BACKGROUND Although the combination of doxorubicin (DOX) and trastuzumab (TRZ) reduces the progression and recurrence of breast cancer, these anticancer drugs are associated with significant cardiotoxic side effects. OBJECTIVE We investigated whether prophylactic administration of flaxseed (FLX) and its bioactive components, α-linolenic acid (ALA) and secoisolariciresinol diglucoside (SDG), would be cardioprotective against DOX + TRZ-mediated cardiotoxicity in a chronic in vivo female murine model. METHODS Wild-type C57BL/6 female mice (10-12 wk old) received daily prophylactic treatment with one of the following diets: 1) regular control (RC) semi-purified diet; 2) 10% FLX diet; 3) 4.4% ALA diet; or 4) 0.44% SDG diet for a total of 6 wks. Within each arm, mice received 3 weekly injections of 0.9% saline or a combination of DOX [8 mg/(kg.wk)] and TRZ [3 mg/(kg.wk)] starting at the end of week 3. The main outcome was to evaluate the effects of FLX, ALA, and SDG on cardiovascular remodeling and markers of apoptosis, inflammation, and mitochondrial dysfunction. Significance between measurements was determined using a 4 (diet) × 2 (chemotherapy) × 2 (time) mixed factorial design with repeated measures. RESULTS In the RC + DOX + TRZ-treated mice at week 6 of the study, the left ventricular ejection fraction (LVEF) decreased by 50% compared with the baseline LVEF (P < 0.05). However, the prophylactic administration of the FLX, ALA, or SDG diet was partially cardioprotective, with mice in these treatment groups showing an ∼68% increase in LVEF compared with the RC + DOX + TRZ-treated group at week 6 (P < 0.05). Although markers of inflammation (nuclear transcription factor κB), apoptosis [poly (ADP-ribose) polymerase-1 and the ratio of BCL2-associated X protein to B-cell lymphoma-extra large], and mitochondrial dysfunction (BCL2-interacting protein 3) were significantly elevated by approximately 2-fold following treatment with RC + DOX + TRZ compared with treatment with RC + saline at week 6, prophylactic administration of FLX, ALA, or SDG partially downregulated these signaling pathways. CONCLUSION In a chronic in vivo female C57BL/6 mouse model of DOX + TRZ-mediated cardiotoxicity, FLX, ALA, and SDG were partially cardioprotective.

The Cardioprotective Role of Flaxseed in the Prevention of Doxorubicin- and Trastuzumab-Mediated Cardiotoxicity in C57BL/6 Mice

The exercise consisted of: 1) a short survey to acquire baseline data on current practices regarding the conduct of animal studies, 2) a series of presentations for promoting awareness and providing advice and practical tools for improving experimental design, and 3) a follow-up survey 12 mo later to assess whether practices had changed. The surveys were compulsory for responsible investigators (n = 16; paired data presented). Other investigators named on animal ethics applications were encouraged to participate (2017, total of 36 investigators; 2018, 37 investigators). The major findings to come from the exercise included 1) a willingness of investigators to make changes when provided with knowledge/tools and solutions that were relatively simple to implement (e.g., proportion of responsible investigators showing improved practices using a structured method for randomization was 0.44, 95% CI (0.19; 0.70), P = 0.003, and deidentifying drugs/interventions was 0.40, 95% CI (0.12; 0.68), P = 0.010); 2) resistance to change if this involved more personnel and time (e.g., as required for allocation concealment); and 3) evidence that changes to long-term practices ("habits") require time and follow-up. Improved practices could be verified based on changes in reporting within publications or documented evidence provided during laboratory visits. In summary, this exercise resulted in changed attitudes, practices, and reporting, but continued follow-up, monitoring, and incentives are required. Efforts to improve experimental rigor will reduce bias and will lead to findings with the greatest translational potential.NEW & NOTEWORTHY The goal of this exercise was to encourage preclinical researchers to improve the quality of their cardiac and metabolic animal studies by 1) increasing awareness of concerns, which can arise from suboptimal experimental designs; 2) providing knowledge, tools, and templates to overcome bias; and 3) conducting two short surveys over 12 mo to monitor change. Improved practices were identified for the uptake of structured methods for randomization, and de-identifying interventions/drugs.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/experimental-design-survey-training-practical-tools/.

CORP: Practical tools for improving experimental design and reporting of laboratory studies of cardiovascular physiology and metabolism

ABSTRACT Bevacizumab is a recombinant humanized monoclonal antibody whose adverse effects include cardiotoxicity. We investigated whether using adenosine triphosphate (ATP) or benidipine either separately or together protects against cardiac damage induced by bevacizumab in rats. Forty Wistar albino male rats were allocated to five groups of eight: bevacizumab (Bv), ATP + bevacizumab (ABv), benidipine + bevacizumab (BBv), ATP + benidipine + bevacizumab (ABBv) and untreated controls. Rats in the ABv group were injected intraperitoneally (i.p.) with 2 mg/kg ATP. The BBv group was given 4 mg/kg benidipine by oral gavage. The ABBv group was injected i.p. with 2 mg/kg ATP and simultaneously administered 4 mg/kg benidipine orally. One hour after administration of ATP, benidipine or normal saline, the Bv, ABv, BBv and ABBv groups were injected i.p. with 10 mg/kg bevacizumab. Malondialdehyde (MDA) and total glutathione (tGSH) levels were measured in cardiac tissue, and troponin I (TP I) and creatine kinase MB (CK-MB) levels were measured in blood samples. Tissue samples were examined for histopathology. We found the lowest TP I, CK-MB and MDA levels and the highest tGSH level in the ABBv group; these results were similar to the control group. Nuclei of cardiomyocytes in the BV group were misshapen and shrunken, and myofibers were disrupted; we also observed eosinophilic degeneration and interstitial edema. Blood capillaries were dilated and congested. We observed amelioration of these findings in the ABBv group. We found that ATP and benidipine alone or in combination reduced cardiac damage associated with the use of bevacizumab. ATP + benidipine combined therapy produced the most favorable results.

Protective effect of adenosine triphosphate and benidipine separately or together against cardiotoxicity caused by bevacizumab

Hypertension (HTN) is a major modifiable cardiovascular risk factor. Despite availability of effective blood pressure-lowering medications, HTN remains poorly controlled. Causes of suboptimal HTN control include the asymptomatic nature of HTN, low patient compliance, inadequate knowledge regarding the sequelae of HTN, and often complex therapeutic regimen. In the current guidelines, combination therapy using single pill combinations (SPC) has been widely recommended for the treatment of HTN. In the present paper, we evaluated the usefulness of perindopril-based SPC in various clinical scenarios in everyday practice. Perindopril-based SPC, including both two- and three-drug combinations, have been marketed since 2008. Our considerations regarding the use of perindopril-based combinations both within the basic HTN management strategy and for treatment individualization are informed by not only the everyday clinical experience but also the results of numerous clinical studies, including large randomized trials. Perindopril-based SPC are characterized by a long duration of action providing stable 24-hour blood pressure control, and the wide range of perindopril-based SPC allows their use in various clinical scenarios, thus facilitating treatment individualization. 

Practical use of single pill combinations in the treatment of hypertension — an analysis focused on perindopril-based combinations

Renin Angiotensin System (RAS): The Common Thread Between Cancer and Heart Failure

In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer d...

Role of renin-angiotensin system antagonists in the prevention of bevacizumab- and sunitinib-mediated cardiac dysfunction

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Role of renin-angiotensin system antagonists in the prevention of bevacizumab- and sunitinib-mediated cardiac dysfunction