Grounding Cardio-Oncology in Basic and Clinical Science

The development of cardio-oncology as a clinical field has been driven by improved therapeutics resulting in a dramatic increase in the number of cancer survivors (~15,500,000 in the United States alone) many of whom suffer cardiovascular complications related to their cancer treatments.¹ Both “traditional” and “targeted” therapies can affect the cardiovascular system resulting in hypertension, heart failure, myocarditis, arrhythmias, vascular disease, and thrombosis. While recurrence of cancer is the eventual cause of death in many “cancer survivors”, cardiovascular disease is responsible for substantial morbidity and mortality in this population. Thus, effective means of mitigating cardiovascular complications of cancer therapies would have substantial impact on health. Unfortunately, definitive strategies to predict, prevent, monitor, and treat chemotherapy-induced cardiovascular syndromes are currently lacking for several reasons. First, mechanistically distinct cancer therapies can cause heterogeneous cardiovascular sequelae. Second, molecular mechanisms that mediate these syndromes are poorly understood. Finally, evidence-based knowledge pertaining to some of the most important clinical questions is not yet available. Because of this situation, most clinical guidelines are based on “consensus statements”.

To illustrate how gaps in basic and clinical knowledge may combine to produce suboptimal disease models on which to base diagnosis and treatment strategies, consider the concept of Type I versus Type II cardiomyopathy.² This paradigm was introduced in 2005 to contrast heart failure syndromes resulting from doxorubicin and trastuzumab. Type I cardiomyopathy (doxorubicin) was defined as irreversible, dose-dependent, likely to recur with re-challenge, and accompanied by histopathological abnormalities. In contrast, Type II cardiomyopathy (trastuzumab) was considered reversible, not dose-related, not elicited by re-challenge, and without histopathological abnormalities. This classification has been widely employed in the design of monitoring and treatment strategies. Unfortunately, recent prospective clinical data do not support this simple dichotomous view of these two cardiomyopathies. Data from both oncology clinical trials as well as “real world” population studies suggest that doxorubicin-induced cardiomyopathy is often reversible, while the cardiomyopathy resulting from trastuzumab may persist.^1,3

While scientific models are always provisional with the expectation that they will require revision in the face of new data, the Type I versus Type II classification was largely based on theoretical considerations. The pathogenesis of trastuzumab-induced cardiomyopathy was obscure at that time and, while doxorubicin-induced cardiomyopathy was poorly understood, the notion of cell death as an important mechanism was gaining traction. Thus, it was logical to posit the cardiomyopathy resulting from doxorubicin should be irreversible. This begs the question of the basis for its reversibility.

To understand this issue, we will first consider how doxorubicin damages cells. Its molecular target in cancer cells is believed to be topoisomerase 2α, whose normal cellular function is to catalyze double stranded DNA break/repair that allows changes in DNA topology required for mitosis, meiosis, and transcription. Doxorubicin may promote DNA damage by trapping topoisomerase 2α in its cleavage-active conformation and, thereby, induce apoptosis. The mechanism for doxorubicin-induced cardiac toxicity continues to be hotly debated with the focus on two, non-mutually exclusive mechanisms.⁴ The first postulates that doxorubicin kills cardiomyocytes by inducing DNA damage through topoisomerase 2β, the isoform in cardiomyocytes - similar to its therapeutic effects in cancer cells. An attractive feature of this model is that other well-known manifestations of doxorubicin cardiotoxicity - including oxidative stress and mitochondrial abnormalities - may be accounted for by changes in gene transcription that also result from the effects of doxorubicin on topoisomerase 2β. The second mechanism for doxorubicin-induced cardiomyopathy postulates that oxidative stress is the primary event.⁵ This model is based on the ability of doxorubicin to stimulate the iron-dependent generation of hydroxyl radicals, which then damage DNA, proteins, lipids, and associated structures (e.g. membranes, organelles) - resulting in cellular dysfunction or cell death. While gene knockout studies in mice provide support for both topoisomerase 2β and oxidative stress/iron mechanisms, questions remain about the relative importance of each, interconnections between the two, and whether other mechanisms exist.

The preceding discussion suggests that a spectrum of toxicities might account for variability in the clinical course of doxorubicin-induced cardiomyopathy. For example, irrespective of signaling mechanism, the predominance of cardiomyocyte dysfunction over cell death would allow for an element of reversibility (Figure). Even if cardiomyocyte death were the predominant sequela, there is potential for reversibility since doxorubicin affects the myocardium in a patchy distribution. This leaves open the possibility that unaffected regions of myocardium may compensate through augmentation of function, and structural/metabolic remodeling - just as non-infarcted cardiac muscle provides compensation following myocardial infarction. This analogy with myocardial infarction is further enforced by the notion that cardiac damage from doxorubicin occurs acutely with each dose of the drug as evidenced by the release of cardiac enzymes. Moreover, attenuation of progression of doxorubicin-induced cardiac dysfunction by standard heart failure medications likely reflects compensation by myocardium that has escaped damage.

Figure. Potential mechanisms for recovery from doxorubicin-induced cardiomyopathy.

Evidence suggests that both cardiomyocyte death (irreversible) and dysfunction (e.g. potentially reversible mitochondrial defects, atrophy, and myofibrillar loss) play roles in pathogenesis. Compensation may be provided by functional augmentation/remodeling of uninvolved myocardium and attenuation of dysfunctional processes as indicated.

The example of doxorubicin illustrates how a deeper molecular understanding of mechanisms of cardiotoxicity coupled with more astute clinical observations can profoundly impact the way we think about cardiovascular disease resulting from cancer drugs. It will be important to apply the same level of basic and clinical rigor to the adverse cardiovascular effects related to the multiple newly emerging targeted cancer chemotherapies. Given the distinct molecules and pathways against which these agents are directed, their mechanisms of cardiovascular toxicity and the clinical course of the associated syndromes is likely to differ markedly.

Cardio-oncology has emerged as an exciting area because of the medical challenges posed by targeted drugs that hold great promise for the treatment and cure of cancer. To advance, however, the field needs to become more firmly grounded in basic and clinical science. More importantly, the heterogeneous nature of the clinical issues will necessitate partnerships between cardio-oncologists and basic/translational scientists to define precise mechanisms for the toxicities of the various therapies, and collaborative efforts between cardio-oncologists and cancer physicians need to be intensified to generate data-driven algorithms to guide patient care.