Ultralyd er i dag et standardverktøy innen hjertediagnostikk. Analyse av ventrikkelfunksjon gjøres subjektivt ved å se på gråskala ultralydopptak av hjertet. Dette gjør dokumentasjon og opplæring vanskelig. Det er derfor ønskelig med kvantitative mål på ventrikkelfunksjon. Kvantitative metoder kan benytte høy tidsoppløsning og dermed også registrere flere detaljer. To teknikker for kvantitativ ventrikkelanalyse er vevs-Doppler og speckle tracking (mønsterfølging). Ved bruk av disse teknikkene er det viktig å sikre kvaliteten av resultatene samtidig som analyseprosessen kan gjennomføres så effektivt som mulig. I denne avhandlingen presenteres flere metoder for å sikre kvalitet og øke effektivitet ved kvantitativ ventrikkelanalyse som alle er relatert til bruk av høy tidsoppløsning. For å kunne gjøre effektiv ventrikkelanalyse behøves analyseverktøy. Et slikt verktøy som fungerer med både vevs-Doppler og speckle tracking presenteres i denne avhandlingen. Dette verktøyet har gjort flere store kliniske studier mulig. Ved analyse av hendelsene som skjer innen en hjertesykel er det viktig å dele opp hjertesykelen i ulike faser. Venstre ventrikkels tømmingsfase avsluttes ved at aortaklaffen lukkes, og denne hendelsen må derfor bestemmes før kvantitative parametre i slutten av tømmingsfasen og i overgangen til fyllingsfasen kan bestemmes. I denne avhandlingen vurderes og testes ulike kandidater for bestemmelse av lukkingen. To gunstige kandidater i hastighetskurver fra basale deler av ventrikkelen ble funnet: andre nullkryssing etter tømming og høyeste positive akselerasjon etter tømming før fylling. Et eget bidrag viser at den siste av disse kan bestemmes automatisk. For å oppnå høy tidsoppløsning kreves høy datarate. En populær metode for å øke datarate er flere parallelle mottaksstråler for hver sendestråle. I vanlig gråtoneavbilding av hjertet er det imidlertid observert at dette medfører uønskede linjelignende strukturer i bildet. I denne avhandlingen vises det at årsaken til dette er at de parallelle strålene deformeres når de passerer strukturene mellom hjertet og proben. Avhandlingen inneholder også et bidrag som viser hvordan bruk av parallelle mottakstråler kan medføre at vevs-Doppler kurver blir hentet fra et annet sted i hjertet enn det intensjonen var. Samlet er avhandlingen et bidrag til fortsatt utvikling og forbedring av kvantitative ultralydmetoder innen hjertediagnostikk.

Reversible protein phosphorylation is an essential component of metazoan signaling and cardiovascular physiology. Protein kinase activity is required for regulation of cardiac ion channel and membrane receptor function, metabolism, and transcription, and aberrant kinase function is widely observed across disparate cardiac pathologies. In fact, multiple generations of cardiac therapies (eg. beta-adrenergic receptor blockers) have targeted cardiac kinase regulatory cascades. In contrast, essentially nothing is known regarding the mechanisms that regulate cardiac phosphatase activity at baseline or in cardiovascular disease. Protein phosphatase 2A (PP2A) is a key phosphatase with multiple roles in cardiac physiology. Here we demonstrate the surprisingly complex regulatory platforms that control PP2A holoenzyme activity in heart. We present the first full characterization of the expression and regulation of the PP2A family of polypeptides in heart. We identify the expression of seventeen different PP2A genes in human heart and define their differential expression and distribution across species and in different cardiac chambers. We show unique subcellular distributions of PP2A regulatory subunits in myocytes, strongly implicating the regulatory subunit in conferring PP2A target specificity in vivo. We report striking differential regulation of PP2A scaffolding, regulatory, and catalytic subunit expression in multiple models of cardiovascular disease as well as in human heart failure samples. Importantly, we demonstrate that PP2A regulation in disease extends far beyond expression and subcellular location, by identifying and describing differential post-translational modifications of the PP2A holoenzyme in human heart failure. Furthermore, we go to characterize a mechanism for this method of post-translational modification that may represent a pathway capable of being therapeutically manipulated in human heart failure. Lastly we provide evidence that dysregulation of phosphatase activity contributes to the cellular pathology associated with a previously described inheritable human arrhythmia syndrome, highlighting the importance of the PP2A in cardiovascular physiology and disease. Together, our findings provide new insight into the functional complexity of PP2A expression, activity, and regulation in heart and in human cardiovascular disease and identify potentially new and specific gene and subcellular targets for the treatment of human arrhythmia and heart failure.

Despite the establishment of heart transplantation as a life-saving therapy for children and adolescents, little research has focused on the biopsychosocial impact of the transplant process. Few studies have captured the subjective experiences of young heart transplant recipients. This program of research examined how pediatric heart transplant recipients construct their worlds and the meanings they ascribe to their transplant experience. A grounded theory approach was implemented which guided data collection and analysis. A total of twenty-seven adolescents participated in semi-structured qualitative interviews. Findings illuminate pediatric heart transplantation to be a pervasive experience, with consequent impact on physical, psychological and social well-being. Participants described various biopsychosocial processes and experiences that occurred over the course of their transplant journey. Data analysis yielded themes of quality of life reflecting notions of temporality including: 1) the pre-transplant experience – a struggle to survive, 2) the transplant surgery and hospitalization – a difficult transition and 3) the post-transplant experience – an awakening and transformation. This research identifies that heart transplantation, which may contain elements of suffering and loss, may ultimately enhance young recipients’ overall quality of life. Results reveal the possibility that adolescent heart transplant recipients not only adapt to transplantation, but also potentially experience associated growth-enhancing experiences. An emergent theoretical model is presented, with implications for practice and research.

Heart failure is a chronic condition that increases the risk for death and disability. Beta blockers and ACE inhibitors have become standard treatments in heart failure because clinical trials have demonstrated their beneficial effect on mortality and morbidity in these patients. As not much is known about adherence to these medications, the main objectives of this project were to determine long term adherence to ACE inhibitors and beta blockers and determine how various degrees of adherence to a beta blocker can affect major health outcomes in patients with heart failure.<p> Data was obtained from Saskatchewan health from January 1, 1994 to December 31, 2003 for all heart failure patients from their first hospitalization for heart failure. Adherence was calculated using the fill frequency measure of adherence, and all survival analyses were completed using the Cox proportional hazards model.<p>Although 14, 000 patients were admitted to hospital for a first admission for heart failure, only 1143 subjects started a beta blocker and 5084 subjects started an ACE inhibitor within 3 months of the index hospitalization. Within the first year, adherence was excellent for both beta blockers (80.8 percent) and ACE inhibitors (82.5 percent). The proportion of patients remaining adherent slowly decreased to reach approximately 60 percent, for both medication classes, after 4 years. There was no significant difference in all-cause mortality between patients with high adherence and low adherence, but there appeared to be a trend towards decreased survival time in those remaining adherent throughout the study period [HR = 1.18 (95% CI: 0.98 to 1.43; p=0.07)].<p>Since the overall rate of adherence to beta blockers was excellent in most patients during the first year, it is possible that non-adherence is not responsible for a significant burden of mortality in Saskatchewan heart failure patients, and perhaps and the focus of quality improvement should be optimal prescribing of evidence-based therapies, and continued adherence over time.

The tumour suppressor p27kip1 (p27) is a potent inhibitor of cell growth and proliferation. We identified NF-κB activator, IKKα, as a novel interacting partner of p27 in a protein microarray screen. Both the IKKα and IKKβ components of the IKK complex were mapped to the C-terminal domain of p27. To investigate the physiological function of the p27-IKK interaction, we employed a well-established model of LPS-induced sepsis which is known to activate the IKK/NF-κB pathway. Lentivirally-mediated overexpression of p27 blocked LPS activation of NF-κB. Furthermore, in LPS-injected animals transduced with TAT-p27, a significant improvement in the left ventricular function of the heart was observed. TAT-p27 treatment was also shown to attenuate the endotoxin effect and significantly improve survival compared to both saline and TAT-LacZ controls. Our results indicate that p27 attenuates inflammation, possibly through inhibiting the IKK-dependent activation of NF-κB, thus supporting a novel link between both cell cycle regulation and inflammation.

Sodium restriction is the primary dietary therapy for individuals with heart failure (HF); however, there is little information available to support or refute the use of sodium restriction to manage HF. The overall goal of this work was to generate data related to dietary sodium in patients with chronic HF that would contribute to the development of evidence-based guidelines. The specific objectives were to investigate the optimal methods for measuring sodium intake in HF, to describe the habitual consumption of sodium and other nutrients in HF, and to evaluate the relationship between sodium intake and clinical outcomes in HF. We studied stable ambulatory HF patients who were optimally medicated and participating in multidisciplinary HF programs. We determined that: (1) a strong relationship exists between 24-hour urine collections and food records for sodium intake assessment in non-HF cardiac patients and HF patients not taking loop diuretics. However, the relationship between urinary sodium excretion and sodium intake in HF patients taking loop diuretics was disturbed, suggesting that food records may be a better method for estimating sodium intake in this group. (2) Mean sodium intake in HF and non-HF cardiac patients was similar, and approximately half of patients in each group had sodium intake levels that exceeded the Dietary Reference Intakes tolerable upper level of 2300 mg/d. We also found that both groups had inadequate intakes of several nutrients, including potassium, calcium, magnesium, folate, and vitamin D and E. (3) Finally, we showed that a high sodium diet (>2800 mg/day) in HF was associated with risk of acute decompensated HF, all-cause hospitalization, and all-cause mortality over a median 3 year follow-up period. This is the first published study that prospectively related sodium intake to clinical outcomes in HF. In summary, these data provide novel contributions related to the measurement of sodium intake that can be used in clinical or academic settings. We also describe inadequacies in intake of several vitamins and minerals, which could be addressed through dietary counselling. Finally, we importantly offer insight into a threshold of sodium intake (>2800 mg/day) that could contribute to adverse clinical outcomes in HF.

The tumour suppressor p27kip1 (p27) is a potent inhibitor of cell growth and proliferation. We identified NF-κB activator, IKKα, as a novel interacting partner of p27 in a protein microarray screen. Both the IKKα and IKKβ components of the IKK complex were mapped to the C-terminal domain of p27. To investigate the physiological function of the p27-IKK interaction, we employed a well-established model of LPS-induced sepsis which is known to activate the IKK/NF-κB pathway. Lentivirally-mediated overexpression of p27 blocked LPS activation of NF-κB. Furthermore, in LPS-injected animals transduced with TAT-p27, a significant improvement in the left ventricular function of the heart was observed. TAT-p27 treatment was also shown to attenuate the endotoxin effect and significantly improve survival compared to both saline and TAT-LacZ controls. Our results indicate that p27 attenuates inflammation, possibly through inhibiting the IKK-dependent activation of NF-κB, thus supporting a novel link between both cell cycle regulation and inflammation.

Access to abstract permanently restricted to Ball State community only / Access to thesis permanently restricted to Ball State community only / School of Physical Education, Sport, and Exercise Science

Despite the establishment of heart transplantation as a life-saving therapy for children and adolescents, little research has focused on the biopsychosocial impact of the transplant process. Few studies have captured the subjective experiences of young heart transplant recipients. This program of research examined how pediatric heart transplant recipients construct their worlds and the meanings they ascribe to their transplant experience. A grounded theory approach was implemented which guided data collection and analysis. A total of twenty-seven adolescents participated in semi-structured qualitative interviews. Findings illuminate pediatric heart transplantation to be a pervasive experience, with consequent impact on physical, psychological and social well-being. Participants described various biopsychosocial processes and experiences that occurred over the course of their transplant journey. Data analysis yielded themes of quality of life reflecting notions of temporality including: 1) the pre-transplant experience – a struggle to survive, 2) the transplant surgery and hospitalization – a difficult transition and 3) the post-transplant experience – an awakening and transformation. This research identifies that heart transplantation, which may contain elements of suffering and loss, may ultimately enhance young recipients’ overall quality of life. Results reveal the possibility that adolescent heart transplant recipients not only adapt to transplantation, but also potentially experience associated growth-enhancing experiences. An emergent theoretical model is presented, with implications for practice and research.

Sodium restriction is the primary dietary therapy for individuals with heart failure (HF); however, there is little information available to support or refute the use of sodium restriction to manage HF. The overall goal of this work was to generate data related to dietary sodium in patients with chronic HF that would contribute to the development of evidence-based guidelines. The specific objectives were to investigate the optimal methods for measuring sodium intake in HF, to describe the habitual consumption of sodium and other nutrients in HF, and to evaluate the relationship between sodium intake and clinical outcomes in HF. We studied stable ambulatory HF patients who were optimally medicated and participating in multidisciplinary HF programs. We determined that: (1) a strong relationship exists between 24-hour urine collections and food records for sodium intake assessment in non-HF cardiac patients and HF patients not taking loop diuretics. However, the relationship between urinary sodium excretion and sodium intake in HF patients taking loop diuretics was disturbed, suggesting that food records may be a better method for estimating sodium intake in this group. (2) Mean sodium intake in HF and non-HF cardiac patients was similar, and approximately half of patients in each group had sodium intake levels that exceeded the Dietary Reference Intakes tolerable upper level of 2300 mg/d. We also found that both groups had inadequate intakes of several nutrients, including potassium, calcium, magnesium, folate, and vitamin D and E. (3) Finally, we showed that a high sodium diet (>2800 mg/day) in HF was associated with risk of acute decompensated HF, all-cause hospitalization, and all-cause mortality over a median 3 year follow-up period. This is the first published study that prospectively related sodium intake to clinical outcomes in HF. In summary, these data provide novel contributions related to the measurement of sodium intake that can be used in clinical or academic settings. We also describe inadequacies in intake of several vitamins and minerals, which could be addressed through dietary counselling. Finally, we importantly offer insight into a threshold of sodium intake (>2800 mg/day) that could contribute to adverse clinical outcomes in HF.