Efficacy of Flaxseed Compared to ACE Inhibition in Treating Anthracycline- and Trastuzumab-Induced Cardiotoxicity.

Background: Although the current combination of surgery, radiation, and chemotherapy is used in the breast-cancer setting, the administration of the anticancer drugs doxorubicin and trastuzumab is associated with an increased risk of developing heart failure. The aim of this study is to determine whether dietary flaxseed is comparable and/or synergistic with the angiotensin-converting enzyme inhibitor perindopril in the treatment of doxorubicin- and trastuzumab-mediated cardiotoxicity. Methods: In a chronic in vivo murine model (n = 110), doxorubicin and trastuzumab (8 mg/kg and 3 mg/kg, respectively) were administered weekly for 3 weeks. Following this period, the mice were randomized to daily consumption of a 10% flaxseed supplemented diet, administration of perindopril (3 mg/kg) via oral gavage, or a combination of both flaxseed and perindopril for an additional 3 weeks. Results: In mice treated with doxorubicin and trastuzumab, the left ventricular ejection fraction decreased from 74% ± 4% at baseline to 30% ± 2% at week 6. Treatment with either flaxseed or perindopril, or with flaxseed and perindopril improved left ventricular ejection fraction to 52% ± 4%, 54% ± 4%, and 55% ± 3%, respectively (P < 0.05). Although histologic analyses confirmed significant loss of sarcomere integrity and vacuolization in the doxorubicin- and trastuzumab-treated mice, treatment with flaxseed or perindopril, or with flaxseed and perindopril improved myocyte integrity. Finally, the level of Bcl-2 interacting protein 3, high-mobility group box 1 protein expression, and the levels of select oxylipins, were significantly elevated in mice receiving doxorubicin and trastuzumab; these markers were attenuated by treatment with either flaxseed or perindopril, or with flaxseed and perindopril. Conclusions: Flaxseed was equivalent to perindopril at improving cardiovascular remodelling by reducing biomarkers of inflammation, mitochondrial damage, and cell death.

Contexte: Si l'association actuelle de la chirurgie, de la radiothérapie et de la chimiothérapie est utilisée pour le traitement du cancer du sein, on observe néanmoins que l'administration de la doxorubicine et du trastuzumab, deux anticancéreux, augmente les risques d'insuffisance cardiaque. Cette étude vise à déterminer si les graines de lin alimentaires ont un effet comparable et/ou synergique à celui du périndopril, un inhibiteur de l'enzyme de conversion de l'angiotensine, dans le traitement de la cardiotoxicité liée à la doxorubicine et au trastuzumab. Méthodologie: Dans un modèle murin chronique in vivo (n = 110), la doxorubicine et le trastuzumab (8 mg/kg et 3 mg/kg, respectivement) ont été administrés une fois par semaine pendant trois semaines. Après cette période, les souris ont été réparties de façon aléatoire dans trois groupes : l'un recevant tous les jours un régime alimentaire contenant 10 % de graines de lin, un autre recevant du périndopril (3 mg/kg) par gavage oral et un troisième recevant à la fois des graines de lin et du périndopril pendant trois semaines supplémentaires. Résultats: Chez les souris recevant la doxorubicine et le trastuzumab, la fraction d'éjection ventriculaire gauche est passée de 74 % ± 4 % au départ à 30 % ± 2 % à la semaine 6. Avec le traitement par les graines de lin seules, le périndopril seul ou les graines de lin et le périndopril en association, la fraction d'éjection ventriculaire gauche est passée à 52 % ± 4 %, à 54 % ± 4 % et à 55 % ± 3 %, respectivement (p < 0,05). Bien que les analyses histologiques aient permis de confirmer une perte significative de l'intégrité des sarcomères et une vacuolisation chez les souris recevant la doxorubicine et le trastuzumab, le traitement par les graines de lin seules, le périndopril seul ou les graines de lin et le périndopril en association a amélioré l'intégrité des myocytes. Enfin, les taux de protéine 3 interagissant avec BCL-2, l'expression de la protéine HMGB1 (high-mobility group box 1) et les taux de certaines oxylipines étaient significativement élevés chez les souris recevant la doxorubicine et le trastuzumab. Ces marqueurs ont été atténués par les graines de lin, le périndopril ou l'association des deux. Conclusions: En diminuant les biomarqueurs de l'inflammation, les dommages aux mitochondries et la mort cellulaire, les graines de lin ont un effet équivalant à celui du périndopril quant à l'amélioration du remodelage cardiovasculaire.

Impact of transcatheter aortic valve implantation on circulating von Willebrand factor in patients with severe aortic stenosis.

INTRODUCTION: Severe aortic stenosis (AS) can lead to degradation of high molecular weight (HMW) von Willebrand factor (VWF) which can result in haemostatic abnormalities. While studies have explored changes in VWF profiles before and after surgical aortic valve replacement (SAVR), the longer-term changes in VWF profiles pre- and post-transcatheter aortic valve implantation (TAVI) are less understood. AIM: Our primary objective was to identify differences in VWF multimer profiles and VWF function pre-TAVI and 1-month post-TAVI. Our secondary objective was to correlate VWF markers with measures of AS severity. METHODS: Adult patients with severe AS referred for TAVI at our institution were prospectively enrolled in this cohort study. Blood samples were collected for plasma analysis at three time points for all patients: 1 day pre-TAVI, 3 days post-TAVI, and 1-month post-TAVI. VWF antigen, activity, propeptide, collagen binding, multimers, and factor VIII coagulant activity were determined at each time point. Correlations between VWF parameters and severity of AS were assessed. RESULTS: Twenty participants (15 males, five females) with severe AS were recruited for the study. There was a significant increase in HMW VWF between pre-procedure and 1-month post-TAVI (p < .05). There was a transient increase in VWF antigen levels and activity at 3-days post TAVI that decreased to pre-TAVI levels at 1-month. There were no statistically significant correlations between VWF markers and AS severity. CONCLUSIONS: This is the first study to elucidate longer-term (>1 week) improvements in HMW VWF after a TAVI procedure in severe AS patients.

Shared Decision-Making in Athletes Diagnosed With a Cardiovascular Condition: A Scoping Review.

This scoping review summarizes existing approaches, benefits, and barriers to shared decision-making (SDM) in the context of sports cardiology. Among 6,058 records screened, 37 articles were included in this review. Most included articles defined SDM as an open dialogue between the athlete, healthcare team, and other stakeholders. The benefits and risks of management strategies, treatment options, and return-to-play were the focus of this dialogue. Key components of SDM were described through various themes, such as emphasizing patient values, considering nonphysical factors, and informed consent. Benefits of SDM included enhancing patient understanding, implementing a personalized management plan, and considering a holistic approach to care. Barriers to SDM included pressure from institutions, consideration of multiple perspectives in decision-making, and the potential liability of healthcare providers. The use of SDM when discussing management, treatment, and lifestyle modification for athletes diagnosed with a cardiovascular condition is necessary to ensure patient autonomy and engagement.

Comparing Flaxseed and Perindopril in the Prevention of Doxorubicin and Trastuzumab-Induced Cardiotoxicity in C57Bl/6 Mice.

BACKGROUND: Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity. METHODS: Over a six-week period, 81 wild-type C57Bl/6 female mice (8-12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study. RESULTS: In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration. CONCLUSION: FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model.

Exercise to Reduce Anthracycline-Mediated Cardiovascular Complications in Breast Cancer Survivors.

While developments in cancer therapeutics have greatly reduced morbidity and mortality in females with breast cancer, it comes at a cost of an increased risk of cardiovascular complications. In particular, anthracyclines, like doxorubicin, which are a mainstay of current chemotherapy regimens, are associated with dose-dependent cardiotoxicity. Exercise has been widely accepted as an effective intervention in reducing cardiovascular risk in a variety of different clinical conditions. However, the benefits of exercise in anthracycline-mediated cardiotoxicity are not clearly understood. First, this review discusses the pre-clinical studies which have elucidated the cardioprotective mechanisms of aerobic and resistance exercise in improving cardiovascular function in the setting of anthracycline treatment. Next, it aims to summarize the results of aerobic and resistance exercise clinical trials conducted in females with breast cancer who received anthracycline-based chemotherapy. The review further discusses the current exercise guidelines for women undergoing chemotherapy and contraindications for exercise. Finally, the review addresses gaps in research, specifically the need for further clinical trials to establish a recommended exercise prescription within this patient population.

Mechanisms of anthracycline-mediated cardiotoxicity and preventative strategies in women with breast cancer.

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.

Modeling transition to turbulence in eccentric stenotic flows.

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.

Numerical modeling of pulsatile turbulent flow in stenotic vessels.

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-omega 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-epsilon turbulence model and the standard k-epsilon 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.