The objective of this thesis is to evaluate the use of Doppler echocardiography markers ofglobal dyssynchrony [total isovolumic time (t-IVT)] in the following 6 studies: 1) Its prognostic role in predicting cardiac events in patients undergoing CABG surgery,compared with conventional global systolic and diastolic measurements. 2) Its additional value in predicting six minute walk test (6-MWT) in patients with leftventricular (LV) ejection fraction (EF) <45%. 3) Its prognostic value in comparison with other clinical, biochemical and echocardiographicvariables in patients with chronic systolic heart failure (HF). 4) The relationship between 6-MWT and cardiac function measurements in a consecutivegroup of patients, irrespective of EF and to identify predictors of exercise capacity. 5) To investigate the effect of age on LV t-IVT and Tei index compared with conventionalsystolic and diastolic parameters. 6) To assess potential additional value of markers of global LV dyssynchrony in predictingcardiac resynchronization therapy (CRT) response in HF patients. Study I Methods: This study included 74 patients before routine CABG who were followed up for18±12 months. Results: At follow-up, 29 patients were hospitalized for a cardiac event or died. LV-ESD wasgreater (P=0.003), fractional shortening (FS) lower (p<0.001), E:A ratio and Tei index higher(all P<0.001), and t-IVT longer (P<0.001) in patients with events. Low FS [0.66 (0.50–0.87),P<0.001], high E:A ratio [l4.13 (1.17–14.60), P=0.028], large LV-ESD [0.19 (0.05–0.84),P=0.029], and long t-IVT [1.37 (1.02–1.84), P=0.035] predicted events and deaths. Conclusion: Despite satisfactory surgical revascularization, long t-IVT and systolicdysfunction suggest persistent ventricular dyssynchrony that contributes to post-CABGcardiac events. Study II Methods: We studied 77 patients (60±12 year, and 33.3% females) with stable HF using 6-MWT.iii Results: E’ wave (r=0.61, p<0.001), E/e’ ratio (r=-0.49, p<0.001), t-IVT (r=-0.44, p<0.001),Tei index (r=-0.43, p<0.001) and NYHA class (r=-0.53, p<0.001) had the highest correlationwith the 6-MWT distance. In multivariate analysis, only E/e’ ratio [0.800 (0.665-0.961),p=0.017], and t-IVT [0.769 (0.619-0.955), p=0.018] independently predicted poor 6-MWTperformance (<300m). Conclusions: In HF, the higher the filling pressures and the more dyssynchronous the LV, thepoorer is the patient’s exercise capacity. Study III Methods: We studied 107 systolic HF patients; age 68±12 year, 25% females and measuredplasma NT-pro-BNP. Results: Over a follow-up period of 3718 months, t-IVT ≥12.3 sec/min, mean E/Em ratio≥10, log NT-pro-BNP levels ≥2.47 pg/ml and LV EF ≤32.5% predicted clinical events. Theaddition of t-IVT and NT-pro-BNP to conventional clinical and echocardiographic variablessignificantly improved the χ2 for the prediction of outcome from 33.1 to 38.0, (p<0.001). Conclusions: Prolonged t-IVT adds to the prognostic stratification of patients with systolicHF. Study IV Methods: We studied 147 HF patients (61±11 year, 50.3% male) with 6-MWT.Results: The 6-MWT correlated with t-IVT (r=-0.49, p<0.001) and Tei index (r=-0.43,p<0.001) but not with any of the other clinical or echocardiographic parameters. Group Ipatients (<300m) had lower Hb (p=0.02), lower EF (p=0.003), larger left atrium (p=0.02),thicker septum (p=0.02), lower A wave (p=0.01) and lateral wall a’ (p=0.047), longerisovolumic relaxation time (r=0.003) and longer t-IVT (p= 0.03), compared with Group II(>300m). Only t-IVT ratio [1.257 (1.071-1.476), p=0.005], LV EF [0.947 (0.903-0.993),p=0.02], and E/A ratio [0.553 (0.315-0.972), p=0.04] independently predicted poor 6-MWTperformance. Conclusion: In HF, the limited 6-MWT is related mostly to severity of global LVdyssynchrony, more than EF or raised filling pressures. Study V Methods: We studied 47 healthy individuals (age 62±12 year, 24 female), arbitrarilyclassified into: M (middle age), S (seniors), and E (elderly). Results: Age strongly correlated with t-IVT (r=0.8, p<0.001) and with Tei index (r=0.7,p<0.001), E/A ratio (r=-0.6, p<0.001), but not with global or segmental systolic function measurements or QRS duration. The normal upper limit of the t-IVT (95% CI) for the three groups was 8.3 s/min, 10.5 s/min and 14.5 s/min, respectively, being shorter in the S compared with the E group (p=0.001). T-IVT correlated with A wave (r=0.66, p<0.001), E/Aratio (r=-0.56, p<0.001), septal e’ (r=-0.49, p=0.001) and septal a’ (r=0.4, p=0.006), but notwith QRS. Conclusions: In normals, age is associated with exaggerated LV global dyssynchrony anddiastolic function disturbances, but systolic function remains unaffected. Study VI Methods: We studied 103 HF patients (67±12 year, 82.5% male) recruited for CRTtreatment. Results: Prolonged t-IVT [0.878 (0.802-0.962), p=0.005], long QRS duration [0.978 (0.960-0.996), p=0.02] and high tricuspid regurgitation pressure drop (TRPD) [1.047 (1.001-1.096),p=0.046] independently predicted response to CRT. A t-IVT ≥11.6 s/min was 67% sensitiveand 62% specific (AUC 0.69, p=0.001) in predicting CRT response. Respective values for aQRS ≥ 151ms were 66% and 62% (AUC 0.65, p=0.01). Combining the two variables had asensitivity of 67% but higher specificity of 88% in predicting CRT response. In atrialfibrillation (AF) patients, only prolonged t-IVT ≥11 s/min [0.690 (0.509-0.937), p=0.03]independently predicted CRT response with a sensitivity of 69% and specificity of 79% (AUC0.78, p=0.015). Conclusion: Combining prolonged t-IVT and broad QRS had higher specificity in predictingresponse to CRT, with the former the sole predictor of response in AF patients.

Purpose: Patients living with advanced heart failure experience dyspnea, fatigue, poor quality of life, depression and cognitive impairment which may threaten their ability to provide informed consent to undergo heart transplant (HTx) or mechanical support (LVAD). Using qualitative and quantitative methods, we asked how patients with advanced heart failure make decisions regarding HTx and LVAD. The variables chosen to reflect the elements of consent included quality of life and symptom severity (voluntariness), depression and cognitive impairment (capacity) and treatment preferences (decision-making). Methods: 76 patients enrolled in the quantitative arm completed the Minnesota Living with Heart Failure Questionnaire; Visual Analog scales for dyspnea, fatigue and overall health; Beck Depression Inventory; Montreal Cognitive Assessment; Standard Gamble and Time Tradeoff. Qualitative methods were used to discover concepts, relationships and decision-making processes described by 17 of the 76 patients considering HTx and LVAD. Results: Patients reported poor quality of life and high symptom severity scores which compelled them to consider surgery as a way to relieve unpleasant symptoms and improve quality of life. Although 30% of patients had evidence of depression and/or cognitive impairment, no patient was deemed incapable of decision-making. Patients were willing to take considerable risk (35%) and trade considerable time (4months) to improve their health. While heart failure-related concepts were important to the decision, entrustment emerged as the meaningful process for decision-making. Conclusions: Patients who participated in this study were capable of decision-making and understood the risks associated with the surgery. Voluntariness was diminished by disease but not absent, and decisions were free of coercion. These results suggest the entrustment model of decision-making is the dominant process for patients considering high-risk surgical procedures and meets criteria for informed consent. Understanding the process of decision-making will help clinicians support and enable treatment decisions made by patients living with advanced heart failure.

Non invasive in vivo imaging will lead to better understanding of Angiotensin II Type 1 Receptor’s (AT1R) role in disease progression and may guide therapy in cardiovascular patients. Two models were used in this project: 5/6 nephrectomy and transient left anterior descending (LAD) ligation. Rats were scanned with [13N]ammonia and [11C]methyl-candesartan, both of which are Positron Emission Tomography (PET) tracers, at 8 weeks (nephrectomy) and 2 weeks (LAD ligation) after surgery. Western blot analysis was used to corroborate PET data. Nephrectomy: Renal AT1R image analysis displayed a 40% decrease in kidney AT1R in nephrectomized animals compared to sham (p<0.05) which was confirmed with Western blot and biodistribution. LAD ligation: Left Ventricle AT1R Western blot analysis exhibited a 60% increase in 20min ligation (p<0.05) with maintained myocardial blood flow. In conclusion, changes in renal AT1R were successfully imaged using [11C]methyl-candesartan in nephrectomized animals, and 20min LAD ligation/reperfusion is an appropriate model to image an increase in cardiac AT1R following ischemic injury.

The definition of optimal selection criteria for maximizing the response rate to Cardiac Resynchronization Therapy (CRT) is still an issue under active debate. Recent clinical approaches propose a classification of patients into classes of mechanisms that could lead to heart failure and study their response to the therapy. In this line of research, the computation of a metric between the motion and deformation patterns of a given subject and well identified classes of CRT responders is considered in this thesis, as the basis of a new strategy to compute patient selection indexes. The thesis proposes first an improved design for the construction of statistical atlases of myocardial motion and deformation, and applies it to the characterization of populations of patients involved in CRT. The added-value of our approach is highlighted in a clinical study, applying the methodology to a large population of patients with a given pattern of dyssynchrony (septal flash) and understanding the link between its correction and CRT response. Finally, we propose a method to extend the analysis to the comparison of individuals to reference populations, either healthy or pathological, using manifold learning techniques to model a disease as progressive deviations from normality along a manifold structure, and demonstrate the potential of our method for inter-subject comparison in CRT patients. / La definición de un criterio óptimo para mejorar la respuesta a la Terapia de Resincronización Cardíaca (TRC) sigue siendo un debate abierto. Estudio clínicos recientemente publicados proponen clasificar pacientes según diversos mecanismos patofisiológicos que pueden inducir insuficiencia cardíaca y estudian su respuesta a la terapia. Siguiendo esta línea de investigación, esta tesis considera el cálculo de una distancia entre los patrones de movimiento y deformación de un individuo y las clases de respondedores a la TRC, siendo la base de una nueva estrategia para calcular índices para seleccionar pacientes. Esta tesis presenta primero un método para construir un atlas estadístico de movimiento y deformación miocárdica, y su aplicación posterior a la caracterización de poblaciones de potenciales candidatos a la TRC. El valor añadido de nuestro método se enfatiza en un estudio clínico, en el cual se aplica la metodología a una gran población de pacientes con un patrón específico de disincronía cardíaca (llamado septal flash), y se relaciona su corrección y la respuesta a la TRC. Finalmente, se extiende el método para comparar individuos a una población de referencia, sana o patológica, usando técnicas de manifold learning para representar una patología como una desviación progresiva de la normalidad, con una estructura no lineal específica, y se demuestra el potencial de nuestro método para comparar entre sí candidatos a la TRC.

The left hemisphere (LH) is accepted as the dominant hemisphere for language processing. There is also evidence confirming the language processing abilities of the right hemisphere (RH), particularly its lexical-semantic processing potential (Chiarello, 1988; Joanette, Goulet, & Hannequin, 1990). The capacity of the RH for language processing is significant to the investigation of language processing following LH lesions. However, the precise neurocognitive mechanisms underlying language processing following lesion remain to be fully elucidated. Subsequently, the overall aim for this thesis is to investigate hemispheric contributions to semantic processing following unilateral lesions, and to explore the significance of the contribution made by the RH. In order to achieve this overall aim, the current thesis firstly explores the hemispheric contributions made to lexical-semantic processing for healthy adults, and then shifts focus to explore the changes in hemispheric processing for participants with unilateral lesions (LH and RH). Comparisons of hemispheric activation between these groups will clarify the underlying hemispheric mechanisms that facilitate language processing following unilateral lesion. This thesis includes four complementary investigations of hemispheric contributions to semantic processing. The first study combined divided visual field (DVF) priming with event-related potentials (ERPs), in order to investigate controlled hemispheric semantic priming for young healthy adults. Two experiments were employed for a between subjects comparison of time-course differences (stimulus onset asynchrony, or SOA, varied between experiments) in hemispheric activation of associated and nonassociated category members. Continuous electroencephalograms were recorded throughout the priming task for each participant, and later analysed with reference to relevant ERP components (N400 and Late Positive Complex). Bilateral N400 priming was revealed for associated category members at both the short and long SOA. There was no significant N400 priming for the nonassociated category member condition. The examination of hemispheric priming of associated and nonassociated category member stimuli over the same time-course was continued in the second study for participants with unilateral LH lesions and matched controls. The second investigation aimed to determine the impact of unilateral LH lesions on controlled hemispheric semantic priming, utilising the DVF priming paradigm with participants following unilateral lesions. This study also aimed to explore associations between hemispheric activation during the online priming task and offline comprehension abilities. Differences in priming were observed between the LH lesion group and the control group, with participants in the LH lesion group requiring the association relationship to elicit priming. Priming also varied for participants as a function of their offline comprehension abilities, with RH priming associated with higher offline scores. The third investigation continued the exploration of hemispheric semantic activation following LH lesion, examining the impact of a LH lesion on interhemispheric control mechanisms, and the modification of hemispheric processing capacities with and without dominant hemisphere control. This investigation again utilised DVF priming with associated and nonassociated category member stimuli, in conjunction with the dual task paradigm. The dual task paradigm is designed to overload one hemisphere’s processing resources in order to remove interhemispheric suppression. Findings indicate that following LH lesions, the RH’s contribution is enhanced under conditions that are designed to overload the LH. The final study shifts from the investigation of participants with LH lesions to the impact of a RH lesion. This exploration of controlled hemispheric semantic priming following RH lesion sought to increase our understanding of the underlying mechanisms for semantic processing following unilateral lesion. The RH’s role in lexical-semantic processing has been documented consistently over approximately the last twenty years, however, there remains limited direct investigation of a RH lesion’s impact on contributions to semantic processing. A single case investigation utilised the same experimental procedure as the second study described. Findings suggest a similar activation pattern between the individual with RH lesion and the control participants, with both exhibiting bilateral activation of the associated and nonassociated category member stimuli. However, a subtle difference was found between the activation of the individual with RH lesion and that of the control group, with the individual with a RH lesion showing increased strategic processing difficulties at the longer SOA. Overall, the current thesis demonstrates the importance of the RH for efficient strategic semantic processing for both healthy adults, and people with unilateral lesions. In addition, this thesis concludes that following a LH lesion, the RH contribution to controlled semantic processing may be associated with successful comprehension, and that RH contributions may be improved with the addition of a secondary task designed to overload LH processing. The present thesis provides evidence to support the use of the DVF priming paradigm in the investigation of hemispheric contributions to semantic processing following unilateral lesion. It is anticipated that these findings will improve the current understanding of the underlying hemispheric contributions to lexical-semantics following a unilateral lesion, and will encourage continuing investigation into the RH’s capacity to impact language recovery.

The left hemisphere (LH) is accepted as the dominant hemisphere for language processing. There is also evidence confirming the language processing abilities of the right hemisphere (RH), particularly its lexical-semantic processing potential (Chiarello, 1988; Joanette, Goulet, & Hannequin, 1990). The capacity of the RH for language processing is significant to the investigation of language processing following LH lesions. However, the precise neurocognitive mechanisms underlying language processing following lesion remain to be fully elucidated. Subsequently, the overall aim for this thesis is to investigate hemispheric contributions to semantic processing following unilateral lesions, and to explore the significance of the contribution made by the RH. In order to achieve this overall aim, the current thesis firstly explores the hemispheric contributions made to lexical-semantic processing for healthy adults, and then shifts focus to explore the changes in hemispheric processing for participants with unilateral lesions (LH and RH). Comparisons of hemispheric activation between these groups will clarify the underlying hemispheric mechanisms that facilitate language processing following unilateral lesion. This thesis includes four complementary investigations of hemispheric contributions to semantic processing. The first study combined divided visual field (DVF) priming with event-related potentials (ERPs), in order to investigate controlled hemispheric semantic priming for young healthy adults. Two experiments were employed for a between subjects comparison of time-course differences (stimulus onset asynchrony, or SOA, varied between experiments) in hemispheric activation of associated and nonassociated category members. Continuous electroencephalograms were recorded throughout the priming task for each participant, and later analysed with reference to relevant ERP components (N400 and Late Positive Complex). Bilateral N400 priming was revealed for associated category members at both the short and long SOA. There was no significant N400 priming for the nonassociated category member condition. The examination of hemispheric priming of associated and nonassociated category member stimuli over the same time-course was continued in the second study for participants with unilateral LH lesions and matched controls. The second investigation aimed to determine the impact of unilateral LH lesions on controlled hemispheric semantic priming, utilising the DVF priming paradigm with participants following unilateral lesions. This study also aimed to explore associations between hemispheric activation during the online priming task and offline comprehension abilities. Differences in priming were observed between the LH lesion group and the control group, with participants in the LH lesion group requiring the association relationship to elicit priming. Priming also varied for participants as a function of their offline comprehension abilities, with RH priming associated with higher offline scores. The third investigation continued the exploration of hemispheric semantic activation following LH lesion, examining the impact of a LH lesion on interhemispheric control mechanisms, and the modification of hemispheric processing capacities with and without dominant hemisphere control. This investigation again utilised DVF priming with associated and nonassociated category member stimuli, in conjunction with the dual task paradigm. The dual task paradigm is designed to overload one hemisphere’s processing resources in order to remove interhemispheric suppression. Findings indicate that following LH lesions, the RH’s contribution is enhanced under conditions that are designed to overload the LH. The final study shifts from the investigation of participants with LH lesions to the impact of a RH lesion. This exploration of controlled hemispheric semantic priming following RH lesion sought to increase our understanding of the underlying mechanisms for semantic processing following unilateral lesion. The RH’s role in lexical-semantic processing has been documented consistently over approximately the last twenty years, however, there remains limited direct investigation of a RH lesion’s impact on contributions to semantic processing. A single case investigation utilised the same experimental procedure as the second study described. Findings suggest a similar activation pattern between the individual with RH lesion and the control participants, with both exhibiting bilateral activation of the associated and nonassociated category member stimuli. However, a subtle difference was found between the activation of the individual with RH lesion and that of the control group, with the individual with a RH lesion showing increased strategic processing difficulties at the longer SOA. Overall, the current thesis demonstrates the importance of the RH for efficient strategic semantic processing for both healthy adults, and people with unilateral lesions. In addition, this thesis concludes that following a LH lesion, the RH contribution to controlled semantic processing may be associated with successful comprehension, and that RH contributions may be improved with the addition of a secondary task designed to overload LH processing. The present thesis provides evidence to support the use of the DVF priming paradigm in the investigation of hemispheric contributions to semantic processing following unilateral lesion. It is anticipated that these findings will improve the current understanding of the underlying hemispheric contributions to lexical-semantics following a unilateral lesion, and will encourage continuing investigation into the RH’s capacity to impact language recovery.

Diss. Linköping : Linköpings universitet, 2004.

Thesis (Ph.D. in Clinical Science) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 130-142). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 311-320).

Goals 2000 and No Child Left behind have developed a new timeline for language acquisition, have promoted the practice of teaching to the test rather than the understanding of content, and High School Exit Exams have led to the widening of the achievement gap between ELL students and their Non-ELL counterparts. In additions, the policies’ narrow definition of success leads to federal sanctions that penalize schools with ELL student populations further contributing to the widening of the gap.