Therapy-naïve malignancy causes cardiovascular disease: a state-of-the-art cardio-oncology perspective.

Cardiovascular disease (CVD) and cancer are the leading causes of mortality worldwide. Although generally thought of as distinct diseases, the intersectional overlap between CVD and cancer is increasingly evident in both causal and mechanistic relationships. The field of cardio-oncology is largely focused on the cardiotoxic effects of cancer therapies (e.g., chemotherapy, radiation). Furthermore, the cumulative effects of cardiotoxic therapy exposure and the prevalence of CVD risk factors in patients with cancer lead to long-term morbidity and poor quality of life in this patient population, even when patients are cancer-free. Evidence from patients with cancer and animal models demonstrates that the presence of malignancy itself, independent of cardiotoxic therapy exposure or CVD risk factors, negatively impacts cardiac structure and function. As such, the primary focus of this review is the cardiac pathophysiological and molecular features of therapy-naïve cancer. We also summarize the strengths and limitations of preclinical cancer models for cardio-oncology research and discuss therapeutic strategies that have been tested experimentally for the treatment of cancer-induced cardiac atrophy and dysfunction. Finally, we explore an adjacent area of interest, called "reverse cardio-oncology," where the sequelae of heart failure augment cancer progression. Here, we emphasize the cross-disease communication between malignancy and the injured heart and discuss the importance of chronic low-grade inflammation and endocrine factors in the progression of both diseases.

Novel roles of cardiac-derived erythropoietin in cardiac development and function.

The role of erythropoietin (EPO) has extended beyond hematopoiesis to include cytoprotection, inotropy, and neurogenesis. Extra-renal EPO has been reported for multiple tissue/cell types, but the physiological relevance remains unknown. Although the EPO receptor is expressed by multiple cardiac cell types and human recombinant EPO increases contractility and confers cytoprotection against injury, whether the heart produces physiologically meaningful amounts of EPO in vivo is unclear. We show a distinct circadian rhythm of cardiac EPO mRNA expression in adult mice and increased mRNA expression during embryogenesis, suggesting physiological relevance to cardiac EPO production throughout life. We then generated constitutive, cardiomyocyte-specific EPO knockout mice driven by the Mlc2v promoter (EPOfl/fl:Mlc2v-cre+/-; EPOΔ/Δ-CM). During cardiogenesis, cardiac EPO mRNA expression and cellular proliferation were reduced in EPOΔ/Δ-CM hearts. However, in adult EPOΔ/Δ- CM mice, total heart weight was preserved through increased cardiomyocyte cross-sectional area, indicating the reduced cellular proliferation was compensated for by cellular hypertrophy. Echocardiography revealed no changes in cardiac dimensions, with modest reductions in ejection fraction, stroke volume, and tachycardia, whereas invasive hemodynamics showed increased cardiac contractility and lusitropy. Paradoxically, EPO mRNA expression in the heart was elevated in adult EPOΔ/Δ-CM, along with increased serum EPO protein content and hematocrit. Using RNA fluorescent in situ hybridization, we found that Epo RNA colocalized with endothelial cells in the hearts of adult EPOΔ/Δ-CM mice, identifying the endothelial cells as a cell responsible for the EPO hyper-expression. Collectively, these data identify the first physiological roles for cardiomyocyte-derived EPO. We have established cardiac EPO mRNA expression is a complex interplay of multiple cell types, where loss of embryonic cardiomyocyte EPO production results in hyper-expression from other cells within the adult heart.

Guidelines on antibody use in physiology research.

Antibodies are one of the most used reagents in scientific laboratories and are critical components for a multitude of experiments in physiology research. Over the past decade, concerns about many biological methods, including those that use antibodies, have arisen as several laboratories were unable to reproduce the scientific data obtained in other laboratories. The lack of reproducibility could be largely attributed to inadequate reporting of detailed methods, no or limited verification by authors, and the production and use of unvalidated antibodies. The goal of this guideline article is to review best practices concerning commonly used techniques involving antibodies, including immunoblotting, immunohistochemistry, and flow cytometry. Awareness and integration of best practices will increase the rigor and reproducibility of these techniques and elevate the quality of physiology research.

Intron retention is a mechanism of erythropoietin regulation in brain cell models.

Intron retention is a mechanism of post-transcriptional gene regulation, including genes involved in erythropoiesis. Erythropoietin (EPO) is a hormone without evidence of intracellular vesicle storage that regulates erythropoiesis. We hypothesize that EPO uses intron retention as a mechanism of post-transcriptional regulation in response to hypoxia and ischemia. Cell models of hypoxia and ischemia for kidney, liver, and brain cells were examined for intron retention by real time quantitative PCR. EPO expression increased in most cells except for blood brain barrier and liver cells. The intron retained transcript ratio decreased in brain cells, except for Astrocytes, but showed no change in kidney or liver after 24 h of ischemia. The shift in intron ratio was maintained when using poly (A) enriched cDNA, suggesting that intron retention is not due to immature transcripts. The expression of EPO was elevated at variable time points amongst cell models with the intron ratio also changing over a time course of 2 to 16 h after ischemia. We conclude that intron retention is a mechanism regulating EPO expression in response to ischemia in a tissue specific manner.

Delta-6 desaturase (Fads2) deficiency alters triacylglycerol/fatty acid cycling in murine white adipose tissue.

The Δ-6 desaturase (D6D) enzyme is not only critical for the synthesis of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from α-linolenic acid (ALA), but recent evidence suggests that it also plays a role in adipocyte lipid metabolism and body weight; however, the mechanisms remain largely unexplored. The goal of this study was to investigate if a D6D deficiency would inhibit triacylglycerol storage and alter lipolytic and lipogenic pathways in mouse white adipose tissue (WAT) depots due to a disruption in EPA and DHA production. Male C57BL/6J D6D knockout (KO) and wild-type (WT) mice were fed either a 7% w/w lard or flax (ALA rich) diet for 21 weeks. Energy expenditure, physical activity, and substrate utilization were measured with metabolic caging. Inguinal and epididymal WAT depots were analyzed for changes in tissue weight, fatty acid composition, adipocyte size, and markers of lipogenesis, lipolysis, and insulin signaling. KO mice had lower body weight, higher serum nonesterified fatty acids, smaller WAT depots, and reduced adipocyte size compared to WT mice without altered food intake, energy expenditure, or physical activity, regardless of the diet. Markers of lipogenesis and lipolysis were more highly expressed in KO mice compared to WT mice in both depots, regardless of the diet. These changes were concomitant with lower basal insulin signaling in WAT. Collectively, a D6D deficiency alters triacylglycerol/fatty acid cycling in WAT by promoting lipolysis and reducing fatty acid re-esterification, which may be partially attributed to a reduction in WAT insulin signaling.

Exploring the well-being of community pharmacy professionals, turnover intention and patient safety: Time to include operational responsibility.

Background: The COVID-19 pandemic added significant occupational pressures on community pharmacists. The objective of this research project was to investigate the level of distress and burnout among community pharmacy professionals and its association with their retention within their occupation as well as patient safety outcomes. Method: We conducted a cross-sectional study on 722 community pharmacy professionals from all Canadian provinces using an online survey, including scientifically validated measures. The data were analyzed using multiple regression analysis. Results: In Canada, 85% of community pharmacy professionals reported their mental health had suffered since the COVID-19 pandemic. Younger pharmacy professionals and those paid hourly reported a worsening level of mental health and an increasing level of turnover intention. Pharmacists with more dynamic/disrupted work schedules and those working for a large pharmacy chain (more than 25 pharmacies in Canada) reported lower levels of mental health quality. Pharmacy professionals working in pharmacies that are open more than 70 hours a week reported a lower level of patient safety culture. Pharmacists' mental health was the significant predictor of their turnover intention, implying a heightened risk to professional effectiveness and retention. Compassion satisfaction was positively associated with patient safety culture and safety behaviour, while compassion fatigue and secondary traumatic stress were significantly associated with pharmacists' level of risk-taking behaviours. Conclusion: This study emphasized the importance of prioritizing the mental health and well-being of community pharmacy professionals and demonstrated individual and systemic factors predicting the well-being and turnover intention of community pharmacists, as well as patient safety culture within their pharmacy. This research makes a case to consider actions to shift the monitoring focus from community pharmacists (also known as "individual responsibility") to community pharmacies (also known as "operational responsibility") for managing patient safety. Additionally, community pharmacists should be provided with the professional autonomy to affect their working conditions and alleviate the stress that has the potential to negatively affect the delivery of care.

Enhanced Telehealth Home-Monitoring Intervention for Vulnerable and Frail Patients after Cardiac Surgery (THE-FACS Pilot Intervention Study).

BACKGROUND: Frail cardiac surgery patients have an increased risk of worse postoperative outcomes. The purpose of this study was to evaluate the implementation of a novel Telehealth Home monitoring Enhanced-Frailty And Cardiac Surgery (THE-FACS) intervention and determine its impact on clinical outcomes in frail patients post-cardiac surgery. METHODS: Frail/vulnerable patients defined by Edmonton Frailty Scale (EFS > 4) undergoing cardiac surgery were prospectively enrolled (November 2019 -March 2020) at the New Brunswick Heart Centre. Exclusion criteria included age < 55 years, emergent status, minimally invasive surgery, lack of home support, and > 10-days postoperative hospital stay. Following standard training on THE-FACS, participants were sent home with a tablet device to answer questions about their health/recovery and measure blood pressure for 30-consecutive days. Transmitted data were monitored by trained cardiac surgery follow-up nurses. Patients were contacted only if the algorithm based on the patient's self-collected data triggered an alert. Patients who completed the study were compared to historical controls. The primary outcome of interest was to determine the number of patients that could complete THE-FACS; secondary outcomes included participant/caregiver satisfaction and impact on hospital readmission. RESULTS: We identified 86 eligible (EFS > 4), out of 254 patients scheduled for elective cardiac surgery during the study period (vulnerable: 34%). The patients who consented to participate in THE-FACS (64/86, 74%) had a mean age of 69.1 ± 6.4 years, 25% were female, 79.7% underwent isolated Coronary Artery Bypass Graft (CABG) and median EFS was 6 (5-8). 29/64 (45%) were excluded post-enrollment due to prolonged hospitalization (15/64) or requirement for hospital-to-hospital transfer (12/64). Of the remaining 35 patients, 21 completed the 30-day follow-up (completion rate:60%). Reasons for withdrawal (14/35, 40%) were mostly due to technical difficulties with the tablet. Hospital readmission, although non-significant, was reduced in THE-FACS participants compared to controls (0% vs. 14.3%). A satisfaction survey revealed > 90% satisfaction and ~ 67% willingness to re-use a home monitoring device. CONCLUSIONS: THE-FACS intervention can be used to successfully monitor vulnerable patients returning home post-cardiac surgery. However, a significant number of frail patients could not benefit from THE-FACS given prolonged hospitalization and technological challenges. Our findings suggest that despite overall excellent satisfaction in participants who completed THE-FACS, there remain major challenges for wide-scale implementation of technology-driven home monitoring programs as only 24% completed the study.

High-impact opportunities to address ischemia: a focus on heart and circulatory research.

Myocardial ischemic injury and its resolution are the key determinants of morbidity or mortality in heart failure. The cause and duration of ischemia in patients vary. Numerous experimental models and methods have been developed to define genetic, metabolic, molecular, cellular, and pathophysiological mechanisms, in addition to defining structural and functional deterioration of cardiovascular performance. The rapid rise of big data, such as single-cell analysis techniques with bioinformatics, machine learning, and neural networking, brings a new level of sophistication to our understanding of myocardial ischemia. This mini-review explores the multifaceted nature of ischemic injury in the myocardium. We highlight recent state-of-the-art findings and strategies to show new directions of high-impact approach to understanding myocardial tissue remodeling. This next age of heart and circulatory physiology research will be more comprehensive and collaborative to uncover the origin, progression, and manifestation of heart failure while strengthening novel treatment strategies.

Extracellular Vesicles as Predictors of Individual Response to Exercise Training in Youth Living with Obesity.

BACKGROUND: Exercise is associated with health benefits, including the prevention and management of obesity. However, heterogeneity in the adaptive response to exercise training exists. Our objective was to evaluate if changes in extracellular vesicles (EVs) after acute aerobic exercise were associated with the responder phenotype following 6-weeks of resistance training (RT). METHODS: This is a secondary analysis of plasma samples from the EXIT trial (clinical trial#02204670). Eleven sedentary youth with obesity (15.7 ± 0.5 yrs, BMI ≥95th percentile) underwent acute exercise (60% HRR, 45 min). Blood was collected at baseline [AT0 min], during [AT15-45 min], and 75 min post-recovery [AT120], and EVs purified using size exclusion chromatography from extracted plasma. Afterward, youth participated in 6-weeks RT and were categorized into responders or non-responders based on changes in insulin sensitivity. RESULTS: We assessed EV biophysical profile (size, zeta potential, protein yield, and EV subtype protein expression) in a single-blind fashion. Overall, there was a general increase in EV production in both groups. Average EV size was larger in responders (~147 nm) vs. non-responders (~124 nm; p < 0.05). EV size was positively associated with absolute change in Matsuda index (insulin sensitivity) following RT (r = 0.44, p = 0.08). EV size distribution revealed responders predominantly expressed EVs sized 150-300 nm, whereas non-responders expressed EVs sized 50-150 nm (p < 0.05). At baseline, responders had ~25% lower TSG101, ~85% higher MMP2 levels. EV protein yield was higher in responders than non-responders at AT15 (p < 0.05). CONCLUSIONS: Our data suggest that youth with obesity that respond to RT produce larger EVs that are TSG101+ and CD63+, with increased EV protein yield during acute exercise.

Virtual Care With Digital Technologies for Rural Canadians Living With Cardiovascular Disease.

Canada is a wealthy nation with a geographically diverse population, seeking health innovations to better serve patients in accordance with the Canada Health Act. In this country, population and geography converge with social determinants, policy, procurement regulations, and technological advances with the goal to achieve equity in the management and distribution of health care. Rural and remote patients are a vulnerable population; when managing chronic conditions like cardiovascular disease, there is currently inequity to accessing specialist physicians at the recommended frequency-increasing the likelihood of poor health outcomes. Ensuring equitable care for this population is an unrealized priority of several provincial and federal government mandates. Virtual care technology might provide practical, economical, and innovative solutions to remedy this discrepancy. We conducted a scoping review of the literature pertaining to the use of virtual care technologies to monitor patients living in rural areas of Canada with cardiovascular disease. A search strategy was developed to identify the literature specific to this context across 3 bibliographic databases. Two hundred thirty-two unique citations were ultimately assessed for eligibility, of which 37 met the inclusion criteria. In our assessment of these articles, we provide a summary of the interventions studied, their reported effectiveness in reducing adverse events and mortality, the challenges to implementation, and the receptivity of these technologies among patients, providers, and policy-makers. Furthermore, we glean insight into the barriers and opportunities to ensure equitable care for rural patients and conclude that there is an ongoing need for clinical trials on virtual care technologies in this context.

Le Canada, pays riche dont la population est répartie dans des régions géographiquement diversifiées, reste à l'affût des innovations en matière de santé pour mieux servir les patients conformément à la Loi canadienne sur la santé. Dans ce pays, la population et la géographie ainsi que les déterminants sociaux, les politiques, la réglementation des marchés publics et les progrès technologiques convergent vers un objectif d'équité dans la gestion et la distribution des soins de santé. Les patients des régions rurales et éloignées constituent une population vulnérable; la prise en charge de maladies chroniques comme les maladies cardiovasculaires est marquée par des inégalités en ce qui concerne l'accès aux médecins spécialistes à la fréquence recommandée ­ ce qui augmente le risque de problèmes de santé. La garantie d'un accès équitable aux soins de santé pour cette population constitue une priorité non concrétisée pour plusieurs gouvernements provinciaux et fédéraux. Les technologies des soins virtuels pourraient offrir des solutions pratiques, économiques et novatrices afin de remédier à la disparité qui persiste. Nous avons effectué une revue exploratoire de la littérature relative à l'utilisation des technologies des soins virtuels pour le suivi des patients atteints de maladies cardiovasculaires vivant dans les régions rurales du Canada. Une stratégie de recherche a été élaborée pour recenser les articles visant spécifiquement ce contexte dans trois bases de données bibliographiques. Au terme de la recherche, 232 références uniques ont été évaluées en fonction des critères d'admissibilité; 37 y répondaient. Dans notre évaluation des articles, nous résumons les interventions étudiées, leur efficacité rapportée quant à la réduction des événements indésirables et de la mortalité, les difficultés de mise en œuvre et la réceptivité des patients, des fournisseurs de soins et des décideurs politiques aux technologies utilisées. En outre, nous offrons un aperçu des obstacles à surmonter et des occasions à saisir pour garantir un accès équitable aux soins de santé dans les régions rurales et nous concluons que des études cliniques sur les technologies des soins virtuels demeurent nécessaires dans ce contexte.

Irisin response to acute moderate intensity exercise and high intensity interval training in youth of different obesity statuses: A randomized crossover trial.

Limited data exist regarding the impact of an acute bout of exercise with varying intensities on irisin levels in the youth of different obesity statuses. The objectives were to (1) compare an acute bout of moderate continuous intensity (MCI) exercise and an acute bout of high-intensity interval training (HIIT) on irisin response in youth with different obesity statuses and, (2) investigate whether changes in irisin levels are correlated with exploratory outcomes. A randomized crossover design study was conducted on 25 youth aged 12-18 years old. Participants were classified as either healthy weight (BMI percentile <85; n = 14) or overweight/obese (BMI percentile ≥85; n = 11). Participants performed an MCI exercise session at 50% of heart rate reserve for 35 min and a HIIT exercise session for 35 min, with intervals every 5 min increasing from 50% heart rate reserve to 85-90% for 2 min. Irisin was measured using an enzyme-linked immunoabsorbent assay from plasma sampling obtained throughout the exercise (at times 0, 7, 14, 21, 28, and 35 min). A time effect was observed throughout the HIIT session [F(1,5) = 6.478, p < 0.001]. Bonferonni post-hoc analysis revealed significant differences in irisin levels post-exercise (35 min) compared to times 7, 14, 21, and 28 min. Irisin increased during HIIT (81.0% ± 71.3; p = 0.012) in youth with a healthy weight. No differences were observed for youth living as overweight or with obesity. Overall, HIIT elicits a higher peak irisin response compared to MCI exercise training in youth.

An Evaluation of Cardiac Health in the Spontaneously Hypertensive Rat Colony: Implications of Evolutionary Driven Increases in Concentric Hypertrophy.

BACKGROUND: The Spontaneously Hypertensive Rat (SHR) Colony was established in 1963 and is the most commonly used rodent model for studying heart failure (HF). Ideally, animal models should recapitulate the clinical disease as closely as possible. Any drift in a genetic model may create a new model that no longer adequately represents the human pathology. Further, instability overtime may lead to conflicting data between laboratories and/or irreproducible results. While systolic blood pressure (SBP) is closely monitored during inbreeding, the sequelae of HF (e.g., cardiac hypertrophy) are not. Thus, the object of this review was to investigate whether the hypertension-induced sequelae of HF in the SHR have remained stable after decades of inbreeding. METHODS: A systematic review was performed to evaluate indices of cardiovascular health in the SHR over the past 60 years. For post hoc statistical analyses, studies were separated into 2 cohorts: Initial (mid to late 1900s) and Current (early 2000s to present) Colony SHRs. Wistar-Kyoto rats (WKY) were used as controls. RESULTS: SBP was consistent between Initial and Current Colony SHRs. However, Current Colony SHRs presented with increased concentric hypertrophy (i.e., elevated heart weight and posterior wall thickness) while cardiac output remained consistent. Since these changes were not observed in the WKY controls, cardiac-derived changes in Current Colony SHRs were unlikely due to differences in environmental conditions. CONCLUSIONS: Together, these data firmly establish a cardiac-based phenotypic shift in the SHR model and provide important insights into the beneficial function of concentric hypertrophy in hypertension-induced HF.

Plain language summary of a fingerprinting technique to monitor blood cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary discussing the results of our study published in the journal Nanomedicine. The study describes how to improve the detection of blood cancer and chart the progress of recovery/remission to reassure patients living with cancer. WHAT DID WE DO?: In our study, we used a new tool called Raman spectroscopy to detect molecules found uniquely in the blood plasma of people with, or recovering from, blood cancer. Our aim was to fine-tune this technique so that it could help doctors better determine if cancer was growing back or not responding to treatment. Gold nanoparticles were used to enhance the signal of these cancer-specific molecules so that Raman spectroscopy (also called nanoSERS) could better identify and expose the cancer in hiding. WHAT IS THE IMPORTANCE OF THESE FINDINGS?: We discovered that this new tool (Raman spectroscopy using gold nanoparticles) can detect trace molecules in the blood found only when cancer cells are present or when a person's cancer is returning. This study, which has identified new potential for Raman spectroscopy as an early-screening tool, opens the possibility for the better monitoring of blood cancer. This could mean both less aggressive and fewer treatments for people diagnosed with this disease. This tool may also be useful for people seeking reassurance that their cancer remains dormant or will be identified for treatment sooner if it returns. These findings can also be applied more broadly, such as in helping scientists test the effectiveness of new treatments as they continue to get better at eliminating cancer cells.