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

ß-Hydroxybutyrate (ßOHB) 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, ßOHB-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. Of importance, when the use of ketones for ATP production and/or as signaling molecules becomes disturbed in the presence of underlying obesity, type 2 diabetes, and/or cardiovascular diseases, these changes may contribute to cardiometabolic disease. As a result of these disturbances in cardiometabolic disease, multiple approaches have been used to elevate circulating ketones with the goal of optimizing either ketone metabolism or ketone-mediated signaling. These approaches have produced significant improvements in heart and skeletal muscle during cardiometabolic disease with a wide range of benefits that include improved metabolism, weight loss, better glycemic control, improved cardiac and vascular function, as well as reduced inflammation and oxidative stress. Herein, we present the evidence that indicates that ketone therapy could be used as an approach to help treat cardiometabolic diseases by targeting cardiac and skeletal muscles.

Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele fraction cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). CH was also evaluated in a replication cohort of 59 individuals with HFpEF. RESULTS: Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of individuals with HFpEF. In accordance, patients with HFpEF, an age ≥70 years, and CH exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF and an age ≥70 years without CH. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2-wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2-wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF.

Stimulating cardiac glucose oxidation lessens the severity of heart failure in aged female mice.

Heart failure is a prevalent disease worldwide. While it is well accepted that heart failure involves changes in myocardial energetics, what alterations that occur in fatty acid oxidation and glucose oxidation in the failing heart remains controversial. The goal of the study are to define the energy metabolic profile in heart failure induced by obesity and hypertension in aged female mice, and to attempt to lessen the severity of heart failure by stimulating myocardial glucose oxidation. 13-Month-old C57BL/6 female mice were subjected to 10 weeks of a 60% high-fat diet (HFD) with 0.5 g/L of Nω-nitro-L-arginine methyl ester (L-NAME) administered via drinking water to induce obesity and hypertension. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of myocardial glucose oxidation and fatty acid oxidation. Additionally, a series of mice subjected to the obesity and hypertension protocol were treated with a pyruvate dehydrogenase kinase inhibitor (PDKi) to stimulate cardiac glucose oxidation. Aged female mice subjected to the obesity and hypertension protocol had increased body weight, glucose intolerance, elevated blood pressure, cardiac hypertrophy, systolic dysfunction, and decreased survival. While fatty acid oxidation rates were not altered in the failing hearts, insulin-stimulated glucose oxidation rates were markedly impaired. PDKi treatment increased cardiac glucose oxidation in heart failure mice, which was accompanied with improved systolic function and decreased cardiac hypertrophy. The primary energy metabolic change in heart failure induced by obesity and hypertension in aged female mice is a dramatic decrease in glucose oxidation. Stimulating glucose oxidation can lessen the severity of heart failure and exert overall functional benefits.

Benzodiazepine use in medical cannabis authorization adult patients from 2013 to 2021: Alberta, Canada.

BACKGROUND: Benzodiazepines are a class of medications that are being frequently prescribed in Canada but carry significant risk of harm. There has been increasing clinical interest on the potential "sparing effects" of medical cannabis as one strategy to reduce benzodiazepine use. The objective of this study as to examine the association of medical cannabis authorization with benzodiazepine usage between 2013 and 2021 in Alberta, Canada. METHODS: A propensity score matched cohort study with patients on regular benzodiazepine treatment authorized to use medical cannabis compared to controls who do not have authorization for medical cannabis. A total of 9690 medically authorized cannabis patients were matched to controls. To assess the effect of medical cannabis use on daily average diazepam equivalence (DDE), interrupted time series (ITS) analysis was used to assess the change in the trend of DDE in the 12 months before and 12 months after the authorization of medical cannabis. RESULTS: Over the follow-up period after medical cannabis authorization, there was no overall change in the DDE use in authorized medical cannabis patients compared to matched controls (- 0.08 DDE, 95% CI: - 0.41 to 0.24). Likewise, the sensitivity analysis showed that, among patients consuming ≤5 mg baseline DDE, there was no change immediately after medical cannabis authorization compared to controls (level change, - 0.04 DDE, 95% CI: - 0.12 to 0.03) per patient as well as in the month-to-month trend change (0.002 DDE, 95% CI: - 0.009 to 0.12) per patient was noted. CONCLUSIONS: This short-term study found that medical cannabis authorization had minimal effects on benzodiazepine use. Our findings may contribute ongoing evidence for clinicians regarding the potential impact of medical cannabis to reduce benzodiazepine use. HIGHLIGHTS: • Medical cannabis authorization had little to no effect on benzodiazepine usage among patients prescribed regular benzodiazepine treatment in Alberta, Canada. • Further clinical research is needed to investigate the potential impact of medical cannabis as an alternative to benzodiazepine medication.

Identification of aryl hydrocarbon receptor allosteric antagonists from clinically approved drugs.

The human aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA-approved drugs binding to the allosteric site between α2 of bHLH and PAS-A domains of AhR, with the aim of inhibiting its canonical pathway activity. Our findings indicated that nilotinib effectively fits into the allosteric pocket and forms interactions with crucial residues F82, Y76, and Y137. Binding free energy value of nilotinib is the lowest among top hits and maintains stable within its pocket throughout entire (MD) simulations time. Nilotinib has also substantial interactions with F295 and Q383 when it binds to orthosteric site and activate AhR. Surprisingly, it does not influence AhR nuclear translocation in the presence of AhR agonists; instead, it hinders the formation of the functional AhR-ARNT-DNA heterodimer assembly, preventing the upregulation of regulated enzymes like CYP1A1. Importantly, nilotinib exhibits a dual impact on AhR, modulating AhR activity via the PAS-B domain and working as a noncompetitive allosteric antagonist capable of blocking the canonical AhR signaling pathway in the presence of potent AhR agonists. These findings open a new avenue for the repositioning of nilotinib beyond its current application in diverse diseases mediated via AhR.

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. Cardiac function was assessed in a cohort of offspring on postnatal days (PD) 4, 14, and 28 by echocardiography; a separate cohort was euthanized for tissue collection and hearts underwent quantitative shotgun proteomic analysis. ID reduced body weight and increased relative heart weights at all time points assessed, despite recovering from anemia by PD28. Echocardiographic studies revealed unique functional impairments in ID male and female offspring, characterized by greater systolic dysfunction in the former and greater diastolic dysfunction in the latter. Proteomic analysis revealed down-regulation of structural components by ID, as well as enriched cellular responses to stress; in general, these effects were more pronounced in males. ID causes functional changes in the neonatal heart, which may reflect an inadequate or maladaptive compensation to anemia. This identifies systolic and diastolic dysfunction as comorbidities to perinatal ID anemia which may have important implications for both the short- and long-term cardiac health of newborn babies. Furthermore, therapies which improve cardiac output may mitigate the effects of ID on organ development.

Integration of longitudinal and circumferential strain predicts volumetric change across the cardiac cycle and differentiates patients along the heart failure continuum.

BACKGROUND: Left ventricular (LV) circumferential and longitudinal strain provide important insight into LV mechanics and function, each contributing to volumetric changes throughout the cardiac cycle. We sought to explore this strain-volume relationship in more detail, by mathematically integrating circumferential and longitudinal strain and strain rate to predict LV volume and volumetric rates of change. METHODS: Cardiac magnetic resonance (CMR) imaging from 229 participants from the Alberta HEART Study (46 healthy controls, 77 individuals at risk for developing heart failure [HF], 70 patients with diagnosed HF with preserved ejection fraction [HFpEF], and 36 patients with diagnosed HF with reduced ejection fraction [HFrEF]) were evaluated. LV volume was assessed by the method of disks and strain/strain rate were assessed by CMR feature tracking. RESULTS: Integrating endocardial circumferential and longitudinal strain provided a close approximation of LV ejection fraction (EFStrain), when compared to gold-standard volumetric assessment (EFVolume: r = 0.94, P < 0.0001). Likewise, integrating circumferential and longitudinal strain rate provided a close approximation of peak ejection and peak filling rates (PERStrain and PFRStrain, respectively) compared to their gold-standard volume-time equivalents (PERVolume, r = 0.73, P < 0.0001 and PFRVolume, r = 0.78, P < 0.0001, respectively). Moreover, each integrated strain measure differentiated patients across the HF continuum (all P < 0.01), with the HFrEF group having worse EFStrain, PERStrain, and PFRStrain compared to all other groups, and HFpEF having less favorable EFStrain and PFRStrain compared to both at-risk and control groups. CONCLUSIONS: The data herein establish the theoretical framework for integrating discrete strain components into volumetric measurements across the cardiac cycle, and highlight the potential benefit of this approach for differentiating patients along the heart failure continuum.

Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation.

Persistent inflammation can trigger altered epigenetic, inflammatory, and bioenergetic states. Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic inflammation of the gastrointestinal tract, with evidence of subsequent metabolic syndrome disorder. Studies have demonstrated that as many as 42% of patients with ulcerative colitis (UC) who are found to have high-grade dysplasia, either already had colorectal cancer (CRC) or develop it within a short time. The presence of low-grade dysplasia is also predictive of CRC. Many signaling pathways are shared among IBD and CRC, including cell survival, cell proliferation, angiogenesis, and inflammatory signaling pathways. Current IBD therapeutics target a small subset of molecular drivers of IBD, with many focused on the inflammatory aspect of the pathways. Thus, there is a great need to identify biomarkers of both IBD and CRC, that can be predictive of therapeutic efficacy, disease severity, and predisposition to CRC. In this study, we explored the changes in biomarkers specific for inflammatory, metabolic, and proliferative pathways, to help determine the relevance to both IBD and CRC. Our analysis demonstrated, for the first time in IBD, the loss of the tumor suppressor protein Ras associated family protein 1A (RASSF1A), via epigenetic changes, the hyperactivation of the obligate kinase of the NOD2 pathogen recognition receptor (receptor interacting protein kinase 2 [RIPK2]), the loss of activation of the metabolic kinase, AMP activated protein kinase (AMPKα1), and, lastly, the activation of the transcription factor and kinase Yes associated protein (YAP) kinase, that is involved in proliferation of cells. The expression and activation status of these four elements are mirrored in IBD, CRC, and IBD-CRC patients and, importantly, in matched blood and biopsy samples. The latter would suggest that biomarker analysis can be performed non-invasively, to understand IBD and CRC, without the need for invasive and costly endoscopic analysis. This study, for the first time, illustrates the need to understand IBD or CRC beyond an inflammatory perspective and the value of therapeutics directed to reset altered proliferative and metabolic states within the colon. The use of such therapeutics may truly drive patients into remission.

Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute a promising drug treatment for heart failure patients with either preserved or reduced ejection fraction. Whereas SGLT2i were originally developed to target SGLT2 in the kidney to facilitate glucosuria in diabetic patients, it is becoming increasingly clear that these drugs also have important effects outside of the kidney. In this review we summarize the literature on cardiac effects of SGLT2i, focussing on pro-inflammatory and oxidative stress processes, ion transport mechanisms controlling sodium and calcium homeostasis and metabolic/mitochondrial pathways. These mechanisms are particularly important as disturbances in these pathways result in endothelial dysfunction, diastolic dysfunction, cardiac stiffness, and cardiac arrhythmias that together contribute to heart failure. We review the findings that support the concept that SGLT2i directly and beneficially interfere with inflammation, oxidative stress, ionic homeostasis, and metabolism within the cardiac cell. However, given the very low levels of SGLT2 in cardiac cells, the evidence suggests that SGLT2-independent effects of this class of drugs likely occurs via off-target effects in the myocardium. Thus, while there is still much to be understood about the various factors which determine how SGLT2i affect cardiac cells, much of the research clearly demonstrates that direct cardiac effects of these SGLT2i exist, albeit mediated via SGLT2-independent pathways, and these pathways may play a role in explaining the beneficial effects of SGLT2 inhibitors in heart failure.

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-INa) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-INa. METHODS: Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question. RESULTS: The SGLT2 inhibitor empagliflozin reduced late-INa in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the long QT syndrome 3 mutations R1623Q or ΔKPQ. Empagliflozin, dapagliflozin, and canagliflozin are all potent and selective inhibitors of H2O2-induced late-INa (half maximal inhibitory concentration = 0.79, 0.58, and 1.26 µM, respectively) with little effect on peak sodium current. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late-INa activator veratridine in a similar manner to tetrodotoxin, ranolazine, and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a three-dimensional homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 (nuclear-binding domain-like receptor 3) inflammasome and improved functional recovery after ischemia. CONCLUSIONS: Our results provide evidence that late-INa may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.

Ameliorative Role of Fluconazole Against Abdominal Aortic Constriction-Induced Cardiac Hypertrophy in Rats.

ABSTRACT: Cytochrome P450 1B1 (CYP1B1) is known to be involved in the pathogenesis of several cardiovascular diseases, including cardiac hypertrophy and heart failure, through the formation of cardiotoxic metabolites named as mid-chain hydroxyeicosatetraenoic acids (HETEs). Recently, we have demonstrated that fluconazole decreases the level of mid-chain HETEs in human liver microsomes, inhibits human recombinant CYP1B1 activity, and protects against angiotensin II-induced cellular hypertrophy in H9c2 cells. Therefore, the overall purpose of this study was to elucidate the potential cardioprotective effect of fluconazole against cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Male Sprague-Dawley rats were randomly assigned into 4 groups such as sham control rats, fluconazole-treated (20 mg/kg daily for 4 weeks, intraperitoneal) sham rats, AAC rats, and fluconazole-treated (20 mg/kg) AAC rats. Baseline and 5 weeks post-AAC echocardiography were performed. Gene and protein expressions were measured using real-time PCR and Western blot analysis, respectively. The level of mid-chain HETEs was determined using liquid chromatography-mass spectrometry. Echocardiography results showed that fluconazole significantly prevented AAC-induced left ventricular hypertrophy because it ameliorated the AAC-mediated increase in left ventricular mass and wall measurements. In addition, fluconazole significantly prevented the AAC-mediated increase of hypertrophic markers. The antihypertrophic effect of fluconazole was associated with a significant inhibition of CYP1B1, CYP2C23, and 12-LOX and a reduction in the formation rate of mid-chain HETEs. This study demonstrates that fluconazole protects against left ventricular hypertrophy, and it highlights the potential repurposing of fluconazole as a mid-chain HETEs forming enzymes' inhibitor for the protection against cardiac hypertrophy.

Generalized Anxiety Disorder 7-Item (GAD-7) Scores in Medically Authorized Cannabis Patients-Ontario and Alberta, Canada.

OBJECTIVES: Despite increasing rates of legalization of medical cannabis worldwide, the current evidence available on its effect on mental health outcomes including anxiety is of mixed results. This study assesses the effect of medical cannabis on generalized anxiety disorder 7-item (GAD-7) scores in adult patients between 2014 and 2019 in Ontario and Alberta, Canada. METHODS: An observational cohort study of adults authorized to use medical cannabis. The GAD-7 was administered at the time of the first visit to the clinic and subsequently over the follow-up time period of up to 3.2 years. Overall changes in GAD-7 scores were computed (mean change) and categorized as: no change (<1 point); improvement; or worsening-over time. RESULTS: A total of 37,303 patients had initial GAD-7 scores recorded and 5,075 (13.6%) patients had subsequent GAD-7 follow-up scores. The average age was 54.2 years (SD 15.7 years), 46.0% were male, and 45.6% noted anxiety symptoms at the baseline. Average GAD-7 scores were 9.11 (SD 6.6) at the baseline and after an average of 282 days of follow-up (SD 264) the average final GAD-7 score recorded was 9.04 (SD 6.6): mean change -0.23 (95% CI, -0.28 to -0.17, t[5,074]: -8.19, p-value <0.001). A total of 4,607 patients (90.8%) had no change in GAD-7 score from their initial to final follow-up, 188 (3.7%) had a clinically significant decrease, and 64 (1.3%) noted a clinically significant increase in their GAD-7 scores. CONCLUSIONS: Overall, there was a statistically significant decrease in GAD-7 scores over time (in particular, in the 6-12-month period). However, this change did not meet the threshold to be considered clinically significant. Thus, we did not detect clinical improvements or detriment in GAD-7 scores in medically authorized cannabis patients. However, future well-controlled clinical trials are needed to fully examine risks or benefits associated with using medical cannabis to treat anxiety conditions.

Substance Use Disorders and Psychoactive Drug Poisoning in Medically Authorized Cannabis Patients: Longitudinal Cohort Study.

OBJECTIVES: Poisoning from psychoactive drugs and substance use disorders (SUD) have been reported among non-medical cannabis users. However, little is known about medical cannabis users and their risk for poisoning and/or development of SUD. This study assessed the risk of emergency department (ED) visits or hospitalization for 1) poisoning by psychoactive drugs and 2) mental/behavioural disorders due to the use of psychoactive drugs and other substances, in medically authorized cannabis patients in Ontario, Canada from 2014-2017. METHODS: A cohort study of adult patients authorized for medical cannabis that were matched to population-based controls. ED visit/hospitalization were assessed with a main diagnostic code for: 1) poisoning by psychoactive drugs; 2) mental and behavioural disorder due to psychoactive drugs or other substance use. Conditional Cox proportional hazards regressions were conducted. RESULTS: 18,653 cannabis patients were matched to 51,243 controls. During a median follow-up of 243 days, the incidence rate for poisoning was 4.71 per 1,000 person-years (95%CI: 3.71-5.99) for cases and 1.73 per 1,000 person-years (95% CI: 1.36-2.19) for controls. The adjusted hazard ratio (aHR) was 2.45 (95%CI: 1.56-3.84). For mental/behavioural disorders, the incident rates were 8.89 (95% CI: 7.47-10.57) and 5.01 (95% CI: 4.36-5.76) in the cannabis and the controls group. The aHR was 2.27 (95%CI: 1.66-3.11). No difference was observed between males and females (P-value for interaction > 0.05). CONCLUSIONS: Our study observed a short-term increased risk of ED visit/hospitalization for poisoning or for mental/behavioural disorders (from use of psychoactive drugs and other substances)- in medically authorized cannabis patients.

Incidence and Predictors of Cannabis-Related Poisoning and Mental and Behavioral Disorders among Patients with Medical Cannabis Authorization: A Cohort Study.

OBJECTIVE: As medical cannabis use increases in North America, establishing its safety profile is a priority. The objective of this study was to assess rates of emergency department (ED) visits and hospitalizations due to poisoning by cannabis, and cannabis-related mental health disorders among medically authorized cannabis patients in Ontario, Canada, between 2014 and 2017. METHODS: This is a retrospective cohort study of patients who received medical cannabis authorization in Ontario, Canada, using data collected in participating cannabis clinics. Outcomes included ED visit/hospitalization with a main diagnosis code for: cannabis/cannabinoid poisoning; and mental/behavioral disorders due to cannabis use. Cox proportional hazard regressions were utilized to analyze the data. RESULTS: From 29,153 patients who received medical authorization, 23,091 satisfied the inclusion criteria. During a median follow-up of 240 days, 14 patients visited the ED or were hospitalized for cannabis poisoning-with an incidence rate of 8.06 per 10,000 person-years (95% CI: 4.8-13.6). A total of 26 patients visited the ED or were hospitalized for mental and behavioral disorders due to cannabis use-with an incidence rate of 15.0 per 10,000 person-years (95% CI: 10.2-22.0). Predictors of cannabis-related mental and behavioral disorders include prior substance use disorders, other mental disorders, age, diabetes, and chronic obstructive pulmonary disease. CONCLUSIONS: The results suggest that the incidence of cannabis poisoning or cannabis-related mental and behavioral disorders was low among patients who were authorized to use cannabis for medical care. Identified predictors can help to target patients with potential risk of the studied outcomes.

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. Thus, we investigated whether inhibition of adipocyte ATGL can mitigate the adverse cardiac effects of chronic adrenergic stimulation and explored the underlying mechanisms. To do this, isoproterenol (ISO) was continuously administered to C57Bl/6N mice for 2 wk with or without an ATGL inhibitor (Atglistatin). We found that Atglistatin alleviated ISO-induced cardiac remodeling and reduced ISO-induced upregulation of galectin-3, a marker of activated macrophages and a potent inducer of fibrosis, in white adipose tissue (WAT), heart, and the circulation. To test whether the beneficial effects of Atglistatin occur via inhibition of adipocyte ATGL, adipocyte-specific ATGL knockout (atATGL-KO) mice were utilized for similar experiments. Subsequently, the same cardioprotective effects of atATGL-KO following ISO administration were observed. Furthermore, Atglistatin and atATGL-KO abolished ISO-induced galectin-3 secretion from excised WAT. We further demonstrated that activation of cardiac fibroblasts by the conditioned media of ISO-stimulated WAT is galectin-3-dependent. In conclusion, the inhibition of adipocyte ATGL ameliorated ISO-induced cardiac remodeling possibly by reducing galectin-3 secretion from adipose tissue. Thus, inhibition of adipocyte ATGL might be a potential target to prevent some of the adverse effects of chronic excess adrenergic drive.NEW & NOTEWORTHY The reduction of lipolysis by adipocyte ATGL inhibition ameliorates cardiac remodeling induced by chronic ß-adrenergic stimulation likely via reducing galectin-3 secretion from adipose tissue. Our findings highlight that suppressing lipolysis in adipocytes may be a potential therapeutic target for patients with heart failure whose sympathetic nervous system is activated. Furthermore, galectin-3 might be involved in the mechanisms by which excessive lipolysis in adipose tissues influences remote cardiac pathologies and thus warrants further investigation.

Medical cannabis authorization and the risk of cardiovascular events: a longitudinal cohort study.

BACKGROUND: Cannabis is increasingly used for therapeutic purpose. However, its safety profile is not well known. This study assessed the risk of cardiovascular-related emergency department (ED) visit and hospitalization in adult patients authorized to use medical cannabis in Ontario, Canada from 2014 to 2017. METHODS: This is a longitudinal cohort study of patients who received medical cannabis authorization and followed-up in cannabis clinics, matched to population-based controls. The primary outcome was an ED visit or hospitalization for acute coronary syndrome (ACS) or stroke; and secondary outcome was for any cardiovascular event. Conditional Cox proportional hazards regression was used to assess the association between cannabis authorization and risk. RESULTS: 18,653 cannabis patients were matched to 51,243 controls. During a median follow-up of 242 days, the incidence rates for ACS or stroke were 7.19/1000 person-years and 5.67/1000 person-years in the cannabis and controls group, respectively- adjusted hazard ratio (aHR) of 1.44 (95% CI 1.08-1.93). When stratified by sex, the association was only statistically significant among males: aHR 1.77 (1.23-2.56). For the secondary outcome (any CV events), the aHR was 1.47 (1.26-1.72). The aHR among males and females were 1.52 (1.24-1.86) and 1.41 (1.11-1.79), respectively. Tested interaction between cannabis authorization and sex was not significant (p > 0.05). CONCLUSIONS: Medical cannabis authorization was associated with an increased risk of ED visits or hospitalization for CV events including stroke and ACS.

The beneficial effects of reducing NLRP3 inflammasome activation in the cardiotoxicity and the anti-cancer effects of doxorubicin.

Doxorubicin (DOX) is a powerful broad-spectrum anti-neoplastic anthracycline antibiotic. However, DOX may cause a dose-dependent cardiotoxicity that can eventually progress to congestive heart failure and death. Numerous molecular mechanisms have been implicated in the cardiotoxic effect of DOX including topoisomerase IIß and generation of free radicals. However, targeting these pathways appears to be insufficient to mitigate the cardiotoxic effects of DOX and/or ultimately reduces the anti-tumor activity of DOX. Thus, there remains a crucial need to identify novel pharmacological targets that can alleviate the cardiotoxic effects of DOX without reducing its anti-tumor activity. Recent studies have suggested that the Nucleotide-Binding Domain-Like Receptor Protein 3 (NLRP3) inflammasome is implicated in tumor progression and the chemoresistance of cancer cells to DOX. Of interest, reducing NLRP3 inflammasome activity alleviates DOX-induced cardiotoxicity. Therefore, we postulate that strategies that target the NLRP3 inflammasome can help mitigate the cardiotoxic effects of DOX while maintaining and/or even enhancing its anti-cancer activity. Herein, we review the current knowledge about the potential implication of the NLRP3 inflammasome in the anti-cancer and cardiotoxic effects of DOX.

Opioid use in medical cannabis authorization adult patients from 2013 to 2018: Alberta, Canada.

BACKGROUND: The opioid overdose epidemic in Canada and the United States has become a public health crisis - with exponential increases in opioid-related morbidity and mortality. Recently, there has been an increasing body of evidence focusing on the opioid-sparing effects of medical cannabis use (reduction of opioid use and reliance), and medical cannabis as a potential alternative treatment for chronic pain. The objective of this study is to assess the effect of medical cannabis authorization on opioid use (oral morphine equivalent; OME) between 2013 and 2018 in Alberta, Canada. METHODS: All adult patients defined as chronic opioid users who were authorized medical cannabis by their health care provider in Alberta, Canada from 2013 to 2018 were propensity score matched to non-authorized chronic opioid using controls. A total of 5373 medical cannabis patients were matched to controls, who were all chronic opioid users. The change in the weekly average OME of opioid drugs for medical cannabis patients relative to controls was measured. Interrupted time series (ITS) analyses was used to assess the trend change in OME during the 26 weeks (6 months) before and 52 weeks (1 year) after the authorization of medical cannabis among adult chronic opioid users. RESULTS: Average age was 52 years and 54% were female. Patients on low dose opioids (< 50 OME) had an increase in their weekly OME per week (absolute increase of 112.1 OME, 95% CI: 104.1 to 120.3); whereas higher dose users (OME > 100), showed a significant decrease over 6 months (- 435.5, 95% CI: - 596.8 to - 274.2) compared to controls. CONCLUSIONS: This short-term study found that medical cannabis authorization showed intermediate effects on opioid use, which was dependent on initial opioid use. Greater observations of changes in OME appear to be in those patients who were on a high dosage of opioids (OME > 100); however, continued surveillance of patients utilizing both opioids and medical cannabis is warranted by clinicians to understand the long-term potential benefits and any harms of ongoing use.

Gaps in evidence for the use of medically authorized cannabis: Ontario and Alberta, Canada.

BACKGROUND: With legal access to medical cannabis in Canada since 2001, there is a need to fully characterize its use at both the individual and population levels. We draw on data from Canada's largest cohort study of medical cannabis to identify the primary reasons for medical cannabis authorization in Canada from 2014 to 2019 in two major provinces: Alberta (AB) and Ontario (ON), and review the extent that evidence supports each indication. METHODS: Self-reported baseline assessments were collected from adult patients in ON (n = 61,835) and AB (n = 3410) who were authorized medical cannabis. At baseline, sociodemographic, primary medical information, and validated clinical questionnaires were completed by patients as part of an individual assessment. Patients' reasons for seeking medical cannabis were compared to published reviews and guidelines to assess the level of evidence supporting medical cannabis use for each condition. RESULTS: Medical cannabis use in both AB and ON was similar in both demographic and reason for authorization. The most common reasons for medical cannabis authorization were: (1) pain (AB = 77%, ON = 76%) primarily due to chronic musculoskeletal, arthritic, and neuropathic pain, (2) mental health concerns (AB = 32.9%, ON = 38.7%) due to anxiety and depression, and (3) sleep problems (AB = 28%, ON = 25%). More than 50 other conditions were identified as reasons for obtaining authorization. CONCLUSION: In both AB and ON, the majority of reasons for medical cannabis authorization are not substantiated by clinical evidence to fully support its efficacy for long-term use. Ongoing epidemiological studies on medical cannabis on these treatments are warranted to fully outline its treatment benefits or risks.