Central and peripheral autonomic influences : analysis of cardio-pulmonary dynamics using novel wavelet statistical methods

The development and implementation of novel signal processing techniques, particularly with regard to applications in the clinical environment, is critical to bringing computer-aided diagnoses of disease to reality. One of the most confounding factors in the field of cardiac autonomic response (CAR) research is the influence of the coupling of respiratory oscillations with cardiac oscillations. This research had three objectives. The first was the assessment of central autonomic influence over heart rate oscillations when the pulmonary system is damaged. The second was to assess the link between peripheral and central autonomic control schema by evaluating the heart rate variability (HRV) of people who were able or unable to adapt to the use of integrated lenses for vision, specifically acconrrmodation, correction (adaptive and non-adaptive presbyopes). The third objective was the development of a wavelet-based toolset by which the first two objectives could be achieved. The first tool is a wavelet based entropy measure that quantifies the level of information by assessing not only the entropy levels, but also the distribution of the entropy across frequency bands. The second tool is a wavelet source separation (WayS) method used to separate the respiratory component from the cardiac component, thereby allowing for analysis of the dynamics of the cardiac signal without the confounding influence of the respiratory signal that occurs when the body is perturbed. With regard to hypothesis one, the entropy method was used to separate the COPD study populations with 93% classification accuracy at rest, and with 100% accuracy during exercise. Changes in COPD and control autonomic markers were evident after respiration is removed. Specifically, the LF/HF ratio slightly decreased on average from pre to post reconstruction for controls, increased on average for COPD. In healthy controls, respiration frequency is distributed across multiple bandwidths, causing large decreases in both LF and HF when removed. With respiration effect removed from COPD population, LE dominates autonomic response, indicating that the frequency is concentrated in the HF autonomic region. Decrease in variance of data set increases probability tat smaller changes can be detected in values. The theory set forth in hypothesis two was validated by the quantification of a correlation between peripheral and central autonomic influences, as evidenced by differences in oculomotor adaptability correlating with differences in HRV. Standard Deviation varies with grouping, not with age. Increasing controlled respiration frequencies resulted in adaptive presbyopes and controls displaying similar sympathetic responses, diverging from non-adaptive group. WayS reduced frequency content in ranges concurrent with breathing rate, indicating a robust analysis. The outcome of hypothesis three was the confirmation that wavelet statistical methods possess significant potential for applications in HRV. Entropy can be used in conjunction with cluster analysis to classify patient populations with high accuracy. Using the WayS analysis, the respiration effect can be removed from HRV data sets, providing new insights into autonomic alterations, both central and peripheral, in disease

Reflex syncope : an integrative physiological approach

Síncope, a forma mais comum de perda temporária de consciência é responsável por até 5% das idas aos serviços de emergência e até 3% dos internamentos hospitalares. É um problema médico frequente, com múltiplos gatilhos, incapacitante, potencialmente perigoso e desafiante em termos diagnósticos e terapêuticos. Assim, é necessária uma anamnese detalhada para primeiro estabelecer a natureza da perda de consciência, mas, após o diagnóstico, as medidas terapêuticas existentes são pouco eficazes. Embora a fisiopatologia da síncope vasovagal ainda não tenha sido completamente esclarecida, alguns mecanismos subjacentes foram já desvendados. Em última análise, a síncope depende de uma falha transitória na perfusão cerebral pelo que qualquer factor que afecte a circulação sanguínea cerebral pode determinar a ocorrência de síncope. Assim, o objectivo do presente estudo é caracterizar o impacto hemodinâmico e autonómico nos mecanismos subjacentes à síncope reflexa, para melhorar o diagnóstico, o prognóstico e a qualidade de vida dos doentes e dos seus cuidadores. Para isso, desenhámos e implementámos novas ferramentas matemáticas e computacionais que permitem uma avaliação autonómica e hemodinâmica integrada, de forma a aprofundar a compreensão do seu envolvimento nos mecanismos de síncope reflexa. Além disso, refinando a precisão do diagnóstico, a sensibilidade e a especificidade do teste de mesa de inclinação (“tilt test”), estabelecemos uma ferramenta preditiva do episódio iminente de síncope. Isso permitiu-nos estabelecer alternativas de tratamento eficazes e personalizadas para os doentes refractários às opções convencionais, sob a forma de um programa de treino de ortostatismo (“tilt training”), contribuindo para o aumento da sua qualidade de vida e para a redução dos custos directos e indirectos da sua assistência médica. Assim, num estudo verdadeiramente multidisciplinar envolvendo doentes com síncope reflexa refractária à terapêutica, conseguimos demonstrar uma assincronia funcional das respostas reflexas autonómicas e hemodinâmicas, expressas por um desajuste temporal entre o débito cardíaco e as adaptações de resistência total periférica, uma resposta baroreflexa atrasada e um desequilíbrio incremental do tónus autonómico que, em conjunto, poderão resultar de uma disfunção do sistema nervoso autónomo que se traduz por uma reserva simpática diminuída. Igualmente, desenhámos, testámos e implementámos uma plataforma computacional e respectivo software associado - a plataforma FisioSinal –incluindo novas formas, mais dinâmicas, de avaliação integrada autonómica e hemodinâmica, que levaram ao desenvolvimento de algoritmos preditivos para a estratificação de doentes com síncope. Além disso, na aplicação dessas ferramentas, comprovámos a eficácia de um tratamento não invasivo, não disruptivo e integrado, focado na neuromodulação das variáveis autonómicas e cardiovasculares envolvidas nos mecanismos de síncope. Esta terapêutica complementar levou a um aumento substancial da qualidade de vida dos doentes e à abolição dos eventos sincopais na grande maioria dos doentes envolvidos. Em conclusão, o nosso trabalho contribuiu para preencher a lacuna entre a melhor informação científica disponível e sua aplicação na prática clínica, sustentando-se nos três pilares da medicina translacional: investigação básica, clínica e comunidade.Syncope, the most common form of transient loss of consciousness, accounts for up to 5% of emergency room visits and up to 3% of hospital admissions. It is a frequent medical problem with multiple triggers, potentially dangerous, incapacitating, and challenging to diagnose. Therefore, a detailed clinical history is needed first to establish the nature of the loss of consciousness. However, after diagnosis, the therapeutic measures available are still very poor. Although the exact pathophysiology of vasovagal syncope remains to be clarified, some underlying mechanisms have been unveiled, dependent not only on the cause of syncope but also on age and various other factors that affect clinical presentation. Ultimately, syncope depends on a failure of the circulation to perfuse the brain, so any factor affecting blood circulation may determine syncope occurrence. Thus, the purpose of the present study is to understand the impact of the hemodynamic and autonomic functions on reflex syncope mechanisms to improve patients diagnose, prognosis and general quality of life. Bearing that in mind, we designed and implemented new mathematical and computational tools for autonomic and hemodynamic evaluation, in order to deepen the understanding of their involvement in reflex syncope mechanisms. Furthermore, by refining the diagnostic accuracy, sensitivity and specificity of the head-up tilt-table test, we established a predictive tool for the impending syncopal episode. This allowed us to establish effective and personalised treatment alternatives to patient’s refractory to conventional options, contributing to their increase in the quality of life and a reduction of health care and associated costs. In accordance, in a truly multidisciplinary study involving reflex syncope patients, we were able to show an elemental functional asynchrony of hemodynamic and autonomic reflex responses, expressed through a temporal mismatch between cardiac output and total peripheral resistance adaptations, a deferred baroreflex response and an unbalanced, but incremental, autonomic tone, all contributing to autonomic dysfunction, translated into a decreased sympathetic reserve. Through the design, testing and implementation of a computational platform and the associated software - FisioSinal platform -, we developed novel and dynamic ways of autonomic and hemodynamic evaluation, whose data lead to the development of predictive algorithms for syncope patients’risk stratification. Furthermore, through the application of these tools, we showed the effectiveness of a non-invasive, non-disruptive and integrated treatment, focusing on neuromodulation of the autonomic and cardiovascular variables involved in the syncope mechanisms, leading to a substantial increase of quality of life and the abolishment of syncopal events in a vast majority of the enrolled patients. In conclusion, our work contributed to fill the gap between the best available scientific information and its application in the clinical practice by tackling the three pillars of translational medicine: bench-side, bedside and community

Estudo da actividade eferente do sistema nervoso autónomo na nefrolitíase recorrente

Tese de doutoramento, Medicina (Fisiologia), Universidade de Lisboa, Faculdade de Medicina, 2012A nefrolitíase é uma doença comum nas sociedades desenvolvidas. Demonstrou-se a associação da litíase renal com algumas doenças metabólicas e cardiovasculares, tais como a hipertensão, a obesidade e a diabetes Mellitus. Demonstrou-se que os indivíduos com cálculos renais apresentam maior probabilidade de sofrer enfartes do miocárdio e acidentes vasculares cerebrais. A ligação da nefrolitíase e o risco cardiovascular não se encontra completamente esclarecida mas aceita-se que, em muitos indivíduos, a nefrolitíase seja uma manifestação clínica precoce de um ambiente adverso mais generalizado, o que aumentaria a prevalência de comorbilidades. Neste trabalho realizámos uma extensa revisão bibliográfica das diferentes hipóteses explicativas para a maior prevalência de doença cardiovascular nos doentes com litíase renal, com maior incidência nas alterações metabólicas que têm sido sugeridas para explicar a maior prevalência de hipertensão, tais como a obesidade e a síndrome metabólica, bem como as possíveis relações entre a hipertensão e alguns factores de risco para a nefrolitíase, como a hipercalciúria e hiperuricosúria. Estudámos uma hipótese inovadora na tentativa de explicar a associação de nefrolitíase com doença cardiovascular: a actividade do sistema nervoso autónomo, cuja influência no desenvolvimento da hipertensão e outras doenças cardiovasculares tem sido referida nos últimos anos. Descreveram-se manifestações de disfunção autonómica em várias comorbidades frequentemente observadas em doentes com cálculos renais. Efectuámos um conjunto de estudos originais para testar a hipótese de uma associação entre disfunção autonómica e nefrolitíase, incluindo um estudo clínico em doentes com nefrolitíase idiopática recorrente. Este teve um desenho caso-controlo e consistiu na realização dum conjunto de cinco provas autonómicas destinadas a avaliar a actividade autonómica eferente. Usaram-se métodos não invasivos baseados na análise da variabilidade da frequência cardíaca e da pressão arterial no domínio do tempo, com recurso a uma adaptação do protocolo de Ewing, e no domínio tempo frequência, com a transformada wavelets e a transformada de Hilbert-Huang. Este estudo documentou anomalias subtis da actividade autonómica em todos os doentes com nefrolitíase. A disfunção autonómica caracterizou-se por hiperactividade do ramo simpático do sistema nervoso autónomo em resposta a vários estímulos e por diminuição do cardioreflexo simpático em resposta ao teste de ortostatismo passivo. A hiperactividade simpática foi responsável por um aumento da pressão arterial na maioria dos pacientes com nefrolitíase. A análise dos resultados no domínio do tempo não demonstrou alterações significativas da actividade parassimpática mas as análises efectuadas no domínio tempo-frequência permitiram identificar alterações subtis no controle vagal da frequência cardíaca. Associámos a disfunção autonómica a algumas comorbilidades existentes no grupo de doentes, principalmente com a existência de antecedentes de hipertensão e obesidade. Além da obesidade, também associámos a diminuição do controle parassimpático da frequência cardíaca com o aumento da excreção urinária de ácido úrico, um dos principais factores de risco para a nefrolitíase recorrente. Não relacionámos a diminuição do cardioreflexo simpático em resposta ao ortostatismo com qualquer factor independente. No nosso estudo, verificámos que os ratos Zucker obesos não desenvolveram espontaneamente cálculos renais pelo que modelo animal de obesidade não foi utilizado nas restantes experiências. Realizámos três estudos em animais com base no modelo experimental de litíase renal induzida em ratos por tratamento com calcitriol e etileno glicol. Num destes, encontrámos um menor controlo simpático da frequência cardíaca e uma grande diminuição do baroreflexo nos ratos com nefrolitíase comparativamente com os ratos do grupo de controlo. Noutro estudo, encontrámos um aumento significativo na actividade basal do nervo renal nos ratos com nefrolitíase quando comparados com ratos do grupo de controlo. Neste estudo, a obstrução urinária subaguda, obtida por 20 minutos de bloqueio do ureter, provocou uma diminuição significativa da actividade do nervo renal ipsilateral no grupo de ratos com nefrolitíase. Consideramos que a demonstração do aumento da actividade nervosa basal nos ratos com nefrolitíase seria um argumento favorável à hipótese de envolvimento da disfunção autonómica. Os resultados sugeriram que o aumento da actividade no nervo renal nos ratos com nefrolitíase não seria totalmente explicado pela obstrução provocada pelos cálculos renais. Efectuámos um conjunto de experiências com um modelo de desenervação renal unilateral em ratos com nefrolitíase induzida por calcitriol e etileno glicol. Neste modelo, seccionámos as fibras nervosas que enervam o rim esquerdo e mantivemos íntegra a enervação do rim contralateral que foi utilizado como controlo. Os ratos recuperaram completamente da cirurgia de desenervação antes de iniciar o tratamento com medicamentos litogénicos. Após quatro semanas de tratamento, os animais foram sacrificados e os rins analisados com o objectivo de comparar as lesões histológicas nos rins desnervados e nos rins de controlo. Este estudo não demonstrou o efeito da desenervação renal na litogénese ou nas lesões renais associadas à presença de cálculos renais. Descrevemos neste trabalho os aspectos histológicos dos rins enervados e desenervados. Apesar das limitações inerentes à extrapolação dos resultados de estudos em animais para a nefrolitíase humana, os nossos resultados confirmam uma disfunção autonómica no modelo do rato de nefrolitíase e representam os primeiros estudos da função autonómica em modelos animais de nefrolitíase experimental.Nephrolithiasis is a common disease in developed societies. It has been shown that kidney stone disease is associated with a number of metabolic and cardiovascular diseases, including hypertension, obesity, and diabetes mellitus. It has also been shown that individuals with kidney stones are more likely to suffer acute myocardial infarction and stroke. The causal link between nephrolithiasis and cardiovascular risk is not completely understood but it is likely that in many individuals, kidney stone disease may be an early clinical manifestation of a more widespread adverse environment that increases the prevalence of the other comorbidities. We carried out a thorough review of the various hypotheses that have been suggested to explain the higher prevalence of cardiovascular disease in individuals with kidney stone disease. Our review focused on the metabolic changes that have been suggested to explain the increased prevalence of hypertension in patients with nephrolithiasis, namely obesity and the metabolic syndrome. We also reviewed possible links between hypertension and some urinary risk factors for nephrolithiasis, namely hypercalciuria and hyperuricosuria. We proposed an innovative hypothesis to explain the association of nephrolithiasis with cardiovascular disease: the activity of the autonomic nervous system. The influence of the autonomic nervous system in the development and maintenance of hypertension and cardiovascular diseases has been extensively documented in medical literature. Manifestations of autonomic dysfunction have also been reported by several authors in other co-morbidities commonly found in kidney stone formers. We conducted a set of original studies to test the hypothesis that there is an association between autonomic dysfunction and recurrent nephrolithiasis. Our research included a clinical study on recurrent idiopathic kidney stone formers. This study had a case-control design and was based on a set of five autonomic tests to assess the efferent autonomic activity using non-invasive methods to analyse heart rate and blood pressure variability in the time domain, using an adaptation of the Ewing protocol; and in the time-frequency domain, using wavelet transform and the Hilbert-Huang transform. This study allowed us to document subtle autonomic abnormalities in all kidney stone formers. The autonomic dysfunction was characterized by hyperactivity of the sympathetic branch of the autonomic nervous system in response to several stimuli, and by decreased cardio reflex in response to a passive tilt test. Sympathetic hyperactivity caused an exaggerated increase in blood pressure in most patients with nephrolithiasis. The analysis of the results in the time domain showed no severe abnormalities in parasympathetic activity, but the analyses made in the time-frequency domain allowed us to identify subtle changes in the vagal control of heart rate. We associated the autonomic dysfunction with some existing co-morbidities in the patients’ group, mainly the existence of a past history of hypertension or obesity. The decrease in the parasympathetic control of heart rate was also associated with hyperuricosuria, one of the main risk factors for nephrolithiasis. However, the decreased sympathetic cardio reflex in response to tilt was not associated with any independent factor. In our study, we found that the Zucker obese rats did not develop kidney stones spontaneously and so this animal model of obesity has not been used in the remaining experiments. We conducted three studies in animal models using an experimental model of nephrolithiasis induced in rats by treatment with calcitriol and ethylene glycol. In one of these studies, we found a lower sympathetic control of heart rate and a striking decrease of the baroreflex in the rats with nephrolithiasis when compared with the rats in the control group. In another study, we found a significant increase in the basal activity of the renal nerve in rats with nephrolithiasis when compared with the rats in the control group. In this study, sub-acute urinary obstruction, induced by a 20-minute blockage of the ureter, caused a significant decrease of the ipsilateral renal nerve activity in the rats with nephrolithiasis. We consider that the increased basal activity of the renal nerve in rats with nephrolithiasis is an important argument in favour of the hypothesis that autonomic dysfunction contributes to the risk for cardiovascular disease in nephrolithiasis. The results suggested that increased renal nerve activity in the rats with nephrolithiasis might not be fully explained by the obstruction caused by kidney stones. We carried out a set of experiments using a model of unilateral kidney denervation in rats with nephrolithias the left kidney, and kept intact the innervation to the contralateral kidney, which was used as a control. The rats recovered from denervation surgery before starting the treatment with lithogenic drugs. After four weeks of treatment, the rats were sacrificed and the kidneys were analysed to compare the histological lesions in the denervated and control kidneys. This study failed to demonstrate an effect of renal denervation in the lithogenic process or in the kidney damage associated with the presence of kidney stones. We describe the histological aspects found in denervated and enervated kidneys. Despite the limitations inherent to the inference of the results of animal studies to human nephrolithiasis, our results are consistent with an autonomic dysfunction in the rat model of nephrolithiasis. These were the first studies to report the results of autonomic evaluation in animal models of experimental nephrolithiasis.is. In this model, we sectioned the nerve fibres that innervate the left kidney, and kept intact the innervation to the contralateral kidney, which was used as a control. The rats recovered from denervation surgery before starting the treatment with lithogenic drugs. After four weeks of treatment, the rats were sacrificed and the kidneys were analysed to compare the histological lesions in the denervated and control kidneys. This study failed to demonstrate an effect of renal denervation in the lithogenic process or in the kidney damage associated with the presence of kidney stones. We describe the histological aspects found in denervated and enervated kidneys. Despite the limitations inherent to the inference of the results of animal studies to human nephrolithiasis, our results are consistent with an autonomic dysfunction in the rat model of nephrolithiasis. These were the first studies to report the results of autonomic evaluation in animal models of experimental nephrolithiasis.Fundação para a Ciência e a Tecnologia (FCT, projeto PIC/IC/83243/2007