Overview of the Canadian Clinician Investigator Trainees' Research Presented at the 2024 CSCI-CITAC Joint Meeting.

The 2024 Annual Joint Meeting (AJM) and Young Investigators' Forum of the Canadian Society for Clinical Investigation (CSCI) and Clinician Investigator Trainee Association of Canada (CITAC) was held on April 11, 2024, in Vancouver, British Columbia. Hosted in collaboration with the University of British Columbia (UBC) and the International Congress on Academic Medicine (ICAM), this meeting marked a significant opportunity for clinician investigator trainees to present their research and connect with national and international peers. The event included 70 trainees, consisting of 58 MD+ (MD/PhD, MD and PhD, MD-MSc, MD and MSc) and 12 Clinician Investigator Program and/or Surgeon-Scientist Training Program trainees.

Exogenous ketone therapy does not protect brain tissue after moderate-sized intracerebral hemorrhage despite signs of early neurological benefit.

Ketone bodies, or ketones, are an alternative energy source and have several nonmetabolic signaling actions, such as inhibiting inflammation. Because of this, exogenous ketone supplementation has been used to help treat various diseases. β-hydroxybutyrate (βHB) is the major ketone body that has reduced neurological injury and brain edema in animal models of ischemic stroke and traumatic brain injury.

Maternal ketone supplementation throughout gestation improves neonatal cardiac dysfunction caused by perinatal iron deficiency.

Iron deficiency (ID) is common during gestation and in early infancy and has been shown to adversely affect cardiac development and function, which could lead to lasting cardiovascular consequences. Ketone supplementation has been shown to confer cardioprotective effects in numerous disease models. Here, we tested the hypothesis that maternal ketone supplementation during gestation would mitigate cardiac dysfunction in ID neonates.

The therapeutic potential of ketones in cardiometabolic disease: impact on heart and skeletal muscle.

β-Hydroxybutyrate (βOHB) is the major ketone in the body, and it is recognized as a metabolic energy source and an important signaling molecule. While ketone oxidation is essential in the brain during prolonged fasting/starvation, other organs such as skeletal muscle and the heart also use ketones as metabolic substrates. Additionally, βOHB-mediated molecular signaling events occur in heart and skeletal muscle cells, and via metabolism and/or signaling, ketones may contribute to optimal skeletal muscle health and cardiac function.

Overview of The the Clinician Investigator Trainees' Research Presented at The 2022 CSCI-CITAC Joint Meeting.

The 2022 Annual Joint Meeting (AJM) and Young Investigators' Forum of the Canadian Society for Clinical Investigation / Société Canadienne de recherches clinique (CSCI/SCRC) and Clinician Investigator Trainee Association of Canada/Association des cliniciens-chercheurs en formation du Canada (CITAC/ACCFC) was held in Montréal, November 13-14, 2022. The theme of this year's AJM was "Strength in Perseverance" and focused on highlighting clinician-investigator trainee achievements and resilience in research engagement through recent challenging and unprecedented times. The opening remarks were given by Nicola Jones (president of CSCI/SCRC) and Heather Whittaker (past president of CITAC/ACCFC).

Perinatal iron restriction is associated with changes in neonatal cardiac function and structure in a sex-dependent manner.

Iron deficiency (ID) is common during gestation and in early infancy and can alter developmental trajectories with lasting consequences on cardiovascular health. While the effects of ID and anemia on the mature heart are well documented, comparatively little is known about their effects and mechanisms on offspring cardiac development and function in the neonatal period. Female Sprague-Dawley rats were fed an iron-restricted or iron-replete diet before and during pregnancy.

Cannabidiol Suppresses Cytokine Storm and Protects Against Cardiac and Renal Injury Associated with Sepsis.

Cytokine release syndrome, also termed "cytokine storm," is the leading cause of morbidity and mortality among patients with various conditions such as sepsis. While cytokine storm is associated with multiple organ damage, acute cardiac and renal injury represents a hallmark of cytokine storm. Since recent reports have suggested that cannabidiol (CBD) may assist in the treatment of inflammatory diseases, our objective was to examine the effect of CBD on cytokine storm-induced cardiac and renal injury using the lipopolysaccharide (LPS)-induced sepsis mouse model.

Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis.

Aims: Sepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular disease. The ketone β-hydroxybutyrate is reported to be cardioprotective in cardiovascular disease and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce the enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis.

Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart.

Aims: Recent evidence has demonstrated that ketone bodies, particularly β-hydroxybutyrate (BHB), are beneficial to the failing heart due to their potential as an alternative energy substrate as well as their anti-inflammatory and anti-oxidative properties. Exogenous supplementation of ketones also helps prevent heart failure (HF) development in rodent models, but whether ketones can be used to treat HF remains unexplored. Herein, we investigated whether chronic supplementation of ketones is beneficial for the heart in a mouse model of established HF.

Resveratrol reduces cardiac NLRP3-inflammasome activation and systemic inflammation to lessen doxorubicin-induced cardiotoxicity in juvenile mice.

Doxorubicin (DOX) is a very effective anticancer agent that is widely used in pediatric cancer patients. Nevertheless, DOX is known to have cardiotoxic effects that may progress to cardiomyopathy later in life. We have recently shown that cotreatment of resveratrol (RES) with DOX in juvenile mice attenuates late-onset hypertension-induced cardiomyopathy.

Cardiac Late Sodium Channel Current Is a Molecular Target for the Sodium/Glucose Cotransporter 2 Inhibitor Empagliflozin.

Background: SGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to identify the underlying molecular mechanisms that afford this protection. Because the induction of the late component of the cardiac sodium channel current (late-) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-.

Methods: Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question.

Ketone therapy for heart failure: current evidence for clinical use.

During conditions that result in depleted circulating glucose levels, ketone bodies synthesized in the liver are necessary fuel substrates for the brain. In other organs, such as the heart, the reliance on ketones for generating energy in the absence of glucose is less important as the heart can utilize alternative fuel sources, such as fatty acids. However, during pathophysiological conditions, such as heart failure, cardiac defects in metabolic processes that normally allow for sufficient energy production from fatty acids and carbohydrates contribute to a decline in contractile function.

Inhibition of ATGL in adipose tissue ameliorates isoproterenol-induced cardiac remodeling by reducing adipose tissue inflammation.

Following cardiac injury, increased adrenergic drive plays an important role in compensating for reduced cardiac function. However, chronic excess adrenergic stimulation can be detrimental to cardiac pathophysiology and can also affect other organs including adipose tissue, leading to increased lipolysis. Interestingly, inhibition of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in lipolysis, in adipocytes ameliorates cardiac dysfunction in a heart failure model.

Vitamin D is an endogenous partial agonist of the transient receptor potential vanilloid 1 channel.

Key Points: 25-Hydroxyvitamin D (25OHD) is a partial agonist of TRPV1 whereby 25OHD can weakly activate TRPV1 yet antagonize the stimulatory effects of the full TRPV1 agonists capsaicin and oleoyl dopamine. 25OHD binds to TRPV1 within the same vanilloid binding pocket as capsaicin. 25OHD inhibits the potentiating effects of PKC-mediated TRPV1 activity.

Empagliflozin suppresses inflammation and protects against acute septic renal injury.

Background: Sepsis-induced systemic inflammation response syndrome is the leading cause of morbidity and mortality among patients in intensive care units in North America. While sepsis is associated with multiple organ damage, acute renal injury represents a hallmark of sepsis. Since systemic and renal inflammation is known to play a vital role in morbidity and mortality associated with sepsis, identifying a potent anti-inflammatory agent may help minimize morbidity and mortality associated with acute septic kidney injury.

Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure.

Background: Previous studies have shown beneficial effects of acute infusion of the primary ketone body, β-hydroxybutyrate, in heart failure (HF). However, whether chronic elevations in circulating ketones are beneficial remains unknown.

Methods: To chronically elevate circulating ketones in mice, we deleted the expression of the ketolytic, rate-limiting-enzyme, SCOT (succinyl-CoA:3-ketoacid-CoA transferase 1; encoded by ), in skeletal muscle.

Resistant Hypertension in Clinical Practice in India: Jaipur Heart Watch.

Background: Hypertension is highly prevalent in India but frequency of resistant hypertension has not been well studied.

Methods: We performed a registry-based study at a single center in patients with primary diagnosis of hypertension (n=3073). Details of co-morbidities, medications and blood pressure (BP) control were obtained.