Anthracycline compounds are major culprits in chemotherapy-induced cardiotoxicity, which is the chief limiting factor in delivering optimal chemotherapy to cancer patients. Although extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity, there is little consensus regarding the best approach. Recent advances in basic mechanisms of anthracycline-induced cardiotoxicity provided a unified theory to explain the old reactive-oxygen species hypothesis and identified topoisomerase 2β as the primary molecular target for cardioprotection. This review outlines current strategies for primary and secondary prevention of anthracycline-induced cardiotoxicity resulting from newly recognized molecular mechanisms and identifies knowledge gaps requiring further investigation.

Anthracyclines are powerful chemotherapy agents that are still widely used today. However, their clinical use is limited by the development of dose-dependent cardiotoxicity. Recently, we showed that topoisomerase 2β (Top2β) is required for anthracycline to induce DNA double-strand breaks and changes in the transcriptome, leading to mitochondrial dysfunction and generation of reactive oxygen species. Furthermore, deleting Top2β from cardiomyocytes prevented the development of anthracycline-induced cardiotoxicity in mice. On the basis of this molecular insight, new strategies should be developed to prevent anthracycline-induced cardiotoxicity. First, Top2α-specific anthracyclines should be tested to determine whether they will spare the heart. Second, Top2β should be studied as a potential biomarker to predict risk of developing cardiotoxicity before anthracycline treatment. Third, inhibiting and deleting Top2β in the heart should also be tested as primary prevention strategies. We propose that Top2β is a promising molecular target that can be used to design interventions to prevent anthracycline-induced cardiotoxicity.

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.

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A dvances in cancer treatment have reduced cancer-related mortality, adding to the ranks of cancer survivors (1). Unfortunately, chemotherapy and radiation often cause acute or chronic cardiovascular complications, which are the major causes of noncancer mortality among survivors. Compared with siblings, cancer survivors are 10 times more likely to develop coronary disease and 15 times more likely to develop heart failure (HF) (2). Thus, screening for cardiovascular complications has been advocated for patients who have received anthracycline and/or radiation. In this issue of the Journal, Armstrong et al. (3) report a cross-sectional analysis of cardiac function in long-term childhood cancer survivors from a single center using transthoracic echocardiography to assess myocardial strain imaging and diastolic function. SJLIFE (St. Jude Lifetime Cohort Study) analyzed 1,807 childhood survivors who were diagnosed with cancer more than 10 years previously and received either anthracycline or chest radiotherapy or both. Systolic dysfunction, defined as left ventricular (LV) ejection fraction (LVEF) < 50%, was detected in only 5.8% of survivors. Among patients with preserved LV function, 28% and 8.7% were found to have abnormal global longitudinal strain (GLS) and diastolic dysfunction, respectively. These findings were consistent with those of previous studies, which demonstrated that asymptomatic cancer survivors have subtle abnormalities of both systolic and diastolic function compared with the normal population (4). A recent meta-analysis suggested that GLS might have prognostic value for the development of cardiotoxicity; however, this was on the basis of results from 8 studies with <500 patients, with most of these studies having only 1 year of follow-up (4). Moreover, the definition of cardiotoxicity was ambiguous, and the majority of patients had LVEFs within the normal range (4). Itshould be noted that abnormal GLS is defined as more than 2 SDs above the mean using sex-specific, age-specific, and vendor-specific strain values identified in a normative Japanese study (5). However, the SJLIFE population is 84% white. The correlation between the incidence of HF and the cumulative dose of anthracycline and radiation is well established in the published research (6). The investigators also demonstrate a dose-response relationship between the cumulative anthracycline or radiation dose and the development of GLS abnormalities. This study therefore confirms the limitation of current standard screening with ejection fraction and highlights the value of strain imaging.

One of six patients were readmitted within 30 days after the aortic valve replacement. On propensity score analysis, there were no significant differences between the early readmission rates between TAVR and SAVR groups. However, the patients undergoing transapical TAVR were at higher risk for readmission, and subsequent deaths when compared with transfemoral TAVR and SAVR. © 2017 Wiley Periodicals, Inc.