertension, QT interval prolongation, heart failure (HF), cardiomyopathy, stroke, acute myocardial infarction (AMI), thromboembolic events and cardiovascular deaths [3,4] since the same targets also play a role in maintaining cardiovascular homeostasis [5][6][7][8][9].…”