Ganglionated plexuses (GPs) are major constituents of the intrinsic cardiac nervous system, the final common integrator of regional cardiac control. We hypothesized that nicotinic stimulation of individual GPs exerts divergent regional influences, affecting atrial as well as ventricular functions. In 22 anesthetized canines, unipolar electrograms were recorded from 127 atrial and 127 ventricular epicardial loci during nicotine injection (100 mcg in 0.1 ml) into either the 1) right atrial (RA), 2) dorsal atrial, 3) left atrial, 4) inferior vena cava-inferior left atrial, 5) right ventricular, 6) ventral septal ventricular or 7) cranial medial ventricular (CMV) GP. In addition to sinus and AV nodal function, neural effects on atrial and ventricular repolarization were identified as changes in the area subtended by unipolar recordings under basal conditions and at maximum neurally-induced effects. Animals were studied with intact AV node or following ablation to achieve ventricular rate control. Atrial rate was affected in response to stimulation of all 7 GPs with an incidence of 50-95% of the animals among the different GPs. AV conduction was affected following stimulation of 6/7 GP with an incidence of 22-75% among GPs. Atrial and ventricular repolarization properties were affected by atrial as well as ventricular GP stimulation. Distinct regional patterns of repolarization changes were identified in response to stimulation of individual GPs. RAGP predominantly affected the RA and posterior right ventricular walls whereas CMVGP elicited biatrial and biventricular repolarization changes. Spatially divergent and overlapping cardiac regions are affected in response to nicotinic stimulation of neurons in individual GPs.

Spinal cord stimulation (SCS) applied to the dorsal aspect of the cranial thoracic cord imparts cardioprotection under conditions of neuronally dependent cardiac stress. This study investigated whether neuronally induced atrial arrhythmias can be modulated by SCS. In 16 anesthetized dogs with intact stellate ganglia and in five with bilateral stellectomy, trains of five electrical stimuli were delivered during the atrial refractory period to right- or left-sided mediastinal nerves for up to 20 s before and after SCS (20 min). Recordings were obtained from 191 biatrial epicardial sites. Before SCS (11 animals), mediastinal nerve stimulation initiated bradycardia alone (12 nerve sites), bradycardia followed by tachyarrhythmia/fibrillation (50 sites), as well as tachyarrhythmia/fibrillation without a preceding bradycardia (21 sites). After SCS, the number of responsive sites inducing bradycardia was reduced by 25% (62 to 47 sites), and the cycle length prolongation in residual bradycardias was reduced. The number of responsive sites inducing tachyarrhythmia was reduced by 60% (71 to 29 sites). Once elicited, residual tachyarrhythmias arose from similar epicardial foci, displaying similar dynamics (cycle length) as in control states. In the absence of SCS, bradycardias and tachyarrhythmias induced by repeat nerve stimulation were reproducible (five additional animals). After bilateral stellectomy, SCS no longer influenced neuronal induction of bradycardia and atrial tachyarrhythmias. These data indicate that SCS obtunds the induction of atrial arrhythmias resulting from excessive activation of intrinsic cardiac neurons and that such protective effects depend on the integrity of nerves coursing via the subclavian ansae and stellate ganglia.

Survivors of out-of-hospital cardiac arrest (OHCA) are at risk for hypoxic-ischemic brain injury, which can cause a broad range of effects from death to subtle cognitive impairment. This dissertation includes two studies of OHCA patients who had made good neurological recovery after OHCA. In both studies, patients were evaluated near the time of hospital discharge, when crucial decisions such as rehabilitation plans are made. In addition, OHCA survivors were compared with a myocardial infarction (MI) control group in both studies. Study 1 explored the frequency, severity, and predictors of cognitive dysfunction in OHCA survivors, and characterized the cognitive profile of these patients using a comprehensive neuropsychological battery. Study 2 explored grey matter volume (GMV) in OHCA survivors, MI patients, and healthy controls, and correlated these with cognitive dysfunction and important clinical characteristics (e.g., downtime). While OHCA patients performed poorer on cognitive testing than MI patients, both groups showed decreased GMVs compared to healthy controls. OHCA survivors who have had good neurological recovery may still face significant challenges when they re-engage in difficult cognitive tasks post-arrest. To date, these cognitive issues after OHCA have been somewhat overlooked in Canada's healthcare system. A better understanding of hypoxic-ischemic brain injury among survivors will aid in the promotion of targeted interventions and rehabilitation efforts, and may help clinicians predict those who are most at risk.

Indiana University-Purdue University Indianapolis (IUPUI) / Electrolyte levels were measured in whole-mixed human saliva collected from cardiology out-patients, to investigate any salivary electrolyte changes occurring in such patients after digitalization. Several recent reports have indicated that clinical symptoms of digitalis intoxication were associated with increased saliva concentrations of K+ and/or Ca++. Because salivary glands contain a highly active Na+, K+-ATPase it seemed logical that these and other salivary electrolytes might be predictably affected by the circulating levels of digitalis. Patients receiving digitoxin (Dtxn) had a higher concentration of Salivary K+ and Ca++ (25.8 ± 2.2 and 2.2 ± 0.2 meq/l, respectively), than the controls not receiving cardiac glycosides (20.1 ± 1.4 and 2.0 ± 0.1 meq/1, respectively). A similar pattern was not found for patients receiving digoxin (Dxn), although the mean Ca++ concentration for females in this group was significantly elevated (control: 1.7 ± 0.2; Dxn: 2.4 ± 0.2 meq/1). The mean serum concentration (ng/ml) of Dtxn was 20.3 ± 1. 9; of Dxn, 1.4 ± 0.2. No change was found in P04, and protein concentrations, or in salivary flow rates between control and experimental groups. The results suggest that salivary electrolyte changes occur after digitalization, but that these changes do not adequately reflect the serum level of digitalis in individual patients. This study was supported in part by PHS 80l-RR5312.

The heart is a dynamic environment that is constantly experiencing some degree of remodeling from the point of development, all the way through adulthood. While many genetic components may contribute to the overall presentation of hypertrophic cardiomyopathy (HCM), mutations occurring in sarcomere components such as myosin binding protein C3 (MYBPC3) are of the greatest popularity for study. Aiming to understand the mechanisms underlying heart diseases and to develop effective treatments that circumvent the need for direct patient study, we investigated the use of a platform to mimic the unique physiological conditions of HCM within an in-vitro setting. Following the induction of mechanical stretch on three human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CM) cell lines containing mutations for MYBPC3 (WT, HET, HOM), all displayed HCM like reactions in calcium waveform. In conclusion, this system demonstrated the potential to apply a constant, static strain to healthy and mutated hiPSC-CMs for the MYBPC3 protein to model HCM in-vitro.

Cardiac hypertrophy, a compensatory growth response to various physiological and pathological stimuli, involves intricate cytoskeletal changes within cardiomyocytes. However, the molecular mechanisms governing these cytoskeletal processes is not yet well defined. Microtubule affinity-regulating kinase 2 (MARK2) is of particular interest as it plays an important role in controlling microtubule dynamics and cell polarity to define cell shape. In this thesis, we aim to determine whether MARK2 is involved in initiating the morphological alterations that drive cardiac hypertrophy. Our image analysis reveals a significant increase in total MARK2 signal during pathological remodeling, particularly in the initial hours. However, no significant change occurs under physiological hypertrophy. Inhibiting MARK2 significantly impacts cell area and length-to-width ratio during pathological remodeling but has no effect under physiological conditions. Additionally, MARK2 inhibition results in decreased microtubule density and reduced Tau phosphorylation at Serine262 in pathological remodeling cardiomyocytes. Furthermore, our findings indicate an increased number of binucleated cardiomyocytes in pathological hypertrophy, with MARK2 inhibition influencing this parameter. Overall, our findings provide clarity in the role that MARK2 has in driving cytoskeleton alterations to shift cell morphology in pathological cardiac hypertrophy and a unique potential therapeutic in preventing the transition to fulminant heart failure.

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