Cardio-Oncology: Time to Get More Mechanistic.

A new discipline, cardio-oncology, has emerged as a major clinical need over the last decade as a result of novel cancer therapies that are associated with cardiovascular complications (1). Direct myocardial toxicity is particularly relevant to cardio-oncology, especially because this phenomenon was appreciated more than 50 years ago with anthracyclines 1, 2. Anthracyclines, such as doxorubicin, have been effective as cornerstone therapies for multiple cancer types, but have been associated with clinical heart failure or cardiomyopathy. Anthracycline-induced cardiac toxicity is felt to be cumulative and dose-dependent, and can present acutely (within days to weeks of a treatment) but is more commonly recognized as a subacute cardiomyopathy (occurring months to years later). Cardiomyopathy is a major toxicity with this class of drugs and limits their use. Myocardial protection is an important potential strategy for attenuating cardiotoxicity, especially in high-risk patients (2). In this regard, several studies, mostly performed in the pediatric cancer population exposed to anthracyclines, suggest a cardioprotective role for dexrazoxane, an iron chelator. However, the role of neurohormonal activation in the progression of typical adult heart failure is well described, and the beneficial effects of renin-angiotensin system inhibition and beta-adrenergic receptor blockade on mortality and morbidity in patients with systolic dysfunction is well validated. For this reason, a number of studies have attempted to demonstrate the utility of these therapies in the cardio-oncology population, especially those treated with anthracyclines. The presumed efficacy of these drugs would be due to inhibiting deleterious cardiac remodeling during or after the completion of cancer therapy. Indeed, ongoing placebo-controlled studies are attempting to validate this concept in cardio-oncology (2).

In this issue of JACC: Basic to Translational Science, Beak et al. (3) use both pharmacological and genetic tools to demonstrate a protective role for alpha-1A-adrenergic receptor (AR) in a murine model for acute doxorubicin cardiotoxicity. Dabuzalgron, an oral alpha-1A-AR agonist prevented doxorubicin-induced cardiac dysfunction (via mouse echocardiography) and decreased myocardial fibrosis (on histology). Conversely, mice genetically deficient in alpha-1A-AR had significantly lower cardiac function and increased myocardial fibrosis burden after doxorubicin treatment. Importantly, dabuzalgron had no protective effect in alpha-1-adrenergic receptor (AR) knockout mice, suggesting “on-target” protection. To further define the downstream targets of protection conferred by dabuzalgron, the authors used both in vitro (using neonatal rat ventricular myocytes) data as well as their mouse model. They provide intriguing data that dabuzalgron preserves mitochondrial function (in part by activating critical mitochondrial biogenesis gene peroxisome proliferator-activated receptor gamma coactivator-1α) and restoring adenosine triphosphate synthesis after doxorubicin treatment. In keeping with these data, dabuzalgron mitigated activation of apoptotic components and abrogated mitochondrial membrane potential effects of doxorubicin in vitro. Additionally, the authors show activation of extracellular signal-regulated kinase (ERK), a canonical downstream signaling of alpha-1A-AR, to be critical in cardioprotection conferred by dabuzalgron. In keeping with the latter, trametinib, a kinase inhibitor of ERK, abrogated the myoprotective effects of dabuzalgron.

The author’s findings are particularly intriguing because the presumed mechanism of protection is inhibition of myocardial cell death at the time of doxorubicin treatment rather than a long-term protection due to attenuation of cardiac remodeling. For example, the authors did control experiments to show that dabuzalgron does not affect heart rate, blood pressure, or heart size in mice. Nevertheless, there are several limitations of this study. First, the dose of doxorubicin used in the authors’ studies, as well as the acuity by which the cardiotoxicity occurs, may not be as relevant to the more commonly encountered chronic cardiomyopathy experienced in clinical practice. Second, experiments performed to understand the mechanism of myocyte death (specifically apoptosis) after doxorubicin treatment are somewhat limited and not in depth. Recent data, for example, suggest an age-dependent regulation of mitochondrial apoptosis, where adult somatic heart tissue is profoundly refractory to pro-apoptotic signaling (4). Nevertheless, as has been previously shown with doxorubicin, there is a critical role for mitochondrial genes (and specifically mitochondrial biogenesis genes such as PGC-1α) in mediating cardioprotection in the authors’ model.

The authors should be congratulated in their mechanistic approach to problems in cardio-oncology. Far too often this has not been the case. In 2005, for example, 1 group proposed dividing the myotoxic effects of cancer therapy into 2 different categories depending on the purported reversibility of myocardial damage (5). In this model, anthracyclines were a “type I” agent in that they cause direct myocyte death leading to irreversible damage. Another known potential cardiotoxin, trastuzumab, was considered reversible and, thus, a type II agent. Although this simple classification may have been intriguing at the time, little experimental approach has been brought forth to define the mechanisms of such classification in toxicity. Indeed, 12 years later, clinical data suggest that this classification hypothesis is irrelevant to the “real-world” population. For example, single-institution studies suggest that many cases of anthracycline-mediated cardiomyopathy are indeed reversible (1). Despite these emerging data, this simplistic classification has been used by the cardiac imaging community to provide guidelines for care for patients (6). From a practical perspective, although the aforementioned classification was an enticing hypothesis based on only 2 cardiotoxins, it is not a reasonable classification for cardio-oncology as a whole. As we have encountered in any patient who presents with new systolic dysfunction, there may be many etiologies to consider, and limiting the classification to only 2 categories in a patient being treated for cancer seems extraordinarily simplistic. This latter point is an important concept to consider in the field of cardio-oncology, given the number of new pathways being targeted for cancer therapy and relatively short time from conception of a new drug to drug approval. In the current paper, for example, Beak et al. (3) tested whether trametinib, a kinase inhibitor of ERK, abrogated myoprotective effects of dabuzalgron. Trametinib, an MEK inhibitor, has actually been approved for treatment for a subset of melanomas, but cardiac dysfunction occurs in about 7% of patients. This has prompted a recommendation by the U.S. Food and Drug Administration for cardiac monitoring during treatment. Instead of contemplating whether trametinib causes an arbitrary type I versus a type II cardiac injury, the field of cardio-oncology should focus on detailed and complete mechanistic studies such as what the authors have done for this paper. In the long term, this will better inform preventive and treatment strategies for patients.