Protein synthesis (mRNA) is tightly regulated under numerous conditions in cardiomyocytes. It can be activated by hormones such as insulin and also by other agents such as phenylephrine (PE) that activates hypertrophy in the heart. Cardiac hypertrophy involves an increase in the muscle mass of the heart, principally in the left ventricular muscle, and the increase is due to enlarged cell size, not increased cell number. A pivotal element of cardiac hypertrophy is an elevation in the rates of protein synthesis, which drives the increase in cell size causing hypertrophy. Unfortunately, we currently lack the understanding of the basic mechanisms that drives hyperactivated protein synthesis. Cardiac hypertrophy is clinically important because it is a major risk factor for heart failure. It initially serves as an adaptive response to increase cardiac output in response to higher demand, but ultimately leads to deterioration of contractility of the heart if hypertrophy is sustained. The main goal of this research project is to understand how hypertrophic agents, such as phenylephrine (PE), activate protein synthesis using adult rat ventricular cardiomyocytes as a model. Specifically, this study focuses on how the translational initiation is controlled by upstream signalling pathways.

Background: Coronary heart disease (CHD) is a leading cause of death in Canada; however, physical activity (PA) has been shown to reduce mortality. Unfortunately, CHD patients are not engaging in enough PA. Purpose: To explore the association of the environmental variables (a) rurality, (b) access to PA opportunities, and (c) community socio-economic status (SES) with PA in CHD patients 3 months after discharge? And how does task self-efficacy may mediate these associations Results: Regressions showed that task self-efficacy predicted PA; however rurality, and SES did not predict PA at 3 months, nor did access to PA opportunities with the exclusion of pools. The lack of associations required no mediational analyses to be performed, except for pools, which demonstrated no mediational influence from self-efficacy. Conclusion: While task self-efficacy was a key PA correlate, there were no associations between the environment and PA (with the exclusion of access to pools).

Arresting the heart with cardioplegia solution is the usual strategy to protect the myocardium during cardiac surgery. However, ischemia-reperfusion injury, due in part to Ca2+ overload, remains a clinical problem. Ca2+ influx during ischemia occurs through reverse mode action of the Na+/Ca2+ exchanger. We therefore tested the hypothesis that delivering the Na+/Ca2+ exchanger blocker SEA0400 to a cardioplegia solution would result in superior myocardial protection during ischemic-cardioplegic arrest. Studies were performed on isolated hearts and individual cardiomyocytes from young adult male Fisher Rats. Hearts arrested with cardioplegia containing SEA0400 showed improved recovery of left ventricular function after reperfusion. The onset of reperfusion arrhythmia was delayed, troponin release was reduced, and mitochondrial damage was minimized. In the isolated cell model, contraction amplitudes were higher during reperfusion in the SEA0400 group without a change in Ca2+ transients. This suggests that cells arrested with cardioplegia containing SEA0400 developed improved myofilament sensitivity to Ca2+.

Background: The purpose of this study is to determine whether precursor events are associated with a post-operative composite outcome in a low-medium risk cardiac surgical population. These precursor events may be promising targets for strategies aimed at quality improvement. Methods: This study was a case control design where the outcome of major adverse events (MACE) was assessed in patients exposed to four intra-operative precursor events. Cases and controls were matched 1:1 using propensity score matching, Univariate comparison of ?1 precursor event in the matched groups was performed. Results: The primary outcome of ?1 precursor event occurred significantly more frequently in the MACE patient group vs the non-MACE patients group (33% vs. 24%; p=0.015). The individual events of bleeding and difficulty weaning from CPB were significantly higher in the MACE group whereas incomplete revascularization/repair and repair/regrafting were not. Conclusion: Quality improvement techniques aimed at mitigating the consequences of precursor events may improve surgical outcomes for these patients.

In cardiac myocytes, multiple receptor mediated signalling pathways converge on cyclic nucleotide production. These second messengers act to achieve changes in cellular function. Despite this, each signalling molecule and receptor can achieve distinct sub-cellular effects. This has led to the theory of cyclic nucleotide compartmentation, which has been postulated to be mediated by phosphodiesterases (PDEs). Research in this field has focused on compartmentation using β-adrenergic stimulation. As an extension of this work, we investigated the effects of two agonists, prostaglandin E2 (PGE2; 10 nM) and forskolin (FSK; 30 nM), on various cellular parameters in the presence of either cilostamide (1 µM) a selective PDE3 inhibitor, or Ro 20-1724 (10 µM) a selective PDE4 inhibitor. In myocytes treated with PGE2, unloaded cell shortening and intracellular calcium transients exhibited significantly different (p<0.05) values of 147 ± 10% and 138 ± 5% of pre-treatment (t=0) values, respectively, in the presence of PGE2 and Ro 20-1724 (all n=5). However, values were not significantly different in cells pre-treated with cilostamide. Conversely, FSK resulted in significant increases of 153 ± 9% (n=5; P>0.05) and 189 ± 20% (n=5; P>0.05) of t=0 in cells treated with cilostamide and Ro 20-1724, respectively. PGE2 enhanced ICa,L was not altered using either PDE inhibitor. However, with FSK as an agonist, a significant increase in peak ICa,L from -6.0 ± 0.8 pA/pF to -7.7 ± 0.4 pA/pF (n=5; P>0.05) was observed in cells pre-treated with Ro 20-1724. SR calcium loading was also increased, but only in cells pre-treated with Ro 20-1724, with values of 127 ± 11% and 156 ± 47% of t=0 (n=5) for FSK and PGE2, respectively. Our results demonstrate that a unique pattern of regulation exists for PGE2 and that it is different from what was found previously with isoproterenol. We have shown that this is achieved by functionally localizing PDEs to distinct compartments. Specifically, PDE4 is localized at the SR, PDE3 at the sarcomere, and a combination of both at the calcium channel. However, our ICa,L results also indicate that the location of the receptor and adenylate cyclases must be considered relevant to compartmentalizing the cAMP signal. / Thesis (Master, Physiology) -- Queen's University, 2009-07-15 11:01:49.571

The electrical heterogeneity of the heart has been recognized as an important feature of normal cardiac function. In cardiac myocytes, considerable electrophysiological differences in sodium channel currents have been reported between the atria and the ventricle. Although, these differences have been primarily attributed to heterogeneous populations of Na+ channel isoforms within cardiac tissue, the link between these electrophysiological differences and certain cardiac pathologies has been loosely studied. We sought to further elucidate the electrophysiological differences between the atria and the ventricle by characterizing INa in both cell types. For these studies we had initially predicted the atria to contain a greater density of TTX-sensitive Na+ channel isoforms compared to that of the ventricle. We used two well-known Na+ channel blockers: lidocaine (100 μM, 30 μM, 10 μM) and tetrodotoxin (TTX; 10 nM, 30 nM). In addition, we also applied hydrogen peroxide (H2O2; 100 μM, 30 μM, 10 μM) to atrial myocytes, which served as our pathological model for reactive oxygen species (ROS). When we applied lidocaine to cardiac myocytes, we observed an overall mixed response in both cell types. Specifically, we noted the most significant differences (p < 0.05) in peak INa, shifts in steady-state inactivation, and impaired recovery from fast inactivation in the presence of 100 μM lidocaine. Given the non-uniform responses to lidocaine, our results support the theory that tissue specific populations of Na+ channel isoforms exist within cardiac myocytes. In order to further elucidate the electrophysiological differences between the ventricle and the atria, we applied TTX, which is selective for TTX-sensitive Na+ currents. Our results indicated no overall significant differences between the ventricle and the atria, suggesting that the population of TTX-sensitive Na+ channel isoforms within the atria specifically, may not be pharmacologically detectable. Finally, our results also demonstrated that the atria are sensitive to ROS, where H2O2 significantly prolonged the action potential duration (APD) in atrial myocytes. Our results also suggest that, in addition to INa, other ion channels may be mediating a component of the H2O2-induced prolongation of the APD in adult rat atrial myocytes. / Thesis (Master, Physiology) -- Queen's University, 2010-08-27 10:04:19.043

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