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

Insights into cardiac remodelling by multi-modal magnetic resonance imaging and spectroscopy

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Risk assessment in patients with an acute ST-elevation myocardial infarction

ST-elevation myocardial infarction (STEMI) is one of the leading causes of mortality and morbidity worldwide. While the survival after acute STEMI has considerably improved, mortality rate still remains high, especially in high-risk patients. Survival after acute STEMI is influenced by clinical characteristics such as age as well as the presence of comorbidities. However, during emergency care increasing access to tools such as the electrocardiogram, chest x-ray and echocardiography can provide additional information helping to further risk stratify patients. In the invasive setting, this can also include coronary angiography, invasive hemodynamic recordings and angiographic assessments of coronary flow and myocardial perfusion. We outline the common investigations used in STEMI and their role in risk assessment of patients with an acute STEMI

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 130, July 1974

This special bibliography lists 291 reports, articles, and other documents introduced into the NASA scientific and technical information system in June 1974

Ultrasound studies of dilated cardiomyopathy in Dobermanns and English cocker spaniels

The basic hypothesis tested in this study was that dogs with dilated cardiomyopathy have abnormal ventricular function, and that this can be detected noninvasively using M-mode, two-dimensional (2D), and Doppler echocardiography, and also by measuring myocardial ultrasonic integrated backscatter. An additional hypothesis was that different breeds of dogs affected with DCM have a different clinical course, and that differences in ventricular function between these breeds can be detected by echocardiography or integrated backscatter measurements that might account for the different prognosisThe aims of this study therefore were (1) to identify echocardiographic variables that distinguished normal dogs from dogs with DCM; (2) to identify differences in ventricular function using echocardiography between Dobermanns and English cocker spaniels with DCM; and (3) to measure ultrasonic integrated backscatter in normal dogs and in Dobermanns and Cocker spaniels with DCM.In this group of Dobermanns, median survival time was 98 days (range 16 - 508 days), whereas median survival in the cocker spaniels was 512 days (range 51 to >1388 days), with 6/11 still alive at the time of writing (p < 0.002). All the measured M-mode variables differed significantly between the normal dogs and the dogs with DCM. Compared with the Dobermanns, the cocker spaniels had significantly increased LV free wall thickening and increased LV diastolic diameter when indexed to body surface area. All the 2D echocardiographic variables were significantly different between the normal dogs and dogs with DCM when corrected for body size, but there were no significant differences between Dobermanns and cocker spaniels. Significant differences were found between normal and DCM dogs in some but not all of the Doppler echocardiographic variables. Cocker spaniels had higher mitral A wave velocities than the normal dogs, and decreased mitral E/A ratios compared with both the other groups. Dobermanns had shorter isovolumic relaxation times than the other groupsIn the second part of this study, measurements were made of ultrasonic integrated backscatter in selected regions of the left ventricle in normal dogs and dogs with DCM. Ultrasonic integrated backscatter is a measurement of the power of the ultrasound signal returned from the myocardium to the transducer. This backscattered signal reflects basic tissue properties, and exhibits dynamic variation with contractile function that may represent fundamental alterations in the shape, size and distribution of scatterers within the myocardium. Consistent cyclic variation in integrated backscatter was observed in the LV free wall and septum of the normal dogs, but this pattern was not consistently seen in the DCM dogs. Differences were not seen between the Dobermanns and cocker spaniels, although the number of cocker spaniels measured was small.In conclusion, the DCM dogs had evidence of markedly reduced systolic function compared with the normal dogs. The affected dogs had left atrial and left ventricular dilation with thinner left ventricular walls. Although there was little evidence of any difference in systolic function between the two affected breeds, there was evidence of different diastolic function, with a tendency for Dobermanns to show a restrictive pattern of transmitral filling, and cocker spaniels to show evidence of delayed relaxation. The different pattern of diastolic dysfunction in the two breeds is consistent with the prognostic value ascribed to transmitral flow patterns in human DCM patients: delayed relaxation patterns have been associated with improved survival times in man. Reduced cyclic variation of ultrasonic integrated backscatter was also seen in the dogs affected with DCM, although no differences were found between the two affected breeds

Right Ventricular Dysfunction in the R6/2 Transgenic Mouse Model of Huntington's Disease is Unmasked by Dobutamine

Background: Increasingly, evidence from studies in both animal models and patients suggests that cardiovascular dysfunction is important in HD. Previous studies measuring function of the left ventricle (LV) in the R6/2 mouse model have found a clear cardiac abnormality, albeit with preserved LV systolic function. It was hypothesized that an impairment of RV function might play a role in this condition via mechanisms of ventricular interdependence.Objective: To investigate RV function in the R6/2 mouse model of Huntington's disease (HD).Methods: Cardiac cine- magnetic resonance imaging (MRI) was used to determine functional parameters in R6/2 mice. In a first experiment, these parameters were derived longitudinally to determine deterioration of cardiac function with disease progression. A second experiment compared the response to a stress test (using dobutamine) of wildtype and early-symptomatic R6/2 mice. Results: There was progressive deterioration of RV systolic function with age in R6/2 mice. Furthermore, beta-adrenergic stimulation with dobutamine revealed RV dysfunction in R6/2 mice before any overt symptoms of the disease were apparent.Conclusions: This work adds to accumulating evidence of cardiovascular dysfunction in R6/2 mice, describing for the first time the involvement of the right ventricle. Cardiovascular dysfunction should be considered, both when treatment strategies are being designed, and when searching for biomarkers for HD

First-pass perfusion CMR two days after infarction predicts severity of functional impairment six weeks later in the rat heart

<p>Abstract</p> <p>Background</p> <p>In humans, dynamic contrast CMR of the first pass of a bolus infusion of Gadolinium-based contrast agent has become a standard technique to identify under-perfused regions of the heart and can accurately demonstrate the severity of myocardial infarction. Despite the clinical importance of this method, it has rarely been applied in small animal models of cardiac disease. In order to identify perfusion delays in the infarcted rat heart, here we present a method in which a T₁weighted MR image has been acquired during each cardiac cycle.</p> <p>Methods and results</p> <p>In isolated perfused rat hearts, contrast agent infusion gave uniform signal enhancement throughout the myocardium. Occlusion of the left anterior descending coronary artery significantly reduced the rate of signal enhancement in anterior regions of the heart, demonstrating that the first-pass method was sensitive to perfusion deficits. <it>In vivo </it>measurements of myocardial morphology, function, perfusion and viability were made at 2 and 8 days after infarction. Morphology and function were further assessed using cine-MRI at 42 days. The perfusion delay was larger in rat hearts that went on to develop greater functional impairment, demonstrating that first-pass CMR can be used as an early indicator of infarct severity. First-pass CMR at 2 and 8 days following infarction better predicted outcome than cardiac ejection fraction, end diastolic volume or end systolic volume.</p> <p>Conclusion</p> <p>First-pass CMR provides a predictive measure of the severity of myocardial impairment caused by infarction in a rodent model of heart failure.</p

Metabolic interventions in heart failure

De kans dat iemand hartfalen ontwikkelt tijdens zijn leven is bijna 1 op 3. De afgelopen jaren is de therapie voor hartfalen verbeterd. De prognose van hartfalen patiënten is vaak slechter dan voor patiënten met kanker. Het hart is één van de grootverbruikers van energie in het lichaam en er wordt gedacht dat verstoringen in de het energie metabolisme hartfalen kunnen veroorzaken. In dit proefschrift onderzochten we verschillende metabole interventies in hartziekten. In deel één onderzochten we klinische aspecten, waaronder de plaats van β-blockers die verschillende metabole bijwerkingen hebben. Behandeling met β-blockers in laag risico patiënten na een bypass operatie was niet geassocieerd met een vermindering van hartziekten. In deel twee onderzochten we de rol van A kinase interacting protein 1 (AKIP1) op veranderingen in het hart bij acute en chronische belasting. Eerder onderzoek in gekweekte hartspiercellen liet zien dat AKIP1 mogelijk geschikt is als aangrijpingspunt voor hartfalen-therapie. Met genetische modificatie zorgden we voor een 40-voudige overexpressie van AKIP1 in hartspiercellen van muizen. In tegenstelling tot onze verwachting had deze toename van AKIP1 geen effect op de hartfunctie wanneer muizen werden blootgesteld aan modellen van verschillende oorzaken voor hartfalen. We zagen wel dat AKIP1 het hart beschermde na een acuut hartinfarct door de afsterving van hartspiercellen tegen te gaan. Deze beschermende werking bleek te berusten op stabilisatie van mitochondriën, de energiefabrieken van het hart. Deze bevindingen suggereren dat AKIP1 verder onderzocht zou moeten worden als potentieel aangrijpingspunt voor therapie bij een hartinfarct

Cardiac dysfunction in the ZDF rat: Possible mechanisms and benefits of exercise

Cardiovascular disease has resulted in an increased risk of premature deaths for the 104 million Americans with prediabetes or diabetes and has accounted for approximately 65% of total diabetic deaths annually. Clinical manifestations of diabetic heart disease include left ventricular hypertrophy, diastolic and systolic dysfunction, and diabetic cardiac autonomic neuropathy, which are regularly observed at varying severities in persons with type 2 diabetes. The Zucker diabetic fatty (ZDF) rat has shown promise as a model of diabetic heart disease since it resembles the blending of cardiac diseases seen in humans and as such can be utilized to investigate diabetic heart disease and therapeutic interventions. We chose to investigate the impact of exercise on diabetic heart disease in the ZDF rat, and to explore a novel mechanism. The objectives of the dissertation were to investigate the cardiac dysfunction in the ZDF model, determine whether aerobic exercise training can reverse electrocardiographic (ECG) and hemodynamic changes induced by diabetes, and identify whether cardiac edema may be one of the factors contributing to diabetic heart disease and a possible target of exercise. Myocardial edema is an imbalance between vascular permeability, lymphatic vessels, lymph flow, and cardiac function. It is unknown if diabetes causes myocardial edema. Little is known about the impact of diabetes on the lymphatic system and its receptors, vascular endothelial growth factor receptor 3 (VEGFR-3) and lymphatic endothelial receptor 1(LYVE-1). These receptors are responsible for the uptake of their respective ligands, VEGF-C and hyaluronan. Each receptor's expression is regulated by prospero homeobox protein 1(PROX-1), which is the master switch for the lymphangiogenesis. Myocardial fluid imbalances have been implicated in the fibrosis and hypertrophy associated with common cardiovascular diseases, which makes edema a suitable target for possible interventions. Diabetes in the ZDF rat caused crucial changes in R wave amplitudes (p<0.001), heart rate variability (p<0.01), QT intervals (p<0.001) and QTc intervals (p<0.001). R wave amplitude augmentation in sedentary diabetic rats from baseline to termination was ameliorated by exercise, resulting in R wave amplitude changes in exercised diabetic rats similar to control rats. Of these changes, aerobic exercise training was only able to correct R wave amplitude changes. In addition, exercise had beneficial effects in this diabetic rat model with regards to ECG correlates of left ventricular mass. Of the 24 hemodynamic parameters tested, 15 were negatively affected by diabetes. The debility of diabetic heart disease was evident in the diastolic filling, isovolumic contraction, ejection, and isovolumic relaxation phases. Importantly, exercise training restored 13 of the 15 hemodynamic parameters affected by diabetes. However, we did not observe differences in left ventricular weights, a direct measure of myocardial edema, or alterations in the levels of VEGF-C, VEGFR-3, LYVE-1, or hyaluronan. We were able to observe systemic differences in plasma interleukin (IL)-2 levels, reductions in dP/dtmax, and differences in PROX-1 protein levels and DNA binding activity that were suggestive of the presence of myocardial edema in the ZDF rat. However, these alterations are indirect measures of myocardial edema, therefore we were unable to conclude in the 19 week old ZDF rat if myocardial edema exists and plays a role in diabetic heart disease