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Pregnancy induces a dramatic change in hemodynamics due to increased blood volume and metabolic demands. The adaptation of the heart leads to physiological cardiac hypertrophy remodeling in healthy individuals during pregnancy. Metabolic syndrome (MetS) is known to predispose individuals to adverse cardiovascular event. Cardiac remodeling during pregnancy in obese individuals with or without MetS remains unclear. This study first observed differences in cardiac remodeling in human patients with excess weight during pregnancy. The pathophysiology of cardiac remodeling with pregnancy was then studied in a diet-induced animal model that recapitulates features of human MetS. Female mice fed with high fat diet (HFD) (45%kcal) for 4 months had increased body weight, impaired glucose tolerance and dyslipidemia. Pregnant female mice were kept on this HFD and were compared to nonpregnant females and normal diet (10%kcal fat) controls. HFD induced early-stage MetS led to cardiac hypertrophy at term that had features of pathological hypertrophy (PH), including fibrosis and upregulation of fetal genes associated with PH. Hearts from pregnant animals on the HFD had a distinct gene expression profile that likely underlies their pathological remodeling. Post-partum mice with preexisting MetS are also more susceptible to future pathological stimuli, with exacerbated cardiac hypertrophy and impaired cardiac function. These results suggested that preexisting MetS could change physiological into pathological cardiac remodeling during pregnancy, and predispose the heart to future cardiovascular risks. / Biomedical Sciences

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Purpose: The current U.S. population exceeds three hundred million with approximately 20% living in non-urban rural areas. A higher percentage of rural residents have diagnosed heart disease and report poorer health compared to non-rural residents; however, it is not known whether risk factor modification for heart disease and health status differ based on degree of rurality. The purposes of this study were: 1) to compare differences in health status and cardiac risk factors between cardiac patients living in large and small/isolated rural areas, and 2) to compare the health status of rural cardiac patients with a national sample. Method: A secondary analysis using data from three separate studies was completed using a comparative descriptive design. The Cardiac Rehabilitation participant sample (n-191) included individuals 3 to 12 months post-cardiac event. The Arizona Heart Institute and Foundation Heart Test measured risk factors and the eight subscales of the Short-Form, Medical Outcomes study measured health status. Findings: No significant differences in health status were found; all participants rated their health moderately high. However, individuals in large rural areas reported significantly better general health than those in the normative sample. No differences in smoking, blood pressure, diabetes, or overweight/obese BMI were found between the two rural groups. Differences in exercise, and anger were present between the two groups. Significant differences were identified in waist circumference between the genders placing women at higher risk for heart disease. Conclusions: Identifying health status and cardiovascular risk factors of rural individuals informs interventions to be tested for rural residents.

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Despite decades of research and thousands of studies on cardiac electrophysiology, cardiovascular disease remains among the leading causes of death in the United States today. Despite substantially beneficial advances, we have largely shifted cardiovascular disease from an acute to a chronic issue. It is therefore clear that our current understanding of the heart's functions remain inadequate and we must search for untapped therapeutic approaches to eliminate these deadly and costly ailments once and for all. This thesis will focus on the electrophysiology of the heart, specifically the mechanisms of cell-to-cell conduction. Canonically, the understood mechanism of cardiac conduction is through gap junctions (GJ) following a cable-like conduction model. While both experimentally and mathematically, this understanding of conduction has explained cardiac electrical behavior, it is also incomplete, as evidenced by recent conflicting modeling and experimental data. The overall goal of this thesis is to explore a structure modulating an ephaptic, or electric field, cellular coupling mechanism: the GJ-adjacent perinexus, with three specific aims. First, I identified the perinexus – a recently-established structure in rodent myocardium – in human atrial tissue. I also observed a significant tendency for open-heart surgery patients with pre-operative atrial fibrillation to have wider perinexi, indicating a possibly targetable mechanism of atrial fibrillation, one of the costliest, and most poorly-understood cardiac diseases. Next, I developed a high-throughput, high-resolution method for quantifying the perinexus. Finally, I sought to reconcile a major controversy in the field: whether cardiac edema could either be beneficial or harmful to cardiac conduction. Using a Langendorff perfusion model, I added osmotic agents of various sizes to guinea pig hearts and measured electrical and structural parameters. My findings suggest that while cardiac conduction is multifaceted and influenced by several parameters, the strongest correlation is an inverse relationship between conduction velocity and the width of the perinexus. This study is the first to osmotically expand and narrow the perinexus and show an inverse correlation with conduction. Importantly, my conduction data cannot be explained by factors consistent with a cable-like conduction mechanism, indicating once again that the perinexus could be a therapeutic target for a myriad of cardiac conduction diseases. / Doctor of Philosophy / The ways by which cells in the heart communicate have been studied extensively and are thought to be well-understood. However, despite decades of research, cardiovascular disease is a major problem in the developed world today and we remain unable to develop treatments to truly cure many major cardiac diseases. Because of this lack of clinical success in preventing or treating conditions such as atrial fibrillation, Brugada syndrome and sudden cardiac death, all of which are associated with disruptions in the heart’s electrical communication systems, I have sought to better understand the ways by which cellular communication is achieved. Currently, we think of cardiac tissue to propagate electrical signals as if it was a series of cables, just like the electrical wires over our streets and in our homes. However, we have seen experimental evidence, along with computer simulations, that supports the idea of a second mechanism of cellular electrical conduction. This second mechanism is called ephaptic, or electric field, coupling and relies on changes in charges inside and outside the cell to trigger the action potential – the electrical signal which tells the cell to contract. In order for ephaptic coupling to occur, two main conditions must be met. First, there must be a suitably-sized cleft, or ephapse, between adjacent cells. Models have estimated this space to be between 10-100 nm wide. Second, there must be a large concentration of sodium channels, as sodium ions are primarily used to set off the action potential. The region in which I am most interested is the cardiac perinexus, which is the space immediately adjacent to plaques of connexin proteins which link adjacent cells. The perinexus is both of an appropriate size (we’ve measured it between 10 and 25 nm on average) and rich in sodium channels, making it an ideal candidate to be a cardiac ephapse. In recent years, our lab has shown experimentally that expanding this space can disrupt cardiac conduction and my first study showed that clinically, patients with chronic atrial fibrillation (a-fib) prior to open-heart surgery have wider perinexi than patients without chronic a-fib. No one, however, has been able to demonstrate that narrowing the perinexus would be therapeutic by making it easier for cells to communicate via this ephaptic mechanism. Knowing I would need a better method for measuring the width of huge numbers of perinexi, I then developed a faster, more precise measurement program. Finally, I perfused several osmotic agents – substances which would theoretically draw fluid into or out of various compartments of cardiac tissue – into guinea pig hearts and observed changes to both their electrical behavior and tissue structure. Using my new perinexal measurement program, I found that changing the perinexus was the only factor that could explain the conduction changes I observed with each osmotic agent and that parameters associated with cable theory, such as gap junctional protein expression or interstitial resistance, could not explain conduction changes. Therefore, I have indicated, along with my clinical study, that the cardiac perinexus could be a therapeutic target for preventing, managing, or possibly even curing cardiac conduction diseases.

Stimulation of cardiac β-adrenoceptors is the primary mechanism by which cardiac output is increased to meet metabolic demands of the body. Recently, nicotinic acid adenine dinucleotide phosphate (NAADP), has been implicated as a novel component of the β-adrenoceptor signalling pathway. NAADP is thought to mobilise Ca²⁺ from acidic endolysosomal stores which then supplements sarcoplasmic reticulum Ca²⁺ load, leading to a positive inotropic effect. Recent progress in the field has been made with the identification of two-pore channel 2 (TPC2) as a candidate NAADP receptor. Isolated ventricular myocytes from mice lacking TPC2 proteins (Tpcn2^-/-) displayed blunted maximal responses to the β-adrenoceptor agonist isoprenaline. This blunted response was also evident in Langendorff-perfused Tpcn2^-/- hearts. Furthermore, a blunted response was observed in guinea pig ventricular myocytes which had been treated with bafilomycin A1, which disrupts the integrity of acidic endolysosomal stores. These data add to the body of evidence that NAADP signalling forms an important additional component of the β-adrenoceptor signalling pathway. Chronic activation of the β-adrenoceptor pathway is associated with certain disease states including heart failure and arrhythmias. Anandamide is an endogenous cannabinoid, ('endocannabinoid'), with similar properties to δ⁹-tetrahydrocannabinol (δ⁹-THC), the primary active constituent of Cannabis sativa. These compounds have widespread physiological effects through actions at cannabinoid CB₁ and CB₂ receptors, which are negatively coupled to adenylyl cyclases and are expressed in cardiac muscle. Exposure of guinea pig ventricular myocytes to anandamide resulted in a reduction in the amplitude of contractions and Ca²⁺ transients. This was associated with a reduction in action potential duration and amplitude of I_CaL. These effects of anandamide could not be prevented by cannabinoid receptor antagonists, and could not be mimicked by cannabinoid receptor agonists. An inhibition of IKs was also observed. Given the reported Gi-protein coupling of cannabinoid receptors, it may be expected that additional negative inotropic actions of anandamide might be observed when adenylyl cyclases are stimulated. However, the effects of anandamide to reduce amplitude of contraction and I_CaL were no greater in the presence of isoprenaline. Furthermore, the effects of anandamide were not prevented by pre-treatment of myocytes with pertussis toxin (PTX). This is in contrast to the actions of adenosine, which displayed clear PTX sensitive actions in the presence of isoprenaline. These data suggest that cannabinoid receptors are not involved in mediating the negative inotropic actions of anandamide. Another endocannabinoid, 2-arachidonoylglycerol, was without significant effect on action potentials or contractions in the absence or presence of isoprenaline. δ⁹-THC shared many of the actions of anandamide. It appears that anandamide and δ⁹-THC exert significant effects on cardiac muscle through direct modulation of ion channel function, although additional actions, for example, on the sarcoplasmic reticulum or myofilaments, cannot be ruled out.

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