abstract / Medicine / Doctoral / Doctor of Philosophy

by Yeung Yuk-Ching. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 119-129). / Abstracts in English and Chinese. / Abstract in English --- p.ii / Abstract in Chinese --- p.v / Glossary --- p.viii / Acknowledgements --- p.x / Publications Arising From this Thesis --- p.xii / List of Tables --- p.xviii / List of Figures --- p.xix / Chapter 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Definition of Heart Rate Variability --- p.1 / Chapter 1.2 --- Physiology --- p.1 / Chapter 1.2.1 --- Review of Autonomic Nervous System and Influence of Heart Rate --- p.1 / Chapter 1.2.2 --- The Role of Baroreceptors in the Control of Circulation --- p.4 / Chapter 1.2.3 --- The Control and Physiological Importance of Heart Rate --- p.7 / Chapter 1.2.3.1 --- Normal Heart Rate --- p.7 / Chapter 1.2.3.2 --- Autonomic Control of Heart Rate --- p.8 / Chapter 1.2.3.2.1 --- Sympathetic Effects --- p.8 / Chapter 1.2.3.2.2 --- Vagal Effects --- p.8 / Chapter 1.2.3.3 --- Reflexes Influencing Heart Rate --- p.9 / Chapter 1.2.3.3.1 --- Baroreceptors --- p.10 / Chapter 1.2.3.3.2 --- Chemoreceptors --- p.10 / Chapter 1.2.3.3.3 --- Atrial Receptors --- p.11 / Chapter 1.2.3.3.4 --- Coronary Chemoreflex --- p.11 / Chapter 1.2.3.3.5 --- Other Reflexes --- p.12 / Chapter 1.2.3.4 --- Influence of Complex Events on Heart Rate --- p.12 / Chapter 1.2.3.4.1 --- Respiratory Influence --- p.12 / Chapter 1.2.3.4.2 --- Effects of Decreases in Venous Return --- p.13 / Chapter 1.2.3.4.3 --- Exercise --- p.13 / Chapter 1.2.3.5 --- Physiological Importance of Heart Rate --- p.14 / Chapter 1.3 --- Spectral Analysis of Blood Pressure and Heart Rate Variability in Evaluating Cardiovascular Regulation --- p.14 / Chapter 1.4 --- Clinical Relevance --- p.15 / Chapter 1.4.1 --- Increased Sympathetic Activity --- p.15 / Chapter 1.4.2 --- Reduced Parasympathetic Activity --- p.15 / Chapter 1.4.3 --- Low Heart Rate Variability --- p.16 / Chapter 1.4.4 --- Depressed Baroreflex Sensitivity --- p.17 / Chapter 1.4.5 --- Prognostic Value of Heart Rate Variability in Disease States --- p.17 / Chapter 1.4.6 --- Abnormality of Autonomic Nervous System in Heart Failure --- p.17 / Chapter 2 --- METHODS FOR ASSESSING HEART RATE VARIABILITY --- p.20 / Chapter 2.1 --- Time Domain Analysis of Heart Rate Variability --- p.20 / Chapter 2.1.1 --- Statistical Methods --- p.21 / Chapter 2.1.2 --- Geometric Methods --- p.22 / Chapter 2.2 --- Spectral Analysis of Heart Rate Variability --- p.23 / Chapter 2.3 --- "Nonlinear Indices (fractal, entropy, chaos theory)" --- p.27 / Chapter 3 --- HEART FAILURE --- p.28 / Chapter 3.1 --- Heart Rate Variability in Heart Failure --- p.28 / Chapter 3.2 --- Effect of Changes in Respiratory Frequency and Posture on Heart Rate Variability Analysis in Heart Failure --- p.34 / Chapter 3.3 --- Effect of Respiratory Rates on Baroreceptor Function in Heart Failure --- p.34 / Chapter 3.4 --- Effect of Treatment on Heart Rate Variability in Heart Failure Patients --- p.35 / Chapter 4 --- AIMS --- p.39 / Chapter 4.1 --- Effect of Changes in Respiratory Frequency and Posture on Heart Rate Variability --- p.39 / Chapter 4.2 --- Effect of Slow Breathing --- p.39 / Chapter 4.3 --- Effect of Therapeutic Interventions in Chronic Heart Failure --- p.39 / Chapter 4.3.1 --- A Comparison of Celiprolol with Metoprolol --- p.39 / Chapter 4.3.2 --- A Comparison of Carvedilol with Metoprolol --- p.40 / Chapter 5 --- STUDIES --- p.41 / Chapter 5.1 --- Impact of Changes in Respiratory Frequency and Posture on Power Spectral Analysis of Heart Rate and Systolic Blood Pressure Variability in Normal Subjects and Patients with Heart Failure --- p.41 / Chapter 5.1.1 --- Subjects --- p.41 / Chapter 5.1.2 --- Recording Technique and Protocol --- p.42 / Chapter 5.1.3 --- Signal Acquisition --- p.42 / Chapter 5.1.4 --- Power Spectral Analysis --- p.43 / Chapter 5.1.5 --- Statistical Analysis --- p.46 / Chapter 5.1.6 --- Results --- p.46 / Chapter 5.1.7 --- Discussion --- p.52 / Chapter 5.1.8 --- Summary --- p.56 / Chapter 5.2 --- Slow Breathing Increases Arterial Baroreflex Sensitivityin Patients with Chronic Heart Failure --- p.57 / Chapter 5.2.1 --- Subjects --- p.57 / Chapter 5.2.2 --- Assessment of Baroreflex Sensitivity --- p.57 / Chapter 5.2.3 --- Statistical Analysis --- p.58 / Chapter 5.2.4 --- Results --- p.59 / Chapter 5.2.5 --- Discussion --- p.62 / Chapter 5.2.6 --- Summary --- p.63 / Chapter 5.3 --- β-Blockers in Heart Failure: a Comparison of a Vasodilating β- Blocker with Metoprolol on Heart Rate Variability by 24 Hour ECG Recordings (Time-Domain & Spectral Analysis) --- p.65 / Chapter 5.3.1 --- Trial Design --- p.65 / Chapter 5.3.2 --- Study Patients --- p.65 / Chapter 5.3.3 --- Study Measurements --- p.66 / Chapter 5.3.4 --- Statistical Analysis --- p.67 / Chapter 5.3.5 --- Results --- p.67 / Chapter 5.3.6 --- Discussion --- p.80 / Chapter 5.3.7 --- Summary --- p.81 / Chapter 5.4 --- Effect of β-Blockade on Baroreceptor and Autonomic Function in Heart Failure-Assessment by Short Term Spectral Analysis --- p.83 / Chapter 5.4.1 --- Trial Design and Study Patients --- p.83 / Chapter 5.4.2 --- Recording Technique and Protocol --- p.83 / Chapter 5.4.3 --- "Signal Acquisition, Power Spectral Analysis and Cross Spectral Analysis" --- p.83 / Chapter 5.4.4 --- Reproducibility --- p.84 / Chapter 5.4.5 --- Statistical Analysis --- p.84 / Chapter 5.4.6 --- Results --- p.84 / Chapter 5.4.7 --- Discussion --- p.93 / Chapter 5.4.8 --- Summary --- p.97 / Chapter 5.5 --- β-Blockade in Heart Failure: A Comparison of Carvedilol with Metoprolol on HRV by 24 hour ECG Recordings (Time-Domain & Spectral Analysis) --- p.98 / Chapter 5.5.1 --- Trial Design and Patient Demographics --- p.98 / Chapter 5.5.2 --- Study Measurements --- p.98 / Chapter 5.5.3 --- Statistical Analysis --- p.99 / Chapter 5.5.4 --- Results --- p.99 / Chapter 5.5.5 --- Discussion --- p.105 / Chapter 5.5.6 --- Conclusions --- p.107 / Chapter 5.6 --- Comparison of Carvedilol and Metoprolol on Baroreceptor Gain in Heart Failure by Short Term Spectral Analysis --- p.108 / Chapter 5.6.1 --- Study Design --- p.108 / Chapter 5.6.2 --- Study Patients --- p.108 / Chapter 5.6.3 --- Recording Technique and Protocol --- p.108 / Chapter 5.6.4 --- "Signal Acquisition, Power Spectral Analysis and Cross Spectral Analysis" --- p.108 / Chapter 5.6.5 --- Statistical Analysis --- p.109 / Chapter 5.6.6 --- Results --- p.109 / Chapter 5.6.7 --- Discussion --- p.112 / Chapter 5.6.8 --- Summary --- p.112 / Chapter 6 --- "GENERAL DISCUSSION, LIMITATIONS & CONCLUSIONS" --- p.113 / Chapter 6.1 --- Discussion --- p.113 / Chapter 6.2 --- Conclusions --- p.117 / Chapter 7 --- REFERENCES --- p.119

Chen Fei. / "October 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

A hipertensão arterial (HA) é uma doença multifatorial na qual há a interação de vários mecanismos, e está relacionada com alterações funcionais e/ou estruturais dos órgãos-alvo. Alterações funcionais dos mecanismos regulatórios da pressão arterial (PA) a curto prazo, como os barorreceptores e os quimiorreceptores, vem sendo bastante exploradas com o objetivo de entender os possíveis mecanismos que podem estar relacionadas à gênese da HA. Diante disso, utilizamos o modelo experimental de desnervação sinoaórtica (DSA) e desnervação seletiva desses aferentes (aórtica DA) e/ou carotídea (DC) e a ligadura da artéria do corpúsculo carotídeo (LA) para avaliarmos a importância relativa dos barorreceptores e quimioreceptores no controle neurogênico da circulação mediando respostas cardíacas e músculo-esqueléticas na HA. Para tanto, utilizamos ratos Wistar (CTR) e espontaneamente hipertensos (SHR) submetidos às diferentes desnervações (SHRDSA/ SHRDA / SHRDC), bem como, a ligadura da artéria do corpúsculo carotídeo (SHRLA). Os animais foram acompanhados durante 10 semanas após as desnervações seletivas, e em seguida foram realizadas as avaliações ecocardiográficas, gasometria arterial, hemodinâmicas, autonômicas e de fluxo sanguíneo regional. Posteriormente, os animais foram eutanasiados para a coleta dos tecidos para as avaliações gênicas e histológicas. Resultados: Os animais SHR apresentaram disfunções hemodinâmicas, autonômicas e gasométricas (alcalose respiratória) quando comparado ao grupo CTR, assim como nas análises de hipertrofia, fluxo e histologia do músculo esquelético, como transição no fenótipo para um perfil mais glicolítico no sóleo e aumento da área de secção transversa das fibras do tipo I e redução das fibras do tipo IIB no músculo diafragma. Nos grupos experimentais hipertensos, os animais com prejuízo do quimiorreflexo (SHRDC, SHRLA e SHRDSA), apresentaram valores maiores de pCO2 em relação ao grupo SHR e SHRDA. Todos os grupos com as diferentes desnervações apresentaram alterações autonômicas, de fluxo sanguíneo e de capilarização. Entretanto, nossos maiores achados foram em relação ao grupo SHRDA, que apresentou valores significativamente maiores que o grupo SHR nos parâmetros PAS (212±2 vs 200±3), PAD (156±4 vs 144±3) PAM (185±9 vs 172±3) e FC (377±4 vs 350±7). Além disso, apresentou aumento da variabilidade da PA (VPAS), bem como o simpático periférico (BFPAS), contrariamente ao observado nos grupos SHRDC e SHRLA em relação ao grupo SHR. No controle autonômico da FC, o grupo SHRDA apresentou menor efeito parassimpático e maior efeito simpático em relação ao grupo SHR. Já os grupos SHRDC e SHRLA apresentaram um menor efeito parassimpático, sem alterações no efeito simpático, embora a resistência vascular periférica estivesse aumentada no grupo SHRLA. As adaptações morfofuncionais cardíacas (ecocardiografia e marcadores de hipertrofia cardíaca) foram mais evidentes no grupo que apresentava disfunção total de ambos receptores (SHRDSA). Conclusão: A ausência do controle reflexo exercido predominantemente pelos barorreceptores arteriais demonstrou uma maior influência do componente aórtico do que o carotídeo sobre a PA. Em adição, a função sistólica parece maior nos grupos SHRDA e SHRDSA, sugerindo que a desnervação aórtica esteja associada com ativação simpática. Não se observou alteração cardíaca na desnervação carotídea. Em relação ao músculo esquelético, todas as desnervações mostraram aumento de capilarização, enquanto somente o grupo SHRDSA mostrou redução de fibras intermediárias. O aumento de capilarização pode estar associado com a liberação do simpático periférico nas desnervações que incluem a retirada dos barorreceptores aórticos, levando ao aumento de VPA e à ausência dos quimiorreceptores nos grupos com desaferentação dos receptores carotídeos / Arterial hypertension (AH) is a multifactorial disease on which there is the interaction of several mechanisms , therefore is related to functional and / or structural changes of the target organ . Functional changes of the regulatory mechanisms of blood pressure (BP) in the short term , as pressoreceptor and chemoreceptors, has been extensively explored in order to understand the possible mechanisms that may be related to the genesis of hypertension. Thus, we used the experimental model of sinoaortic denervation (DSA) and selective denervation of those afferent aortic (DA) and / or carotid (DC) and the ligature of the carotid body artery (LA) to evaluate the relative importance of baroreceptors and chemoreceptors on control of neurogenic circulation mediating cardiac and musculoskeletal responses in HA. There by, we used Wistar rats (CTR) and spontaneously hypertensive rats (SHR) subjected to different denervation (SHRDSA / SHRDA / SHRDC) and the ligature of the carotid body artery (SHRLA). The animals were followed for 10 weeks after the selective denervation it was performed echocardiographic evaluations, blood gas, hemodynamic, autonomic and regional blood flow. Subsequently, the animals were euthanized for tissue collection for genetic and histological evaluations. Results: SHR animals showed hemodynamic, autonomic dysfunction and gas exchange (respiratory alkalosis) compared to CTR group as well as the analysis of hypertrophy, flow and histology of skeletal muscle, such as the transition to a more glycolytic phenotype profile in soleus and increased cross-sectional area of type I fibers and reduction of type IIB fibers in the diaphragm . In hypertensive experimental groups, animals with prejudice chemoreflex (SHRDC, SHRLA and SHRDSA) , showed higher pCO2 compared to SHR and SHRDA group. All groups with different denervation showed autonomic changes in blood flow and capillarization. However, our major findings were compared to SHRDA group, which was significantly higher than the SHR in SBP (212 ± 2 vs 200 ± 3), DBP (156 ± 4 vs 144 ± 3), MAP (185 ± 9 vs 172 ± 3) and HR (377 ± 4 vs 350 ± 7) parameters. Furthermore, we showed an increase in BP variability (BPV) and in the peripheral sympathetic (BFPAS), otherwise showed in the groups SHRDC and SHRLA compared to SHR . Autonomic control of HR, the SHRDA group showed lower sympathetic and higher parasympathetic effect effect in relation to SHR. Already SHRDC and SHRLA groups had a lower parasympathetic effect without changes in sympathetic, although peripheral vascular resistance was increased in SHRLA group. The cardiac morphofunctional adaptations (echocardiography and cardiac hypertrophy markers) were more evident in the group that had total dysfunction of both receptors (SHRDSA). Conclusion: The absence of reflex control exerted by arterial baroreceptors predominantly showed a greater influence of the aortic component of the carotid on BP. In addition, systolic function appears higher in groups SHRDA and SHRDSA, suggesting that aortic denervation is associated with sympathetic activation. No cardiac abnormality was observed in the carotid denervation. Regarding skeletal muscle, all denervations showed an increased of capillarization, while only SHRDSA group showed reduction of intermediate fibers. Increased capillarization may be associated with the release of the peripheral sympathetic denervation, including removal of the aortic baroreceptors, leading to increased VPA and the absence of chemoreceptors in groups with deafferentation of the carotid receptors

A hipertensão arterial (HA) é uma doença multifatorial na qual há a interação de vários mecanismos, e está relacionada com alterações funcionais e/ou estruturais dos órgãos-alvo. Alterações funcionais dos mecanismos regulatórios da pressão arterial (PA) a curto prazo, como os barorreceptores e os quimiorreceptores, vem sendo bastante exploradas com o objetivo de entender os possíveis mecanismos que podem estar relacionadas à gênese da HA. Diante disso, utilizamos o modelo experimental de desnervação sinoaórtica (DSA) e desnervação seletiva desses aferentes (aórtica DA) e/ou carotídea (DC) e a ligadura da artéria do corpúsculo carotídeo (LA) para avaliarmos a importância relativa dos barorreceptores e quimioreceptores no controle neurogênico da circulação mediando respostas cardíacas e músculo-esqueléticas na HA. Para tanto, utilizamos ratos Wistar (CTR) e espontaneamente hipertensos (SHR) submetidos às diferentes desnervações (SHRDSA/ SHRDA / SHRDC), bem como, a ligadura da artéria do corpúsculo carotídeo (SHRLA). Os animais foram acompanhados durante 10 semanas após as desnervações seletivas, e em seguida foram realizadas as avaliações ecocardiográficas, gasometria arterial, hemodinâmicas, autonômicas e de fluxo sanguíneo regional. Posteriormente, os animais foram eutanasiados para a coleta dos tecidos para as avaliações gênicas e histológicas. Resultados: Os animais SHR apresentaram disfunções hemodinâmicas, autonômicas e gasométricas (alcalose respiratória) quando comparado ao grupo CTR, assim como nas análises de hipertrofia, fluxo e histologia do músculo esquelético, como transição no fenótipo para um perfil mais glicolítico no sóleo e aumento da área de secção transversa das fibras do tipo I e redução das fibras do tipo IIB no músculo diafragma. Nos grupos experimentais hipertensos, os animais com prejuízo do quimiorreflexo (SHRDC, SHRLA e SHRDSA), apresentaram valores maiores de pCO2 em relação ao grupo SHR e SHRDA. Todos os grupos com as diferentes desnervações apresentaram alterações autonômicas, de fluxo sanguíneo e de capilarização. Entretanto, nossos maiores achados foram em relação ao grupo SHRDA, que apresentou valores significativamente maiores que o grupo SHR nos parâmetros PAS (212±2 vs 200±3), PAD (156±4 vs 144±3) PAM (185±9 vs 172±3) e FC (377±4 vs 350±7). Além disso, apresentou aumento da variabilidade da PA (VPAS), bem como o simpático periférico (BFPAS), contrariamente ao observado nos grupos SHRDC e SHRLA em relação ao grupo SHR. No controle autonômico da FC, o grupo SHRDA apresentou menor efeito parassimpático e maior efeito simpático em relação ao grupo SHR. Já os grupos SHRDC e SHRLA apresentaram um menor efeito parassimpático, sem alterações no efeito simpático, embora a resistência vascular periférica estivesse aumentada no grupo SHRLA. As adaptações morfofuncionais cardíacas (ecocardiografia e marcadores de hipertrofia cardíaca) foram mais evidentes no grupo que apresentava disfunção total de ambos receptores (SHRDSA). Conclusão: A ausência do controle reflexo exercido predominantemente pelos barorreceptores arteriais demonstrou uma maior influência do componente aórtico do que o carotídeo sobre a PA. Em adição, a função sistólica parece maior nos grupos SHRDA e SHRDSA, sugerindo que a desnervação aórtica esteja associada com ativação simpática. Não se observou alteração cardíaca na desnervação carotídea. Em relação ao músculo esquelético, todas as desnervações mostraram aumento de capilarização, enquanto somente o grupo SHRDSA mostrou redução de fibras intermediárias. O aumento de capilarização pode estar associado com a liberação do simpático periférico nas desnervações que incluem a retirada dos barorreceptores aórticos, levando ao aumento de VPA e à ausência dos quimiorreceptores nos grupos com desaferentação dos receptores carotídeos / Arterial hypertension (AH) is a multifactorial disease on which there is the interaction of several mechanisms , therefore is related to functional and / or structural changes of the target organ . Functional changes of the regulatory mechanisms of blood pressure (BP) in the short term , as pressoreceptor and chemoreceptors, has been extensively explored in order to understand the possible mechanisms that may be related to the genesis of hypertension. Thus, we used the experimental model of sinoaortic denervation (DSA) and selective denervation of those afferent aortic (DA) and / or carotid (DC) and the ligature of the carotid body artery (LA) to evaluate the relative importance of baroreceptors and chemoreceptors on control of neurogenic circulation mediating cardiac and musculoskeletal responses in HA. There by, we used Wistar rats (CTR) and spontaneously hypertensive rats (SHR) subjected to different denervation (SHRDSA / SHRDA / SHRDC) and the ligature of the carotid body artery (SHRLA). The animals were followed for 10 weeks after the selective denervation it was performed echocardiographic evaluations, blood gas, hemodynamic, autonomic and regional blood flow. Subsequently, the animals were euthanized for tissue collection for genetic and histological evaluations. Results: SHR animals showed hemodynamic, autonomic dysfunction and gas exchange (respiratory alkalosis) compared to CTR group as well as the analysis of hypertrophy, flow and histology of skeletal muscle, such as the transition to a more glycolytic phenotype profile in soleus and increased cross-sectional area of type I fibers and reduction of type IIB fibers in the diaphragm . In hypertensive experimental groups, animals with prejudice chemoreflex (SHRDC, SHRLA and SHRDSA) , showed higher pCO2 compared to SHR and SHRDA group. All groups with different denervation showed autonomic changes in blood flow and capillarization. However, our major findings were compared to SHRDA group, which was significantly higher than the SHR in SBP (212 ± 2 vs 200 ± 3), DBP (156 ± 4 vs 144 ± 3), MAP (185 ± 9 vs 172 ± 3) and HR (377 ± 4 vs 350 ± 7) parameters. Furthermore, we showed an increase in BP variability (BPV) and in the peripheral sympathetic (BFPAS), otherwise showed in the groups SHRDC and SHRLA compared to SHR . Autonomic control of HR, the SHRDA group showed lower sympathetic and higher parasympathetic effect effect in relation to SHR. Already SHRDC and SHRLA groups had a lower parasympathetic effect without changes in sympathetic, although peripheral vascular resistance was increased in SHRLA group. The cardiac morphofunctional adaptations (echocardiography and cardiac hypertrophy markers) were more evident in the group that had total dysfunction of both receptors (SHRDSA). Conclusion: The absence of reflex control exerted by arterial baroreceptors predominantly showed a greater influence of the aortic component of the carotid on BP. In addition, systolic function appears higher in groups SHRDA and SHRDSA, suggesting that aortic denervation is associated with sympathetic activation. No cardiac abnormality was observed in the carotid denervation. Regarding skeletal muscle, all denervations showed an increased of capillarization, while only SHRDSA group showed reduction of intermediate fibers. Increased capillarization may be associated with the release of the peripheral sympathetic denervation, including removal of the aortic baroreceptors, leading to increased VPA and the absence of chemoreceptors in groups with deafferentation of the carotid receptors