Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, increased vagal tone, slowed conduction velocity, prolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atria, without corresponding alterations in the ventricles. Microarray results suggest the involvement of the inflammatory cytokine, TNFα, in exercised-induced atrial remodelling. Accordingly, exercise induces TNFα-dependent activation of both NFκB and p38MAPK, while TNFα inhibition (with etanercept), TNFα gene ablation, or p38 inhibition, prevents atrial structural remodelling and AF vulnerability in response to exercise, without affecting the beneficial physiological changes. Our results identify TNFα as a key factor in the pathology of intense exercise-induced AF.

Metastasis results in most of the cancer deaths in clear cell renal cell carcinoma (ccRCC). MicroRNAs (miRNAs) regulate many important cell functions and play important roles in tumor development, metastasis and progression. In our previous study, we identified a miRNA signature for metastatic RCC. In this study, we validated the top differentially expressed miRNAs on matched primary and metastatic ccRCC pairs by quantitative polymerase chain reaction. We performed bioinformatics analyses including target prediction and combinatorial analysis of previously reported miRNAs involved in tumour progression and metastasis. We also examined the co-expression of the miRNAs clusters and compared expression of intronic miRNAs and their host genes. We observed significant dysregulation between primary and metastatic tumours from the same patient. This indicates that, at least in part, the metastatic signature develops gradually during tumour progression. We identified metastasis-dysregulated miRNAs that can target a number of genes previously found to be involved in metastasis of kidney cancer as well as other malignancies. In addition, we found a negative correlation of expression of miR-126 and its target vascular endothelial growth factor (VEGF)-A. Cluster analysis showed that members of the same miRNA cluster follow the same expression pattern, suggesting the presence of a locus control regulation. We also observed a positive correlation of expression between intronic miRNAs and their host genes, thus revealing another potential control mechanism for miRNAs. Many of the significantly dysregulated miRNAs in metastatic ccRCC are highly conserved among species. Our analysis suggests that miRNAs are involved in ccRCC metastasis and may represent potential biomarkers.

The detailed physiological consequences of aerobic training, in patients with hypertrophic cardiomyopathy (HCM) are not well understood. In athletes and non-athletes with HCM, there are two hypothetical concerns with respect to exercise: exercise-related worsening of the phenotype (e.g. promoting hypertrophy, fibrosis), and/or triggering of arrhythmia. The former concern is unproven and animal studies suggest an opposite effect, where exercise has been shown to be protective. The main reason for exercise restriction in HCM is fear of exercise-induced arrhythmia. Whilst the safety of sports in HCM has been reviewed, even more recent data suggest a substantially lower risk for sudden cardiac death (SCD) in HCM than previously thought, and there is an ongoing debate about restrictions of exercise imposed on individuals with HCM. This review outlines the pathophysiology of HCM, the impact of acute and chronic exercise (and variations of exercise intensity, modality, and athletic phenotype) in HCM including changes in autonomic function, blood pressure, cardiac dimensions and function, and cardiac output, and the underlying mechanisms that may trigger exercise-induced lethal arrhythmias. It provides a critical evaluation of the evidence regarding risk of SCD in athletes and the potential benefits of targeted exercise prescription in adults with HCM. Finally, it provides considerations for personalized recommendations for sports participation based on the available data.

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Background: Death due to out-of-hospital cardiac arrest (OHCA) is most commonly attributed to “no obvious cause” after review of the prehospital and in-hospital documentation. To establish cause of death in younger patients, autopsy and toxicology data are important, especially in younger patients. We examined the probable cause of death in a large urban cohort of younger OHCA patients. Methods: A prospective population-based registry of all OHCAs attended by Emergency Medical Services (EMS) in the Toronto area was used to identify cases from 2009-2012. Identified OHCAs were cases aged 2-45 who died and assigned ‘no obvious cause’ based on abstracted data from ambulance call reports and in-hospital chart review, including narrative review and contributing factors compliant with the Resuscitation Outcomes Consortium Epistry Manual of Operations. Cases with inadequate information (coroners and/or EMS), or with expected death (e.g. DNR or long term care) or homicide were then excluded. The remaining cases were adjudicated by 3 reviewers using additional data from coroner investigative statements, autopsy, toxicology and police reports, and classified as primary cardiac or another non-cardiac etiology. Results: A total of 2048 OHCA cases with no obvious cause were identified; of these, 547 were excluded. Of the remaining 1501 cases with complete information, 48.2% were treated by EMS. Of the treated cases, 41.3 % (299/724) of those assigned to ‘no obvious cause’ had an adjudicated cardiac etiology. Of the untreated group, 21.2% (165/777) had an adjudicated cardiac etiology. The majority consisted of drug overdoses (214/425; 50.3%) and other non-cardiac causes (49.7%) including trauma (Figure 1). Conclusions: In younger OHCA patients who die, the category "OHCA of no obvious cause”, on detailed review, is most often due to a non-cardiac cause. This observation may contribute to a better understanding of the etiology of sudden cardiac death in younger patients.

Background: Out-of-Hospital-Cardiac Arrest (OHCA) in young individuals is a tragic and unexpected event, often occurring in seemingly healthy individuals. We examined the etiologies and medications in a large urban cohort of young sudden death patients in order to ascertain the accuracy of this assumption. Methods: A prospective population-based registry of all OHCAs in the Toronto area was used to identify cases from 2009-2012. Eligible cases were defined as OHCA patients aged 2-45 who had “no obvious cause” as defined by Emergency Medical Services (EMS) and hospital records, who died, and had a coroner record available. All cases were subsequently classified as primary cardiac or non-cardiac etiology by 3 reviewers (KA, AP, PD) using all available sources of information, including EMS reports, in-hospital data coroner investigative statements, autopsy, toxicology and police reports. Disagreement was resolved by consensus. Cardiac etiology was classified as one of: structural heart disease (HD), ischemic HD, primary arrhythmic, other or undetermined. A positive drug screen was defined as any psychoactive drug, ethanol, or drug of abuse detected at therapeutic, significant or toxic concentrations post-mortem. Cases were further subdivided by age (2-34 vs. 35-45) and gender. Results: A total of 470 patients were identified as having adjudicated primary cardiac etiologies. Causes of death and drug information are detailed in Table 1. Both men and women had a relatively high rate of psychoactive drug use (antipsychotics, antidepressants, and opioids). Overall, women had higher rates of medications compared to men. Conclusions: Younger, seemingly healthy OHCA patients die more often from structural heart disease than from primary arrhythmia disorders. The high rates of psychoactive drug use, as well as high rates of positive toxicology screens in this cohort suggests that prior illness and drugs may play an important role in the cause of sudden death.