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While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic agents used to treat cancer. Despite their reported dose-dependent cardiotoxicity, AC-based chemotherapy has become the mainstay of breast cancer therapy due to its efficacy. Elucidating the mechanisms of anthracycline-mediated cardiotoxicity and associated therapeutic interventions continue to be the main focus in the field of cardio-oncology. Herein, we summarized the current literature surrounding the mechanisms of anthracycline-induced cardiotoxicity, including the role of topoisomerase II inhibition, generation of reactive oxygen species, and elevations in free radicals. Furthermore, this review highlights the molecular mechanisms of potential cardioprotective interventions in this setting. The benefits of pharmaceuticals, including dexrazoxane, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, statins, and antioxidants in this setting, are reviewed. Finally, the mechanisms of emerging preventative interventions within this patient population including nutraceuticals and aerobic exercise are explored.

While anthracyclines (ACs) are a class of chemotherapeutic agents that have improved the prognosis of many women with breast cancer, it is one of the most cardiotoxic agents used to treat cancer. Despite their reported dose-dependent cardiotoxicity, AC-based chemotherapy has become the mainstay of breast cancer therapy due to its efficacy. Elucidating the mechanisms of anthracycline-mediated cardiotoxicity and associated therapeutic interventions continue to be the main focus in the field of cardio-oncology. Herein, we summarized the current literature surrounding the mechanisms of anthracycline-induced cardiotoxicity, including the role of topoisomerase II inhibition, generation of reactive oxygen species, and elevations in free radicals. Furthermore, this review highlights the molecular mechanisms of potential cardioprotective interventions in this setting. The benefits of pharmaceuticals, including dexrazoxane, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, statins, and antioxidants in this setting, are reviewed. Finally, the mechanisms of emerging preventative interventions within this patient population including nutraceuticals and aerobic exercise are explored.

Breast cancer is the leading cause of cancer in Canadian women and as a result constitutes a significant cause of morbidity and mortality in this patient population. Although overall survival is significantly improved by treatment with anti-cancer drugs including Doxorubicin and Trastuzumab, approximately 1 in 4 Canadian women are at risk of developing chemotherapy induced cardiotoxicity. Current guidelines recommend serial cardiac monitoring using transthoracic echocardiography (TTE) or multigated acquisition scan (MUGA) for the non-invasive assessment of left ventricular ejection fraction (LVEF). Recent studies suggest that echocardiographic deformation measures including tissue velocity imaging and strain parameters can detect adverse cardiac changes prior to quantifiable differences in LVEF. Early detection of chemotherapy mediated cardiotoxicity would allow for early intervention with the use of cardioprotective agents in women with breast cancer. The prophylactic use of angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), β-blockers, statins, anti-oxidants, and nutraceutical agents as cardioprotective agents have been studied in the Cardio-Oncology setting. While animal models and initial clinical trials prove promising, further studies are required to prevent the devastating consequences of chemotherapy mediated cardiotoxicity in women with breast cancer.

BACKGROUND Cardiotoxicity from breast cancer (BC) therapy, specifically with anthracyclines, is a significant cause of morbidity and mortality in women with BC. Although aerobic exercise (AE) during anthracycline therapy has been shown to reduce side effects including fatigue, nausea, and pain, the cardioprotective benefits of exercise remain unclear. Thus, we investigated the effect of a 24-week home-based AE program on cardiac function in women with BC receiving anthracyclines using echocardiography. METHODS AND RESULTS Women with BC were randomized to either a control group (standard of care) or to standard of care with a 24-week home-based AE program. Based on our previous exercise feasibility study in this patient population, the graduated exercise program consisted of 2 self-directed sessions per week (performed at 35-85% incremental heart rate reserve intensity) to achieve a minimum of 90 minutes of exercise weekly. Serial transthoracic echocardiography (TTE) was conducted at baseline and at 24-weeks to assess cardiovascular systolic and diastolic function, and strain parameters. A total of 11 women with BC (49 ± 10 years old) were recruited and randomized to either control (n = 5) or AE (n = 6). Ten patients received adriamycin and cyclophosphamide for 8 weeks and 1 patient received fluorouracil, epirubicin, and cyclophosphamide for 9 weeks. Additionally, 5 patients received adjuvant radiation therapy. A total of 5 women had baseline cardiovascular risk factors including hypertension (n=1), hyperlipidemia (n=1), smoking history (n=2), and family history of premature coronary artery disease (n=2). The characteristics of patients in the two groups were similar. Participants randomized to AE demonstrated an average of 94% adherence to the program. There were no significant differences between the two groups in the measured cardiovascular morphologic or functional parameters (Table 1). At baseline, mean LVEF was 63±1% in the control group and 63±2% in the AE group (Figure 1). At 24-weeks, mean LVEF was 60±2% and 59±8% in the control and exercise groups, respectively (p = NS). Additionally, at baseline, mean GLS was -18.8±0.4% in the control group and -18.7±1.1% in the AE group. At 24-weeks, mean GLS was -17.6±1.0% in the control group and -17.7±2.1% in the AE group (p = NS). CONCLUSION These preliminary echocardiographic findings indicate that although a 24-week home-based AE program was feasible, we were unable to demonstrate cardioprotection in women with BC receiving chemotherapy in comparison to standard of care.

Direct numerical simulations (DNS) of steady and pulsatile flow through 75% (by area reduction) stenosed tubes have been performed, with the motivation of understanding the biofluid dynamics of actual stenosed arteries. The spectral-element method, providing geometric flexibility and high-order spectral accuracy, was employed for the simulations. The steady flow results are examined here while the pulsatile flow analysis is dealt with in Part 2 of this study. At inlet Reynolds numbers of 500 and 1000, DNS predict a laminar flow field downstream of an axisymmetric stenosis and comparison to previous experiments show good agreement in the immediate post-stenotic region. The introduction of a geometric perturbation within the current model, in the form of a stenosis eccentricity that was 5% of the main vessel diameter at the throat, resulted in breaking of the symmetry of the post-stenotic flow field by causing the jet to deflect towards the side of the eccentricity and, at a high enough Reynolds number of 1000, jet breakdown occurred in the downstream region. The flow transitioned to turbulence about five diameters away from the stenosis, with velocity spectra taking on a broadband nature, acquiring a -5/3 slope that is typical of turbulent flows. Transition was accomplished by the breaking up of streamwise, hairpin vortices into a localized turbulent spot, reminiscent of the turbulent puff observed in pipe flow transition, within which r.m.s. velocity and turbulent energy levels were highest. Turbulent fluctuations and energy levels rapidly decayed beyond this region and flow relaminarized. The acceleration of the fluid through the stenosis resulted in wall shear stress (WSS) magnitudes that exceeded upstream levels by more than a factor of 30 but low WSS levels accompanied the flow separation zones that formed immediately downstream of the stenosis. Transition to turbulence in the case of the eccentric stenosis was found to be manifested as large temporal and spatial gradients of shear stress, with significant axial and circumferential variations in instantaneous WSS.

Direct numerical simulations (DNS) of stenotic flows under conditions of steady inlet flow were discussed in Part 1 of this study. DNS of pulsatile flow through the 75% stenosed tube (by area) employed for the computations in Part 1 is examined here. Analogous to the steady flow results, DNS predicts a laminar post-stenotic flow field in the case of pulsatile flow through the axisymmetric stenosis model, in contrast to previous experiments, in which intermittent disturbed flow regions and turbulent breakdown were observed in the downstream region. The introduction of a stenosis eccentricity, that was 5% of the main vessel diameter at the throat, resulted in periodic, localized transition to turbulence. Analysis in this study indicates that the early and mid-acceleration phases of the time period cycle were relatively stable, with no turbulent activity in the post-stenotic region. However, towards the end of acceleration, the starting vortex, formed earlier as the fluid accelerated through the stenosis at the beginning of acceleration, started to break up into elongated streamwise structures. These streamwise vortices broke down at peak flow, forming a turbulent spot in the post-stenotic region. In the early part of deceleration there was intense turbulent activity within this spot. Past the mid-deceleration phase, through to minimum flow, the inlet flow lost its momentum and the flow field began to relaminarize. The start of acceleration in the following cycle saw a recurrence of the entire process of a starting structure undergoing turbulent breakdown and subsequent relaminarization of the post-stenotic flow field. Peak wall shear stress (WSS) levels occurred at the stenosis throat, with the rest of the vessel experiencing much lower levels. Turbulent breakdown at peak flow resulted in a sharp amplification of instantaneous WSS magnitudes across the region corresponding to the turbulent spot, accompanied by large axial and circumferential fluctuations, even while ensemble-averaged axial shear stresses remained mostly low and negative. WSS levels dropped rapidly after the mid-deceleration phase, when the relaminarization process took over, and were almost identical to laminar, axisymmetric shear levels through most of the acceleration phase.

Pulsatile turbulent flow in stenotic vessels has been numerically modeled using the Reynolds-averaged Navier-Stokes equation approach. The commercially available computational fluid dynamics code (CFD), FLUENT, has been used for these studies. Two different experiments were modeled involving pulsatile flow through axisymmetric stenoses. Four different turbulence models were employed to study their influence on the results. It was found that the low Reynolds number k-ω turbulence model was in much better agreement with previous experimental measurements than both the low and high Reynolds number versions of the RNG (renormalization-group theory) k-ε turbulence model and the standard k-ε model, with regard to predicting the mean flow distal to the stenosis including aspects of the vortex shedding process and the turbulent flow field. All models predicted a wall shear stress peak at the throat of the stenosis with minimum values observed distal to the stenosis where flow separation occurred.

Mean flow predictions obtained from a host of turbulence models were found to be in poor agreement with recent direct numerical simulation results for turbulent flow distal to an idealized eccentric stenosis. Many of the widely used turbulence models, including a large eddy simulation model, were unable to accurately capture the poststenotic transition to turbulence. The results suggest that efforts toward developing more accurate turbulence models for low-Reynolds number, separated transitional flows are necessary before such models can be used confidently under hemodynamic conditions where turbulence may develop.

High-order simulations of flow through stenotic vessels were performed using the spectral/hp element method. Asymmetric flow features, that were observed downstream of the stenosis, produced fluctuating regions of wall shear stress. Local stenosis morphologies were also found to affect flow characteristics.