Oncocardiology—Past, Present, and Future

Abstract

IMPORTANCE Oncocardiology is a medical discipline that focuses on the identification, prevention, and treatment of cardiovascular complications related to cancer therapy. This discipline has gained interest from the cardiology community in recent years because of a remarkable increase in the number of cancer survivors and the proliferation of new cancer therapies causing cardiovascular complications, such as hypertension, heart failure, vascular complications, and cardiac arrhythmia. In this review, we provide historical perspectives, highlight new discoveries, and speculate on the opportunity created by merging the research interests and clinical practices of cardiology and oncology. OBSERVATIONS The old paradigm of anthracycline cardiotoxic effects is replaced by new insights that anthracycline targets topoisomerase II β to cause DNA double-strand breaks and a profound change in the transcriptome leading to the generation of reactive oxygen species and the development of mitochondriopathy. Prevention of anthracycline cardiotoxic effects should be based on inhibiting or degrading topoisomerase II β. New challenges were posed by the introduction of trastuzumab and tyrosine kinase inhibitors that revolutionized cancer therapy. The on-target cardiotoxic effects of trastuzumab were owing to a prosurvival benefit of Her2 that binds to neuregulin, whereas the off-target effect of multitargeted tyrosine kinase inhibitors may be mediated by disruption of the vascular endothelial growth factor signaling pathway or the stress-induced angiogenesis. Sensitive imaging techniques, such as global strain, and biomarkers have allowed for early detection of cardiotoxic effects. Early treatment with heart failure medications may be beneficial in preventing the development of late cardiotoxic effects. CONCLUSIONS AND RELEVANCE Close collaboration between cardiologists and oncologists is required to meet the demand of an increasing number of cancer survivors. New insights based on mechanistic studies or genetic discoveries will pave the way for better prevention, diagnosis, and treatment of cancer therapy-induced cardiovascular complications.

Cardiovascular Complications of Cancer Therapy

“…In the cardiomyocytes, doxorubicin targets topoisomerase 2β to induce DNA double-strand breaks and doxorubicin-bound topoisomerase 2β binds promoters of anti-oxidative and electron-transport genes to reduce their transcripts and protein expression (24,25) (Figure 1). Therefore, doxorubicin-treated cells have a marked increase in reactive oxygen species (ROS) and are defective in mitochondria biogenesis.…”

“…Doxorubicin-bound topoisomerase 2β binds to promoters of anti-oxidative genes and PGC-1 that are required for expression of anti-oxidative enzymes and electron transport chains. Thus, topoisomerase 2β is able to account for the three hallmarks of doxorubicin-induced cardiotoxicity: cardiomyocyte death, generation of ROS, and mitochondriopathy (24,25). …”

“… Frequency of Use: This was determined using inpatient and outpatient doses dispensed at MD Anderson Cancer Center during the time period of January 1, 2014 through December 21, 2014. + <1,000 doses dispensed ++ 1,000–5,000 doses dispensed +++ 5,000–10,000 doses dispensed ++++ >10,000 doses dispensed References: (1,2,24,29) …”

NT-proBNP correlates with LVEF decline in HER2-positive breast cancer patients treated with trastuzumab

“…There are multiple pathways that could be involved in the development of cardiotoxicity due to cardio-toxic cancer treatment, and therefore multiple biomarkers may be useful in detecting cardiotoxicity. The pathway of anthracycline involves inhibition of topoisomerase IIb in myocardial cells with apoptosis and radical oxygen species formation as result [24], but less is known about the specific pathway involved in trastuzumab-induced cardiotoxicity. For example, troponin is released in patients with ischemic heart disease, but until now it has not been proven efficient in detecting cardiotoxicity due to trastuzumab treatment.…”

Temporal changes in treatments and outcomes after acute myocardial infarction among cancer survivors and patients without cancer, 1995 to 2013

“…Radiation therapy is a well established risk factor for coronary artery disease, the consequences of which may become clinically significant many years later . Certain cancer therapies, such as anthracyclines, antimetabolites, hormone therapies, and new targeted and biologic agents, can have adverse cardiac effects …”