Through the implementation of co-design, the research team collaborated with patient partners and community organizations to explore usability and practicality factors of patients eligible for cardiac rehabilitation in Atlantic Canada. A survey and semi-structured focus groups were conducted to examine participants’ perceptions of cardiac rehabilitation programs and virtual technology contributions to care delivery and accessibility opportunities. Data identified key barriers to cardiac rehabilitation programs, suggested improvements to virtual health solutions tailored to patient needs, particularly for individuals with disabilities, to inform the development of evidence-based guidelines. By addressing existing gaps in care access, this research contributes to the advancement of patient-centered health solutions that are more usable and cost-effective.

Background:In this study we evaluated our ability to implement team-based cardiogenic shock (CS-Team), focussing on: 1) early screening; 2) CS-Team activation; and 3) use of invasive monitoring to guide therapy. Methods:All patients admitted to the coronary care unit (CCU) over 12 months were screened for CS. A diagnosis of CS was made when both hypotension and hypoperfusion were present. The CS-Team was composed of the CCU attending, an interventional cardiologist, and a cardiac surgeon. Multivariate analysis was carried out with mortality as the outcome of interest. Results:Screening was documented in 74% (1160 of 1562) of patients admitted to a critical care unit; of these, 1080 were not in CS. We identified 80 patients in CS (Society for Cardiovascular Angiography & Interventions [SCAI] stages C-E), which represented 6.9% of all screened patients. Patients in CS had significantly higher in-hospital mortality (35% vs 2%, P < 0.0001). CS-Team was activated in 35 of 80 patients (44%). CS-Team activation resulted in significantly greater use of invasive monitoring (pulmonary artery catheter [49% vs 7%, P < 0.0001], cardiac catheterization [94% vs 76%, P < 0.032], and mechanical circulatory support [51% vs 2%, P < 0.001]). Independent predictors of mortality were severity of CS (SCAI grades D or E) (odds ratio [OR] 18.78, 95% confidence interval [CI] 4.89-96.65) and age, in years (OR 1.07, 95% CI 1.01-1.14), whereas CS-Team was not predictive of mortality (OR 0.66, 95% CI 0.16-2.41). Conclusions:We found that: 1) early screening by frontline staff was feasible but had limitations (26% screening failure); 2) CS-Team activation appeared discretionary (limited activation to 45% of patients); and 3) CS-Team activation resulted in a significant increase in the use of invasive monitoring that helped guide therapy.

Dysfunctional adipose tissue (AT) is strongly linked to the development of cardiovascular diseases (CVD). Accumulation of AT around vital organs is detrimental to their respective function and overall health. Although there is strong evidence linking the accumulation of pericardial AT with CVD development, a comprehensive investigation on the adaptation of pAT in obesity is scarce. Here, by applying pair-wise bottom-up proteomics in pAT of humans and mice, we found pAT presents a browning signature, as demonstrated by enrichment of mitochondria, presence of UCP1, and greater metabolic capacity compared to subcutaneous AT. In mice fed a high-fat diet or obese patients, the pAT undergoes whitening, characterized by adipocyte hypertrophy, reduced mitochondrial content, respiratory capacity, and UCP1 levels. Lipectomy of pAT from obese mice decreased pathological ventricular hypertrophy. Conversely, selective β3-adrenergic agonist treatment rescued pAT browning status and is associated with improved heart structure and function, including ventricular thickness, and fibrosis in obese mice. Importantly, lipectomy of pAT abrogated the positive effects of β3-adrenergic agonism in cardiac function of obese mice. Altogether, our work positions pAT as a mechanistic driver of obesity-related cardiac dysfunction and establish β3-adrenergic-mediated browning of pAT as a novel therapeutic treatment strategy. ### Competing Interest Statement The authors have declared no competing interest. Natural Sciences and Engineering Research Council of Canada, 400362

The poor bioavailability of curcuminoids remains a major challenge due to their hydrophobic nature, which is currently being addressed through advancements in nano- and micro-emulsion technologies. Curcuminoids and other water-insoluble phyto-polyphenols offer significant health benefits as anti-inflammatory, antioxidant, anticancer, radioprotective, and neuroprotective agents. Conventional emulsion-based delivery systems; such as liposomes, micelles, or solid lipid particles; rely on various emulsifying surfactants and/or excipients, some of which may pose health risks. In this study, a novel class of all-natural, additive-free, oil-free, and emulsion-free turmeric phyto-nanoparticles (TPNPs, developed directly from turmeric rhizomes) were evaluated in human monocyte/macrophage cell-line model to assess cellular bioavailability kinetics and anti-inflammatory activity. TPNPs are enriched with curcuminoids (24.85% by mass), form a homogeneous particle population, exhibit higher antioxidant capacity, and demonstrate significantly improved cellular uptake in both monocytes and macrophages compared to standard purified curcuminoids, which also formed nanoparticles in cell culture media. The pharmacodynamic anti-inflammatory effect of TPNPs was evidenced by increased expression of the cytoprotective enzyme heme oxygenase-1 (HMOX1), and a more effective reduction in lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) secretion than that achieved by standard purified curcuminoids. TPNPs may thus serve as a safe and effective curcuminoid nanocarrier. ### Competing Interest Statement The authors have declared no competing interest. MITACS:

Background: Exercise promotes health and has therapeutic effects on disease. Over time, the body improves its maximal exercise capacity through training adaptations such as an increase in VO2 max. In mice, voluntary wheel running allows for a natural setting to test spontaneous running behavior under non-stressed conditions. There is a need to design sensitive animal-based assay that improves resolution for differentiating exercise performance from a regular cyclometer (which presents a single value from a summary of dynamic data collected over time) and offer circadian analyses. The purpose of this work is to examine the exercise behaviors of mice with a focus on circadian rhythm of running. We hypothesize our newly developed pi cyclometer (SqueakSpeed) will mirror VDO M2.1 behaviors, with enhanced circadian rhythm insights. Methods: Using a hand-built cyclometer programmed through the Raspberry Pi computer, voluntary wheel running behaviors in CD-1 male mice (~8-10 weeks) were recorded for 6 consecutive days. This features a Hall Effect sensor and neodymium magnets attached on the running wheels that will detect changes to wheel rotation, speed, acceleration, and distance (continuously) and publish the data to a server in real-time. To compare capabilities, running wheels will also be equipped with the VDO M2.1 WR Cycling Computer to track distance, which will be manually recorded once a day. Accuracy from both devices were mechanically validated by using a DC motor with a speed controller. Results: The main findings include that voluntary wheel running distance over 6 days produces inaccuracies by the VDO. The VDO showed fluctuations in distance over the last 3 days ranging from ~4 km differences, while SqueakSpeed showed consistent measurements with a steady increase of about ~1 km each day. In a separate experiment, SqueakSpeed recorded ~3.7 km at ~0.1 m/s while VDO measured ~7.6 km at ~0.6 m/s for 24 hours in-vivo. When both devices were compared using a motor, an absolute value of 3.7 km was set before SqueakSpeed stopped recording in comparison to the VDO which stopped at ~4km. Conclusion: The findings indicate that the VDO exhibits measurement inaccuracies, particularly over extended periods of voluntary wheel running, with fluctuations in recorded distances. In contrast, SqueakSpeed provides more consistent and reliable measurements, demonstrating a steady and predictable increase in distance. Discrepancies between the two devices were also observed in both in-vivo and motor-driven experiments, further highlighting the VDO’s overestimations. These results suggest that SqueakSpeed may be a more accurate tool for assessing running distances and can be used in differentiating exercise performance in applications such as doping. The author(s) acknowledge financial support from the Natural Sciences and Engineering Research Council of Canada (NSERC). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Dysfunctional adipose tissue (AT) is strongly linked to the development of cardiovascular diseases (CVD). Accumulation of AT around vital organs is detrimental to their respective function and overall health. Although there is strong evidence linking the accumulation of pericardial AT with CVD development, a comprehensive investigation on the adaptation of pAT in obesity is scarce. Here, by applying pair-wise bottom-up proteomics in pAT of humans and mice, we found pAT presents a browning signature, as demonstrated by enrichment of mitochondria, presence of UCP1, and greater metabolic capacity compared to subcutaneous AT. In mice fed a high-fat diet or obese patients, the pAT undergoes whitening, characterized by adipocyte hypertrophy, reduced mitochondrial content, respiratory capacity, and UCP1 levels. Lipectomy of pAT from obese mice decreased pathological ventricular hypertrophy. Conversely, selective β 3 -adrenergic agonist treatment rescued pAT browning status and is associated with improved heart structure and function, including ventricular thickness, and fibrosis in obese mice. Importantly, lipectomy of pAT abrogated the positive effects of β 3 -adrenergic agonism in cardiac function of obese mice. Altogether, our work positions pAT as a mechanistic driver of obesity-related cardiac dysfunction and establish β 3 -adrenergic-mediated browning of pAT as a novel therapeutic treatment strategy.

Background: The spleen filters aged and damaged red blood cells and supports immune function; however, it is often regarded as a vestigial organ. Splenectomy (SPX) is associated with excellent outcomes in the near-term, yet long-term studies show patients are more susceptible to bacterial infections and have an increased risk for cardiovascular disease and mortality. While it is known that the spleen regulates red blood cell turn over, there are few studies that look at the short- and long-term impact on hemoglobin (Hb) levels. Objective: Understand how splenectomy affects red blood cell (RBC) hemoglobin levels over long term. Hypothesis: Splenectomy will lead to reduced hemoglobin levels over time. Methods: All animal procedures were approved by the University of Guelph ACC. 24 male and female Wistar rats received SPX, and 12 male and female rats received the sham surgery. Whole blood was collected before surgery and at 16 weeks post SPX or sham under isoflurane. To assess RBC levels, Hb concentration was measured using the Hemocue Hb 201+ (HemoCue AB, Sweden). Results: At 8 weeks of age before surgery, males had a ~10% higher Hb than females. Sham surgery was associated with a ~10% increase in Hb concentration between 8 and 16 weeks of age, where males were consistently ~6% higher than females at this time point. In contrast, no increase in Hb concentration was observed with splenectomy within the same time frame. Conclusions: Interestingly, SPX was associated with a blunting of age-related increases in Hb levels. Whether this is related to a change in RBC levels or a change in Hb within the RBC remains to be determined. Regardless, this work suggests that the spleen plays a critical role in mediating age-related changes in Hb homeostasis and further work is needed to establish to understand the role of the spleen on Hb and RBCs. NSERC and CIHR This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Chemotherapy and radiation treatment cause cardiac injury and dysfunction. It remains unclear how cancer affects cardiac structure and function in therapy-naïve mice. Emerging data shows that epithelial ovarian cancer affects hemodynamics by causing cardiac atrophy, intrinsic cardiac dysfunction and arterial hypotension in mice. As pancreatic cancer is associated with heart disease risk, we wanted to explore if impaired hemodynamics occurs in other types of cancer. Methods: We utilized a patient-derived xenograft (PDX) model of pancreatic ductal adenocarcinoma (PDAC), established by implanting fresh tumor fragments from a human PDAC patient into NSG mice. Cardiovascular hemodynamic parameters were analyzed at 28-weeks post-tumor implantation, which coincided with an advanced stage of tumor development. Results: Invasive hemodynamic assessments showed a decrease in systolic and diastolic blood pressure. Conclusion: Independent of chemotherapy, pancreatic cancer causes arterial hypotension, impairing perfusion and overall recovery. Monitoring cardiovascular health is crucial to prevent further deterioration, optimize outcomes, and improve the quality of life for pancreatic cancer patients throughout their journey. Amelia R. Malicki, Leslie M. Ogilvie, Alexa N. King, Patrick Sanosa, Jana Michaud, Bridget Coyle-Asbil, Praveen Bhoopathi, Vignesh Vudatha, Jose G. Trevino, Keith R. Brunt, Jeremy A. Simpson. Decreases in blood pressure in a patient-derived xenograft model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5162.

ABSTRACT Muscle atrophy and weakness are prevalent features of cancer. While extensive research has characterized skeletal muscle wasting in cancer cachexia, limited studies have investigated how cardiac structure and function are affected by therapy-naïve cancer. In cell-based models of orthotopic, syngeneic epithelial ovarian cancer (EOC) and pancreatic ductal adenocarcinoma (PDAC), and a patient-derived pancreatic xenograft model (PDX), we evaluated cardiac structure, function, and metabolism. Tumor-bearing mice showed cardiac atrophy and intrinsic systolic and diastolic dysfunction; associated with hypotension and exercise intolerance. In hearts of ovarian tumor-bearing mice, fatty acid-supported mitochondrial respiration decreased and carbohydrate-supported respiration increased, establishing a substrate shift in cardiac metabolism that is characteristic of heart failure. EOC decreased cytoskeletal and cardioprotective gene expression, which was paralleled by downregulation of transcription factors that regulate cardiomyocyte size and function. PDX tumors altered myosin heavy chain isoform expression – a molecular phenotype observed in heart failure. Markers of autophagy and ubiquitin-proteasome system were upregulated with cancer, providing evidence of catabolic signaling that promotes cardiac wasting. Together, metabolic stress, cardiac gene dysregulation, and upregulation of catabolic pathways contribute to cardiac atrophy and failure during cancer. Finally, we demonstrate that pathological cardiac remodeling is induced by human cancer, providing translational evidence of cancer-induced cardiomyopathy.

Background: Diaphragm atrophy can contribute to dyspnea in patients with heart failure (HF) with its link to central neurohormonal overactivation. HF medications that cross the blood-brain barrier could act centrally and improve respiratory function, potentially alleviating diaphragmatic atrophy. Therefore, we compared the benefit of central- vs peripheral-acting HF drugs on respiratory function, as assessed by a single cardiopulmonary exercise test (CPET) and outcomes in HF patients. Methods: A retrospective study was conducted of 624 ambulatory adult HF patients (80% male) with reduced left ventricular ejection fraction <= 40% and a complete CPET, followed at a single institution between 2001 and 2017. CPET parameters, and the outcomes all-cause death, a composite endpoint (all-cause death, need for left ventricular assist device, heart transplantation), and all-cause and/or HF hospitalizations, were compared in patients receiving central-acting (n = 550) vs peripheral-acting (n = 74) drugs. Results: Compared to patients who receive peripheral-acting drugs, patients who receive central-acting drugs had better respiratory function (peak breath-by breath oxygen uptake [VO2], P = 0.020; forced expiratory volume in 1 second [FEV1], P = 0.007), and ventilatory efficiency (minute ventilation / carbon dioxide production [VE/VCO2], P < 0.001; end-tidal carbon dioxide tension [PETCO2], P = 0.015; and trend for forced vital capacity [FVC], P = 0.056). Many of the associations between the CPET parameters and drug type remained significant after multivariate adjustment. Moreover, patients receiving central-acting drugs had fewer composite events (P = 0.023), and HF hospitalizations (P = 0.044), although significance after multivariant correction was not achieved, despite the hazard ratio being 0.664 and 0.757, respectively. Conclusions: Central-acting drugs were associated with better respiratory function as measured by CPET parameters in HF patients. This could extend to clinically meaningful composite outcomes and hospitalizations but required more power to be definitive in linking to drug effect. Central-acting HF drugs show a role in mitigating diaphragm weakness.

The production of the omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from alpha-linolenic acid (ALA) relies on the delta-6 desaturase (D6D) enzyme encoded by the Fads2 gene. While EPA and DHA reduce hepatic triacylglycerol (TAG) storage and regulate lipogenesis, the independent impact of ALA is less understood. To address this gap in knowledge, hepatic fatty acid metabolism was investigated in male wild-type (WT) and Fads2 knockout (KO) mice fed diets (16% kcal from fat) containing either lard (no n-3 LCPUFA), flaxseed oil (ALA-rich), or menhaden oil (EPA/DHA rich) for 21 weeks. Fat content and composition, as well as markers of lipogenesis, glyceroneogenesis, and TAG synthesis, were analyzed using histology, gas chromatography, and reverse transcription quantitative PCR (RT-qPCR). Mice fed the menhaden diet had significantly lower hepatic TAG compared to both lard- and flax-fed mice, concomitant with changes in n-3 and n-6 LCPUFA in both TAG and phospholipid (PL) fractions (all P < 0.05). Flax-fed WT mice had lower liver TAG content compared to their KO counterparts. Menhaden-fed mice had significantly lower expression of key lipogenic (Scd1, Srebp-1c, Fasn, Fads1, and Fads2), glyceroneogenic (Pck1), and TAG synthesis (Agpat3) genes compared to lard, with flax-fed mice showing some intermediate effects. Gene expression effects were independent of D6D activity, since no differences were detected between WT and KO mice fed the same diet. This study demonstrates that EPA/DHA and not ALA itself is critical for the prevention of hepatic steatosis.

The objective of this omega-3 feeding study was to elucidate the independent effects of α-linolenic acid (ALA) versus eicosapentaenoic (EPA)/docosahexaenoic acid (DHA) on visceral adiposity and inflammatory signaling in diet-induced obese delta-6 desaturase ( Fads2 ) knockout (KO) mice. Male wildtype (WT) and Fads2 KO mice were fed a high-fat diet (45% kcal from fat) containing either lard (no omega-3s), flaxseed (ALA), or menhaden (EPA/DHA) for 21 weeks. Epididymal white adipose tissue (eWAT) was analyzed for changes in tissue weight, adipocyte size, triacylglycerol (TAG) and fatty acid content, and inflammatory markers. Despite no differences in final body weight, menhaden-fed mice had lower eWAT weight, smaller adipocytes, and lower TAG content compared to lard-fed mice regardless of Fads2 genotype. The eWAT of flaxseed-fed WT mice resembled menhaden-fed mice, while the eWAT of flaxseed-fed KO mice resembled lard-fed mice. No differences were observed in the expression of genes regulating eWAT inflammatory signaling ( Tnfα , Nfκb , Mapk14 , Mcp1 , Ccl5 , Tlr4 , Nlrp3 , or Adipoq ) or the abundance of select proteins (p38-MAPK or MCP-1). In conclusion, a high-fat diet containing EPA/DHA, but not ALA, attenuates adipocyte hypertrophy and lowers TAG content but has no effect on eWAT inflammation in a mouse model of long-term diet-induced obesity.

This paper reports on research being conducted under the National Research Council of Canada's Aging in Place Program in collaboration with academic and healthcare partners. The research focuses on understanding the journey of patients through cardiac rehabilitation from the perspective of older patients with disabilities. Our approach involves engaging with patient partners having lived experiences requiring improved access to cardiac rehabilitation. Our goal is to understand the status of inclusivity, the unique needs of patients, and the strategies and techniques to bridge gaps in care, and to engineer virtual care solutions that are more inclusive and accommodative to older adult patients with disabilities. This paper emphasizes the significance of the study as an initial stride toward understanding the unique needs of older patients with disabilities. The paper also discusses likely avenues to inform the design and development of future digital health solutions informed by patient-centric perspectives.

Background: Exercise promotes health and has therapeutic effects on disease. Over time, the body improves its maximal exercise capacity through training adaptations such as an increase in VO2 max. In mice, voluntary wheel running allows for a natural setting to test spontaneous running behaviour under non-stressed conditions. There is a need to design sensitive animal-based assay that improves resolution for differentiating exercise performance from a regular cyclometer (which presents a single value from a summary of dynamic data collected over time) and offer circadian analyses. The purpose of this work is to examine the exercise behaviours of mice with a focus on circadian rhythm of running. We hypothesize the pi cyclometer (ROSLT) will mirror VDO M2.1 behaviors, enhancing circadian rhythm insights. Methods: Using a hand-built cyclometer programmed through the Raspberry Pi computer, voluntary wheel running behaviours in CD-1 mice (~8-10 weeks) were recorded for 6 consecutive days. This features a Hall Effect sensor and neodymium magnets attached on the running wheels that will detect changes to wheel rotation, speed, acceleration, and distance (continuously) and publish the data to a server in real-time. To compare capabilities, running wheels will also be equipped with the VDO M2.1 WR Cycling Computer to track distance which will be manually recorded once a day. Accuracy from both devices were mechanically validated. Results: The main findings include that voluntary wheel running distance over 6 days produces inaccuracies by the VDO. The VDO showed fluctuations in distance over the last 3 days, while ROSLT showed consistent measurements. Conclusion: This comparison shows that ROSLT expands on the running activity of mice each day while maintaining accuracy and precision. This novel dynamic circadian cyclometer will advance our research abilities and can be used in differentiating exercise performance in applications such as doping. ### Competing Interest Statement The authors have declared no competing interest.

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.