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ABSTRACT In pathological left ventricular hypertrophy (LVH) with a normal intrinsic myocardial function, eccentric chamber remodelling (cardiac dilatation) can produce a right shift in systolic pressure-volume (P-V) relations (systolic chamber dysfunction). Whether comparable degrees of cardiac dilatation in physiological (exercise-induced eccentric left ventricular remodelling) and pathological LVH produce similar effects on chamber function has not been determined. Hence, the aim of my thesis was to determine the impact of cardiac dilatation on systolic chamber function in chronically exercised rats with comparable increases in cardiac diastolic volumes as those produced by two rat models of pathological dilatation. Methods: Two models of cardiac dilatation were used, namely: (1) a model of pathological cardiac hypertrophy and dilatation (induced by chronic β-adrenoreceptor agonist administration to either Sprague-Dawley or spontaneously hypertensive rats), and (2) a model of physiological cardiac hypertrophy and dilatation (induced in Sprague-Dawley rats by 4-5 months of voluntary running activity on exercise wheels). 33 Sprague-Dawley rats were placed on spontaneous running wheels for 4-5 months (Exer group) and 24 Sprague-Dawley sedentary control rats (Con group) were placed individually in normal rat cages. To induced pathological dilatation, the β-agonist, isoproterenol (ISO) was administered daily to Sprague-Dawley rats for 7 months (SD-ISO, n=10) and to spontaneously hypertensive rats (SHR) for 4-5 months (SHR+ISO, n=22). Saline was administered daily to controls (SD, n=10; SHR, n=21) and to normotensive Wistar Kyoto rats (WKY, n=17). In isolated, perfused heart preparations, left ventricular (LV) dilatation was determined from the diastolic pressure-volume (P-V) relation and the volume intercept of the diastolic P-V relation (LV V0). Systolic chamber function was assessed by comparing LV developed pressures at specific filling volumes. Intrinsic systolic myocardial function was determined from the slope of the LV systolic developed stress-strain relation (myocardial systolic elastance). Results: ISO adminstered to SD and to SHR rats produced cardiac dilatation [LV V0 (ml): SD 0.20±0.01, SD-ISO 0.27±0.02, p<0.005; SHR 0.21±0.01, SHR-ISO 0.30±0.01, p<0.001], systolic chamber dysfunction (decrease in left ventricular developed pressures at incremental filling volumes) but normal intrinsic systolic myocardial function. Habitual exercise resulted in a right shifted LV diastolic P-V relation and an increased LV V0 (Exer 0.22±0.01, Con 0.18±0.01, p<0.005). In exercised rats (Exer-dilated, n=10) with equivalent dilatation as SD-ISO and SHR-ISO (LV V0 within 95% CI of SD-ISO and SHR-ISO), despite comparable LV diastolic P-V relations and LV V0 values (0.28±0.01); both systolic chamber function and intrinsic systolic myocardial function were normal. Conclusions: These data provide evidence to indicate that as compared to pathological dilatation, a similar extent of exercise-induced dilatation does not produce the same adverse effects on systolic chamber function.

Heart failure prevalence is projected to rise in the United States over the ensuing decades. Typical health education should be focused on primary prevention strategies; however, for those stricken with the disease, health educators should determine appropriate secondary prevention strategies for individuals to live a healthy life. One such strategy, recently approved for coverage by the Centers for Medicare and Medicaid, is cardiac rehabilitation. The impetus for the policy change was the heart failure ACTION trial. The trial unfortunately did not include patients that lived too far from cardiac rehabilitation centers, thus putting rural heart failure patients at a disadvantage. The purpose of the current study was to delineate how rural heart failure patients were referred to cardiac rehabilitation from an inpatient setting, to determine what factors were associated with initiation of cardiac rehabilitation, and to gain insight into rural heart failure patients’ motivation to partake in exercise. A purposive sample of rural heart failure patients were used for the study. Patients were selected from a rural hospital based upon their ejection fraction, per Medicare requirements. Participants completed a demographic survey as well as surveys regarding motivation to partake in exercise; six weeks later, the researcher determined if the rural heart failure participants initiated outpatient cardiac rehabilitation. Cardiac rehabilitation diagnosis, increased distance to cardiac rehabilitation, transportation and assistance, higher income, Caucasian race, and higher levels of educational attainment were independently associated with cardiac rehabilitation initiation. Further, higher levels of perceived autonomous motivation, autonomy support, and competence were associated with cardiac rehabilitation initiation. Conversely, low levels of perceived amotivation scores were associated with cardiac rehabilitation initiation. Not all heart failure patients in the current study were managed by a cardiologist while hospitalized. Lastly, the impetus of attaining the cardiac rehabilitation order for a primary diagnosis of heart failure came from the inpatient exercise physiologists.

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Increases in cardiac afterload caused by disease conditions results in remodeling of heart structure by hypertrophy and alterations in the molecular regulation of contractile performance. These adaptations can be regulated by various Ca2+-dependent signaling processes. STIM1 is an important regulator of Ca2+ signaling in different cell types by sensing endoplasmic reticular Ca2+ levels and coupling to plasma membrane Orai channels. The role of STIM1 in heart is not well understood, given the robust Ca2+ regulatory machinery present within cardiac myocytes. Previous reports indicate that STIM1 may play a role in regulation of cardiac hypertrophy. The goal of this work is to understand how STIM1 can affect contractile Ca2+ regulation in normal and diseased myocytes. We induced cardiac hypertrophy by slow progressive pressure overload in adult cats. Isolated adult feline ventricular myocytes (AFMs) exhibited increased STIM1 expression and activity, which correlated with altered Ca2+ handling. Use of BTP2 to block Orai channels resulted in a reduction of action potential (AP) duration and diastolic spark rate of hypertrophied myocytes, without affecting myocytes from sham-operated animals. Overexpressed STIM1 in cultured AFMs caused persistent Ca2+ influx that resulted in increased diastolic spark rates and prolonged APs, similar to myocytes from banded animals. STIM1 mediated Ca2+ influx could load the sarcoplasmic reticulum and activated CaMKII, which increased spark rates and lead to spontaneous APs. Importantly, STIM1 operated by associating with Orai channels because these effects could be blocked with either BTP2 or with a dominant negative Orai construct. Prolonged Ca2+ entry through this pathway eventually causes cell death. In conclusion, the work presented in this thesis establishes a role for STIM1-Orai in contractile Ca2+ regulation. / Biomedical Sciences

Myocardial injury leads to scar formation and pathological fibrosis that has a significant impact on the development and progression of cardiac disease. Increasing evidence suggests alteration in the chromatin landscape of cells can exacerbate the extracellular matrix deposition and enhance disease progression. Chromatin alterations and fibrosis mediate several cardiac cellular changes, including scar formation, DNA damage, collagen deposition, and increased TGFB expression which are all disease-driving mechanisms during heart failure. Targeting epigenetic dependent fibrosis pathways is thus a promising strategy for the prevention and treatment after myocardial injury. The polycomb complex protein Bmi1, an epigenetic regulator, is associated with numerous biological functions including mediating DNA damage, cellular fate, and proliferation. However, there is currently a lack of understanding on how Bmi1 mediated epigenetic modifications affect adult heart function after injury. It was previously determined that Bmi1 modulates the epigenetic landscape of cardiac stem cells that mediates various molecular processes during a stress condition. In the present study, using a Bmi1 global and fibroblast specific knockout model, cardiac function was assessed through echocardiography using adult mice following cardiac injury. The loss of Bmi1 caused a significant decrease in heart function after injury, which was associated with increased fibrosis and DNA damage. Specifically, we found that the adult cardiac fibroblasts, isolated from the Bmi1 knockout model, had increased expression of pro-fibrotic genes including TGFB, aSMA, and Collagen1a1. Through multiomic sequencing, we found significant changes in the pathological fibrotic signaling pathways of TGFB, specifically with SMAD3 chromatin accessibility with the loss of Bmi1 epigenetic regulation. Concluding, Bmi1 epigenetic regulation mediates repair during pathological challenge by regulating adult cardiac fibroblasts and pathological fibrosis after cardiac injury. / Biomedical Sciences

The overwhelming prevalence of cardiac related deaths is the motivation behind this thesis to develop body centric antennas for wireless cardiac monitoring. Cardiac monitoring can diagnose a number of conditions including: arrhythmia, ischemia, premature atrial complexes, abnormal sinus rhythms, heart blocks, atrial fibrillation, and more. A body centric antenna operating within the ISM band (2.4-2.48GHz) has been designed, simulated, and tested. The simulation and testing indicate low mutual coupling between antennas of varying distances has been achieved. In addition, the simulation and testing indicate that a thin layer of skin over the test subject further reduces mutual coupling.

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Activation of TLRs mediated the NF-κB signaling pathway plays an important pathophysiological role in cardiac hypertrophy. Triad3A, a ubiquitin E3 ligase, has been reported to negatively regulate NF-κB activation pathway via promoting ubiquitination and degradation of TLR4 and TLR9 in innate immune cells. The role of Triad3A in cardiac hypertrophic development remains unknown. The present study investigated whether there is a link between Triad3A and TLR4 and TLR9 in pressure overload induced cardiac hypertrophy. We observed that Triad3A levels were markedly reduced following transverse aortic constriction (TAC) induced cardiac hypertrophy. Similarly, stimulation of neonatal rat cardiac myocytes (NRCMs) with angiotensin-II (Ang II) significantly decreased Triad3A expression. To determine the role of Triad3A in TAC-induced cardiac hypertrophy, we transduced the myocardium with adenovirus expressing Triad3A followed by induction of TAC. We observed that increased expression of Triad3A significantly attenuated cardiac hypertrophy and improved cardiac function. To investigate the mechanisms by which Triad3A attenuated cardiac hypertrophy, we examined the Triad3A E3 ubiquitination on TLR4 and TLR9. We found that Triad3A promoted TLR4 and TLR9 degradation through ubiquitination. Triad3A mediated TLR4 and TLR9 degradation resulted in suppression of NF-κB activation. Our data suggest that Triad3A plays a protective role in the development of cardiac hypertrophy, at least through catalyzing ubiquitination-mediated degradation of TLR4 and TLR9, thus negatively regulating NF-κB activation.