A Model for the Genesis of Arterial Pressure Mayer Waves from Heart Rate and Sympathetic Activity

Both theoretic models and cross-spectral analyses suggest that an oscillating sympathetic nervous outflow generates the low frequency arterial pressure fluctuations termed Mayer waves. Fluctuations in heart rate also have been suggested to relate closely to Mayer waves, but empiric models have not assessed the joint causative influences of hemt rate and sympathetic activity. Therefore, we constructed a model based simply upon the hemodynamic equation deriving from Ohm's Law. With this model, we determined time relations and relative contributions of heart rate and sympathetic activity to the genesis of arterial pressure Mayer waves. We assessed data from eight healthy young volunteers in the basal state and in a high sympathetic state known to produce concurrent increases in sympathetic nervous outflow and Mayer wave amplitude. We fit the Mayer waves (0.05-0.20 Hz) in mean arterial pressure by the weighted sum ofleading oscillations in heart rate and sympathetic nerve activity. This model of our data showed heart rate oscillations leading by 2-3.75 seconds were responsible for almost half of the variance in arterial pressure (basal R^2=0.435±0.140, high sympathetic R^2=0.438±0.180). Surprisingly, sympathetic activity (lead 0-5 seconds) contributed only modestly to the explained variance in Mayer waves during either sympathetic state (basal: ∆R^2=0.046±0.026; heightened: ∆R^2=0.085±0.036). Thus, it appears that heart rate oscillations contribute to Mayer waves in a simple linear fashion, whereas sympathetic fluctuations contribute little to Mayer waves in this way. Although these results do not exclude an important vascular sympathetic role, they do suggest that additional Ji1ctors, such as sympathetic transduction into vascular resistance, modulate its influence.Binda and Fred Shuman Foundation; National Institute on Aging (AG14376)

A Model for the Genesis of Arterial Pressure Mayer Waves from Heart Rate and Sympathetic Activity

Both theoretic models and cross-spectral analyses suggest that an oscillating sympathetic nervous outflow generates the low frequency arterial pressure fluctuations termed Mayer waves. Fluctuations in heart rate also have been suggested to relate closely to Mayer waves, but empiric models have not assessed the joint causative influences of hemt rate and sympathetic activity. Therefore, we constructed a model based simply upon the hemodynamic equation deriving from Ohm's Law. With this model, we determined time relations and relative contributions of heart rate and sympathetic activity to the genesis of arterial pressure Mayer waves. We assessed data from eight healthy young volunteers in the basal state and in a high sympathetic state known to produce concurrent increases in sympathetic nervous outflow and Mayer wave amplitude. We fit the Mayer waves (0.05-0.20 Hz) in mean arterial pressure by the weighted sum ofleading oscillations in heart rate and sympathetic nerve activity. This model of our data showed heart rate oscillations leading by 2-3.75 seconds were responsible for almost half of the variance in arterial pressure (basal R^2=0.435±0.140, high sympathetic R^2=0.438±0.180). Surprisingly, sympathetic activity (lead 0-5 seconds) contributed only modestly to the explained variance in Mayer waves during either sympathetic state (basal: ∆R^2=0.046±0.026; heightened: ∆R^2=0.085±0.036). Thus, it appears that heart rate oscillations contribute to Mayer waves in a simple linear fashion, whereas sympathetic fluctuations contribute little to Mayer waves in this way. Although these results do not exclude an important vascular sympathetic role, they do suggest that additional Ji1ctors, such as sympathetic transduction into vascular resistance, modulate its influence.Binda and Fred Shuman Foundation; National Institute on Aging (AG14376)

Arrhythmic risk in elderly patients candidates to transcatheter aortic valve replacement. predicative role of repolarization temporal dispersion

Degenerative aortic valve stenosis (AS) is associated to ventricular arrhythmias and sudden cardiac death, as well as mental stress in specific patients. In such a context, substrate, autonomic imbalance as well as repolarization dispersion abnormalities play an undoubted role. Aim of the study was to evaluate the increase of premature ventricular contractions (PVC) and complex ventricular arrhythmias during mental stress in elderly patients candidate to the transcatheter aortic valve replacement (TAVR). In eighty-one elderly patients with AS we calculated several short-period RRand QT-derived variables at rest, during controlled breathing and during mild mental stress, the latter being represented by a mini-mental state evaluation (MMSE). All the myocardial repolarization dispersion markers worsened during mental stress (p < 0.05). Furthermore, during MMSE, low frequency component of the RR variability increased significantly both as absolute power (LFRR) and normalized units (LFRRNU) (p < 0.05) as well as the low-high frequency ratio (LFRR/HFRR) (p < 0.05). Eventually, twenty-four (30%) and twelve (15%) patients increased significantly PVC and, respectively, complex ventricular arrhythmias during the MMSE administration. At multivariate logistic regression analysis, the standard deviation of QTend (QTesd), obtained at rest, was predictive of increased PVC (odd ratio: 1.54, 95% CI 1.14–2.08; p = 0.005) and complex ventricular arrhythmias (odd ratio: 2.31, 95% CI 1.40–3.83; p = 0.001) during MMSE. The QTesd showed the widest sensitive-specificity area under the curve for the increase of PVC (AUC: 0.699, 95% CI: 0.576–0.822, p < 0.05) and complex ventricular arrhythmias (AUC: 0.801, 95% CI: 0.648–0.954, p < 0.05). In elderly with AS ventricular arrhythmias worsened during a simple cognitive assessment, this events being a possible further burden on the outcome of TAVR. QTesd might be useful to identify those patients with the highest risk of ventricular arrhythmias. Whether the TAVR could led to a QTesd reduction and, hence, to a reductionof thearrhythmicburdenin thissettingofpatients isworthytobe investigated

Positive End-Expiratory Pressure may alter breathing cardiovascular variability and baroreflex gain in mechanically ventilated patients

<p>Abstract</p> <p>Background</p> <p>Baroreflex allows to reduce sudden rises or falls of arterial pressure through parallel RR interval fluctuations induced by autonomic nervous system. During spontaneous breathing, the application of positive end-expiratory pressure (PEEP) may affect the autonomic nervous system, as suggested by changes in baroreflex efficiency and RR variability. During mechanical ventilation, some patients have stable cardiorespiratory phase difference and high-frequency amplitude of RR variability (HF-RR amplitude) over time and others do not. Our first hypothesis was that a steady pattern could be associated with reduced baroreflex sensitivity and HF-RR amplitude, reflecting a blunted autonomic nervous function. Our second hypothesis was that PEEP, widely used in critical care patients, could affect their autonomic function, promoting both steady pattern and reduced baroreflex sensitivity.</p> <p>Methods</p> <p>We tested the effect of increasing PEEP from 5 to 10 cm H2O on the breathing variability of arterial pressure and RR intervals, and on the baroreflex. Invasive arterial pressure, ECG and ventilatory flow were recorded in 23 mechanically ventilated patients during 15 minutes for both PEEP levels. HF amplitude of RR and systolic blood pressure (SBP) time series and HF phase differences between RR, SBP and ventilatory signals were continuously computed by complex demodulation. Cross-spectral analysis was used to assess the coherence and gain functions between RR and SBP, yielding baroreflex-sensitivity indices.</p> <p>Results</p> <p>At PEEP 10, the 12 patients with a stable pattern had lower baroreflex gain and HF-RR amplitude of variability than the 11 other patients. Increasing PEEP was generally associated with a decreased baroreflex gain and a greater stability of HF-RR amplitude and cardiorespiratory phase difference. Four patients who exhibited a variable pattern at PEEP 5 became stable at PEEP 10. At PEEP 10, a stable pattern was associated with higher organ failure score and catecholamine dosage.</p> <p>Conclusions</p> <p>During mechanical ventilation, stable HF-RR amplitude and cardiorespiratory phase difference over time reflect a blunted autonomic nervous function which might worsen as PEEP increases.</p

Short term control of the cardiovascular system: Assessment with the isometric handgrip exercise

This study aims at assessing the short term control of the Cardio Vascular system (CV), through a physiological test which involves strictly autonomic response: the handgrip isometric exercise, under vagal influence during the first minute. CVS parameters are extracted from RR and the arterial blood pressure (ABP) signals, respectively giving frequency and amplitude information on the CVS. Mean time series, spectral values and baroreflex sensitivity (BRS), seen as the spectral controller gain between RR and ABP, help to approach the underlying mechanisms of the autonomic control. Results give evidence of two major effects: - The relation between heart rate and contractility (positive staircase or Treppe effect). - The drop of BRS, due to the decrease of heart variability

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

Characterization and interpretation of cardiovascular and cardiorespiratory dynamics in cardiomyopathy patients

Aplicat embargament des de la data de defensa fins el dia 20/5/2022The main objective of this thesis was to study the variability of the cardiac, respiratory and vascular systems through electrocardiographic (ECG), respiratory flow (FLW) and blood pressure (BP) signals, in patients with idiopathic (IDC), dilated (DCM), or ischemic (ICM) disease. The aim of this work was to introduce new indices that could contribute to characterizing these diseases. With these new indices, we propose methods to classify cardiomyopathy patients (CMP) according to their cardiovascular risk or etiology. In addition, a new tool was proposed to reconstruct artifacts in biomedical signals. From the ECG, BP and FLW signals, different data series were extracted: beat to beat intervals (BBI - ECG), systolic and diastolic blood pressure (SBP and DBP - BP), and breathing duration (TT - FLW). -Firstly, we propose a novel artifact reconstruction method applied to biomedical signals. The reconstruction process makes use of information from neighboring events while maintaining the dynamics of the original signal. The method is based on detecting the cycles and artifacts, identifying the number of cycles to reconstruct, and predicting the cycles used to replace the artifact segments. The reconstruction results showed that most of the artifacts were correctly detected, and physiological cycles were incorrectly detected as artifacts in fewer than 1% of the cases. The second part is related to the cardiac death risk stratification of patients based on their left ventricular ejection (LVEF), using the Poincaré plot analysis, and classified as low (LVEF > 35%) or high (LVEF = 35%) risk. The BBI, SBP, and IT series of 46 CMP patients were applied. The linear discriminant analysis and support vector machines (SVM) classification methods were used. When comparing low risk vs high risk, an accuracy of 98 12% was obtained. Our results suggest that a dysfunction in the vagal activity could prevent the body from correctly maintaining circulatory homeostasis Next, we studied cardio-vascular couplings based on heart rate (HRV) and blood pressure (BPV) variability analyses in order to introduce new indices for noninvasive risk stratification in IDC patients. The ECG and BP signals of 91 IDC patients, and 49 healthy subjects were used. The patients were stratified by their sudden cardiac death risk as: high risk (IDCHR), when after two years the subject either died or suffered complications, or low risk (IDCLR) otherwise. Several indices were extracted from the BBI and SBP, and analyzed using the segmented Poincaré plot analysis, the high-resolution joint symbolic dynamics, and the normalized short time partial directed coherence methods. SVM models were built to classify these patients based on their sudden cardiac death risk. The SVM IDCLR vs IDCHR model achieved 98 9% accuracy with an area under the curve (AUC) of 0.96. Our results suggest that IDCHR patients have decreased HRV and increased BPV compared to both the IDCLR patients and the control subjects, suggesting a decrease in their vagal activity and the compensation of sympathetic activity. Lastly, we analyzed the cardiorespiratory interaction associated with the systems related to ICM and DCM disease. We propose an analysis based on vascular activity as the input and output of the baroreflex response. The aim was to analyze the suitability of cardiorespiratory and vascular interactions for the classification of ICM and DCM patients. We studied 41 CMP patients and 39 healthy subjects. Three new sub-spaces were defined: 'up' for increasing values, 'down' for decreasing values, and 'no change' otherwise, and a three-dimensional representation was created for each sub-space that was characterized statistically and morphologically. The resulting indices were used to classify the patients by their etiology through SVM models achieving 92.7% accuracy for ICM vs DCM patients comparison. The results reflected a more pronounced deterioration of the autonomous regulation in DCM patients.El objetivo de esta tesis fue estudiar la variabilidad de los sistemas cardíaco, respiratorio y vascular a través de señales electrocardiográficas (ECG), de flujo respiratorio (FLW) y de presión arterial (BP), en pacientes con cardiopatía idiopática (IDC). dilatada (DCM) o isquémica (ICM). El objetivo de este trabajo fue introducir nuevos indices que contribuyan a caracterizar estas enfermedades. Proponemos métodos para clasificar pacientes con cardiomiopatía (CMP) de acuerdo con su riesgo cardiovascular o etiología. Además, se propuso una nueva herramienta para reconstruir artefactos en señales biomédicas. De las señales de ECG, BP y FLW, se extrajeron diferentes series temporales: intervalos latido-a-latido (BBI - ECG), presión arterial sistólica y diastólica (SBP y DBP - BP) y la duración de la respiración (TT - FLW). En primer lugar, proponemos un método de reconstrucción de artefactos aplicado a señales biomédicas. El proceso de reconstrucción usa la información de eventos vecinos manteniendo la dinámica de la señal. El método se basa en detectar ciclos y artefactos, en identificar el número de ciclos a reconstruir y en predecir los ciclos utilizados para reemplazar los artefactos. La mayoría de los artefactos probados fueron detectados y reconstruidos correctamente y los ciclos fisiológicos fueron detectados incorrectamente como artefactos en menos del 1% de los casos, La segunda parte está relacionada con la estratificación de riesgo de muerte cardiovascular en función de la fracción de eyección ventricular izquierda (FEVI), mediante el análisis de Poincaré, en bajo (FEVI > 35%) y alto riesgo (FEVI 5 35%). Se utilizaron las series BBI, SBP y TT de 46 pacientes con CMP. Se utilizaron para la clasificación el análisis discriminante lineal y las máquinas de soporte vectorial (SVM). Al comparar los pacientes de bajo y alto riesgo, se obtuvo una exactitud del 98%. Los resultados sugieren la disfunción de la actividad vagal en pacientes de alto riesgo. A continuación, estudiamos los acoplamientos cardiovasculares basados en el análisis de la variabilidad de la frecuencia cardiaca (HRV) y la presión arterial (BPV) para introducir nuevos índices de estratificación de riesgo en pacientes con IDC. Se utilizaron las señales de ECG y BP de 91 pacientes con IDC y 49 sujetos sanos. Los pacientes fueron estratificados por su riesgo cardíaco como: alto riesgo (IDCHR), cuando después de dos años el sujeto murió, o bajo riesgo (IDCLR) en otro caso. Se extrajeron indices utilizando el análisis de Poincaré segmentado, la dinámica simbólica articulada de alta resolución y la coherencia parcial dirigida a corto plazo normalizada. Se construyeron modelos SVM para clasificar a estos pacientes en función de su riesgo cardiovascular. El modelo IDCLR vs IDCHR logró una exactitud del 98% con un área bajo la curva de 0.96. Los resultados sugieren que los pacientes IDCHR tienen sus HRV y BPV disminuidos en comparación con los pacientes IDCLR, lo que sugiere una disminución en su actividad vagal y la compensación de la actividad simpática. Finalmente, analizamos la interacción cardiorrespiratoria asociada con los sistemas relacionados con ICM y DCM. Proponemos un análisis basado en la actividad vascular como entrada y salida de la respuesta baroreflectora. El objetivo fue analizar la capacidad de las interacciones cardiorrespiratorias y vasculares para la clasificación de pacientes con ICM y DCM. Estudiamos 41 pacientes con CMP y 39 sujetos sanos. Se definieron tres sub-espacios: 'up' para valores crecientes, 'down' para los decrecientes, y 'no-change' en otro caso, y se creó una representación tridimensional que se caracterizó estadística y morfológicamente. Los indices resultantes se usaron para clasificar a los pacientes por su etiología con modelos SVM que lograron una exactitud de 92% cuando los pacientes ICM y DCM fueron comparados. Los resultados reflejaron un deterioro más pronunciado de la regulación autónoma en pacientes con DCM.Postprint (published version

Stress-reactivity in the Dutch hypertension and offspring study : an epidemiological approach to the psychophysiology of early hypertension

Blood pressure is constantly and carefully regulated to maintain perfusion of organs and tissues under different conditions. Since the beginning of this century, many mechanisms have been discovered which detect and maintain tissue blood flow and arterial pressure at levels that are optimal for survival during conditions ranging from sleep to exercise. The complexity and the number of the control systems results in a large number of opportunities for dysregulation, which may cause a temporary or sustained uncontrolled rise in blood pressure. Yet, in a majority of hypertensive subjects the cause is still unknown and hypertension is therefore called essential or primary. The pathogenesis of primary hypertension is generally accepted to be based on genetic as well as enviromnental factors and the interaction of genetic susceptibility with environmental factors. Evidence for influences of environmental factors can be found in the relation of blood pressure with diet, obesity, fitness and behavioral stress

NONINVASIVE ASSESSMENT AND MODELING OF DIABETIC CARDIOVASCULAR AUTONOMIC NEUROPATHY

Noninvasive assessment of diabetic cardiovascular autonomic neuropathy (AN): Cardiac and vascular dysfunctions resulting from AN are complications of diabetes, often undiagnosed. Our objectives were to: 1) determine sympathetic and parasympathetic components of compromised blood pressure regulation in patients with polyneuropathy, and 2) rank noninvasive indexes for their sensitivity in diagnosing AN. Continuous 12-lead electrocardiography (ECG), blood pressure (BP), respiration, regional blood flow and bio-impedance were recorded from 12 able-bodied subjects (AB), 7 diabetics without (D0), 7 with possible (D1) and 8 with definite polyneuropathy (D2), during 10 minutes supine control, 30 minutes 70-degree head-up tilt and 5 minutes supine recovery. During the first 3 minutes of tilt, systolic BP decreased in D2 while increased in AB. Parasympathetic control of heart rate, baroreflex sensitivity, and baroreflex effectiveness and sympathetic control of heart rate and vasomotion were reduced in D2, compared with AB. Baroreflex effectiveness index was identified as the most sensitive index to discriminate diabetic AN. Four-dimensional multiscale modeling of ECG indexes of diabetic autonomic neuropathy: QT interval prolongation which predicts long-term mortality in diabetics with AN, is well known. The mechanism of QT interval prolongation is still unknown, but correlation of regional sympathetic denervation of the heart (revealed by cardiac imaging) with QT interval in 12-lead ECG has been proposed. The goal of this study is to 1) reproduce QT interval prolongation seen in diabetics, and 2) develop a computer model to link QT interval prolongation to regional cardiac sympathetic denervation at the cellular level. From the 12-lead ECG acquired in the study above, heart rate-corrected QT interval (QTc) was computed and a reduced ionic whole heart mathematical model was constructed. Twelve-lead ECG was produced as a forward solution from an equivalent cardiac source. Different patterns of regional denervation in cardiac images of diabetic patients guided the simulation of pathological changes. Minimum QTc interval of lateral leads tended to be longer in D2 than in AB. Prolonging action potential duration in the basal septal region in the model produced ECG and QT interval similar to that of D2 subjects, suggesting sympathetic denervation in this region in patients with definite neuropathy