Kinematic Modeling of the Determinants of Diastolic Function

Multiple modalities are routinely used in clinical cardiology to determine cardiovascular function, and many of the indexes derived from these modalities are causally interconnected. A correlative approach to cardiovascular function however, where indexes are correlated to disease presence and progression, fails to fully capitalize on the information content of the indexes. Causal quantitative modeling of cardiovascular physiology on the other hand offers a predictive rather than accommodative approach to cardiovascular function determination. In this work we apply a kinematic modeling approach to understanding diastolic function. We discuss novel insights related to the physiological determinants of diastolic function, and define novel causal indexes of diastolic function that go beyond the limitations of current established clinical indexes. Diastolic function is typically characterized by physiologists and cardiologists as being determined by the interplay between chamber stiffness, chamber relaxation/viscoelasticity, and chamber filling volume or load. In this work we provide kinematic modeling based analysis of each of these clinical diastolic function determinants. Considering the kinematic elastic (stiffness) components of filling, we argue for the universality of diastolic suction and define a novel in-vivo equilibrium volume. Application of this novel equilibrium volume in the clinical setting results in a novel approach to determination of global chamber stiffness. Considering the viscoelastic components of filling, we demonstrate the limitations associated with ignoring viscoelastic effects, an assumption often made in the clinical setting. We extend the viscoelastic component of filling into the invasive hemodynamic domain, and demonstrate the causal link between invasively recorded LV pressure and noninvasively recorded transmitral flow by describing a method for extracting flow contours from pressure signals alone. Finally, in considering load, we solve the problem of load dependence in diastolic function analysis. Indeed all traditional clinical indexes of diastolic function are load dependent, and therefore are imperfect indexes of intrinsic diastolic function. Applying kinematic modeling, we derive a load independent index of diastolic function. Validation involves showing that the index is indeed load-independent and can differentiate between control and diastolic dysfunction states. We apply this novel analysis to derive surrogates for filling pressure, and generalize the kinematic modeling approach to the analysis of isovolumic relaxation. To aid widespread adoption of the load independent index, we derive and validate simplified expressions for model-based physiological parameters of diastolic function. Our goal is to provide a causal approach to cardiovascular function analysis based on how things move, to explain prior phenomenological observations of others under a single causal paradigm, to discover `new physiology\u27, facilitate the discovery of more robust indexes of cardiovascular function, and provide a means for widespread adoption of the kinematic modeling approach suitable for the general clinical setting

Magnetic Resonance Imaging of Neural and Pulmonary Vascular Function: A Dissertation

Magnetic resonance imaging (MRI) has emerged as the imaging modality of choice in a wide variety experimental and clinical applications. In this dissertation, I will describe novel MRI techniques for the characterization of neural and pulmonary vascular function in preclinical models of disease. In the first part of this dissertation, experimental results will be presented comparing the identification of ischemic lesions in experimental stroke using dynamic susceptibility contrast (DSC) and a well validated arterial spin labeling (ASL). We show that DSC measurements of an index of cerebral blood flow are sensitive to ischemia, treatment, and stroke subregions. Further, we derived a threshold of cerebral blood flow for ischemia as measured by DSC. Finally, we show that ischemic lesion volumes as defined by DSC are comparable to those defined by ASL. In the second part of this dissertation, a methodology of visualizing clots in experimental animal models of stroke is presented. Clots were rendered visible by MRI through the addition of a gadolinium based contrast agent during formation. Modified clots were used to induce an experimental embolic middle cerebral artery occlusion. Clots in the cerebral vasculature were visualized in vivousing MRI. Further, the efficacy of recombinant tissue plasminogen activator (r-tPA) and the combination of r-tPA and recombinant annexin-2 (rA2) was characterized by clot visualization during lysis. In the third part of this dissertation, we present results of the application of hyperpolarized helium (HP-He) in the characterization of new model of experimental pulmonary ischemia. The longitudinal relaxation time of HP-He is sensitive to the presence of paramagnetic oxygen. During ischemia, oxygen exchange from the airspaces of the lungs to the capillaries is hindered resulting in increased alveolar oxygen content which resulted in the shortening of the HP-He longitudinal relaxation time. Results of measurements of the HP-He relaxation time in both normal and ischemic animals are presented. In the final part of this dissertation, I will present results of a new method to measure pulmonary blood volume (PBV) using proton based MRI. A T1 weighted, inversion recovery spin echo sequence with cardiac and respiratory gating was developed to measure the changes in signal intensity of lung parenchyma before and after the injection of a long acting intravascular contrast agent. PBV is related to the signal change in the lung parenchyma and blood before and after contrast agent. We validate our method using a model of hypoxic pulmonary vasoconstriction in rats

Magnetic Resonance Imaging of Neural and Pulmonary Vascular Function

Magnetic resonance imaging (MRI) has emerged as the imaging modality of choice in a wide variety experimental and clinical applications. In this dissertation, I will describe novel MRI techniques for the characterization of neural and pulmonary vascular function in preclinical models of disease. In the first part of this dissertation, experimental results will be presented comparing the identification of ischemic lesions in experimental stroke using dynamic susceptibility contrast (DSC) and a well validated arterial spin labeling (ASL). We show that DSC measurements of an index of cerebral blood flow are sensitive to ischemia, treatment, and stroke subregions. Further, we derived a threshold of cerebral blood flow for ischemia as measured by DSC. Finally, we show that ischemic lesion volumes as defined by DSC are comparable to those defined by ASL. In the second part of this dissertation, a methodology of visualizing clots in experimental animal models of stroke is presented. Clots were rendered visible by MRI through the addition of a gadolinium based contrast agent during formation. Modified clots were used to induce an experimental embolic middle cerebral artery occlusion. Clots in the cerebral vasculature were visualized in vivo using MRI. Further, the efficacy of recombinant tissue plasminogen activator (r-tPA) and the combination of r-tPA and recombinant annexin-2 (rA2) was characterized by clot visualization during lysis. In the third part of this dissertation, we present results of the application of hyperpolarized helium (HP-He) in the characterization of new model of experimental pulmonary ischemia. The longitudinal relaxation time of HP-He is sensitive to the presence of paramagnetic oxygen. During ischemia, oxygen exchange from the airspaces of the lungs to the capillaries is hindered resulting in increased alveolar oxygen content which resulted in the shortening of the HP-He longitudinal relaxation time. Results of measurements of the HP-He relaxation time in both normal and ischemic animals are presented. In the final part of this dissertation, I will present results of a new method to measure pulmonary blood volume (PBV) using proton based MRI. A T1 weighted, inversion recovery spin echo sequence with cardiac and respiratory gating was developed to measure the changes in signal intensity of lung parenchyma before and after the injection of a long acting intravascular contrast agent. PBV is related to the signal change in the lung parenchyma and blood before and after contrast agent. We validate our method using a model of hypoxic pulmonary vasoconstriction in rats

Blood volume expansion following supramaximal exercise : occurrence and contribution to maximal oxygen uptake

Previously published research using various types of exercise has shown that central hemodynamic factors such as blood volume (BV) and maximal cardiac output (Qmax) are of large importance in the mediation of improvements in VO2max. Whether this is true for adaptations induced by sprint-interval training (SIT) is unclear. Three experimental studies were carried out investigating the occurrence and contribution of hypervolemia to SIT-induced improvements in VO2max. Forty-eight study participants performed the interventions. Significant increases in BV and Qmax were observed after the 6-week training interventions in conjunction with the expected increases in VO2max (Paper Ⅰ and Ⅱ). The hypervolemic response was shown not only to be associated with the increase in VO2max but also to be the primary mediator of it, as demonstrated by the elimination of the exercise-induced increases in VO2max when BV was normalized to pre-intervention levels by phlebotomy. This demonstrates that central adaptations are paramount for the SIT-induced increase in VO2max. In addition, systemic oxygen extraction increased as a consequence of decreased venous oxygen content during maximal exercise (Paper Ⅱ). This suggests that both peripheral and central factors are responsible for the adaptations in VO2max observed with SIT and refutes previous theories proposing that the increase in VO2max was mediated primarily by peripheral adaptations. Metabolic and intravascular perturbation has been proposed as an important stimuli for exercise adaptation. Since SIT is one of the most intense forms of exercise available the immediate effects after SIT are interesting in order to understand how such small amounts of exercise can lead to cardiovascular adaptations usually associated with more prolonged types of exercise. Acute effects of one session of SIT caused pronounced disturbance of the intravascular milieu and perturbations of the muscle metabolism. The variable that correlated best with changes in plasma and muscle volume was glucose-6-phosphate (Paper Ⅲ). Similarly, plasma osmolality and plasma concentration of arginine and citrulline was shown to be the best predictors of improvements in VO2max after a training intervention of 6-weeks (Paper Ⅳ). Overall, the present work demonstrates that brief supramaximal exercise leads to improvements in VO2max and that these improvements are mediated mainly by central adaptations. Peripheral adaptations occur concurrently but cannot alone explain the improvements in VO2max, as previously hypothesized. The data presented show that both central and peripheral adaptations are involved in the improvement of VO2max after an SIT intervention

The prognostic value of cardiopulmonary exercise testing in interstitial lung disease:a systematic review

The heterogeneity of interstitial lung disease (ILD) results in prognostic uncertainty concerning end of life discussions and optimal timing for transplantation. Effective prognostic markers and prediction models are needed. Cardio-Pulmonary Exercise Testing (CPET) provides a comprehensive assessment of the physiological changes in the respiratory, cardiovascular, and musculoskeletal systems in a controlled laboratory environment. It has shown promise as a prognostic factor for other chronic respiratory conditions. We sought to evaluate the prognostic value of CPET in predicting outcomes in longitudinal studies of ILD . Medline, Embase and Cochrane systematic review databases were used to identify studies reporting prognostic value of CPET in predicting outcomes in longitudinal studies of ILD. Study quality was assessed using the Quality in Prognosis Study risk of bias tool.Thirteen studies were included that reported the prognostic value of CPET in ILD. All studies reported at least one CPET parameter predicting clinical outcomes in ILD; with survival being the principle outcome assessed. Maximum oxygen consumption, reduced ventilatory efficiency and exercise induced hypoxaemia were all reported to have prognostic value in ILD. Issues with study design (primarily due to inherent problems of retrospective studies, patient selection and presentation of numerous CPET parameters), insufficient adjustment for important confounders and inadequate statistical analyses limits the strength of conclusions that can be drawn at this stage.There is insufficient evidence to confirm the value of CPET in facilitating ‘real-world’ clinical decisions in ILD. Additional prospective studies are required to validate the putative prognostic associations reported in previous studies in carefully phenotyped patient populations. <br/

Quantitative Evaluation of Pulmonary Emphysema Using Magnetic Resonance Imaging and x-ray Computed Tomography

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality affecting at least 600 million people worldwide. The most widely used clinical measurements of lung function such as spirometry and plethysmography are generally accepted for diagnosis and monitoring of the disease. However, these tests provide only global measures of lung function and they are insensitive to early disease changes. Imaging tools that are currently available have the potential to provide regional information about lung structure and function but at present are mainly used for qualitative assessment of disease and disease progression. In this thesis, we focused on the application of quantitative measurements of lung structure derived from 1H magnetic resonance imaging (MRI) and high resolution computed tomography (CT) in subjects diagnosed with COPD by a physician. Our results showed that significant and moderately strong relationship exists between 1H signal intensity (SI) and 3He apparent diffusion coefficient (ADC), as well as between 1H SI and CT measurements of emphysema. This suggests that these imaging methods may be quantifying the same tissue changes in COPD, and that pulmonary 1H SI may be used effectively to monitor emphysema as a complement to CT and noble gas MRI. Additionally, our results showed that objective multi-threshold analysis of CT images for emphysema scoring that takes into account the frequency distribution of each Hounsfield unit (HU) threshold was effective in correctly classifying the patient into COPD and healthy subgroups. Finally, we found a significant correlation between whole lung average subjective and objective emphysema scores with high inter-observer agreement. It is concluded that 1H MRI and high resolution CT can be used to quantitatively evaluate lung tissue alterations in COPD subjects

Automated Determination of Arterial Input Function Areas in Perfusion Analysis

Perfusion in biological system refers to capillary-level blood flow in tissues, and is a critical parameter used for detecting physiological changes. Medical imaging provides an effective way to measure tissue perfusion. Quantitative analysis of perfusion studies requires the accurate determination of the arterial input function (AIF), which describes the delivery of intravascular tracers to tissues. Automating the process of finding the AIF can save operating time, remove the inter-operator variability, and correct the errors in the presence of the dispersion of the arterial system. Even though several methods are currently developed for automatically extracting an AIF, they are specific to a single modality and particular to a certain tissue. In this thesis, we developed an algorithm to automatically determine an AIF by classifying the characteristic parameters of image pixels' dynamic evaluation curves between blood feeding areas and tissues. This automated AIF determination can be used to facilitate the generation of parametric maps for perfusion studies based on various imaging modalities and covering a variety of tissues. Automatic AIF determination was accomplished by extracting characteristic parameters such as maximum slope, maximum enhancement, time to peak, time to wash-out, and wash-out slope. Multi-dimensional data containing the characteristic parameters were converted and reduced into two-dimensional (2-D) representations, which were presented as a plurality of 2-D plots. Then physiological phases were localized within the simplified representations. Automated segmentation of non-AIF tissues and determination of AIF areas were accomplished by automatically finding peaks and valleys of each physiological phase on the plurality of 2-D plots. The algorithm was tested in CT myocardial perfusion studies, in which a pig was used as a model of myocardial ischemia and perfusion. PET gastrointestinal (GI) perfusion studies were performed using this algorithm, in which GI perfusion was evaluated when cardiac outputs were controlled with four modes. This automated AIF determination study was compared with manual selection of AIF in PET imaging and microsphere studies to assess the effectiveness of this algorithm. In the CT myocardial perfusion study, the perfusion of infarcted myocardium was significantly lower than that of non-infarcted areas and lower than that when it was normal. In the PET abdominal perfusion study, PET imaging data gives lower value of standard deviation relative to the mean than that in microsphere results. In the manual AIF selection study, a slight change in selecting the AIF region caused a big influence on the result. On the contrary, the automated AIF selection remains consistent in the entire study and reduces inter-operator variation. A conclusion was made that this technique is applicable to several imaging modalities, such as PET, CT and MRI, and is effective on many tissues. In addition, this algorithm is straightforward and provides consistent results. More importantly, this automated AIF determination technique replaces the conventional spatial classification method with the functional classification method, taking more physiological considerations and explanations involved

Functional Imaging of the Lungs using Magnetic Resonance Imaging of Inert Fluorinated Gases

Fluorine-19 (19F) magnetic resonance imaging (MRI) of the lungs using inhaled inert fluorinated gases can potentially provide high quality anatomical and functional images of the lungs. This technique is able to visualize the distribution of the inhaled gas, similar to hyperpolarized (HP) helium-3 (3He) and xenon-129 (129Xe) MRI. Inert fluorinated gases have the advantages of being nontoxic, abundant, and inexpensive compared to HP gases. Due to the high gyromagnetic ratio of 19F, there is sufficient thermally polarized signal for imaging, and averaging within a single breath-hold is possible due to short longitudinal relaxation times. Since inert fluorinated gases do not need to be hyperpolarized prior to their use in MRI, this eliminates the need for an expensive polarizer and expensive isotopes. Inert fluorinated gas MRI of the lungs has been studied extensively in animals since the 1980s, and more recently in healthy volunteers and patients with lung diseases. This thesis focused on the development of static breath-hold inert fluorinated gas MR imaging techniques, as well as the development functional imaging biomarkers in humans and animal models of pulmonary disease. Optimized ultrashort echo time (UTE) 19F MR imaging was performed in healthy volunteers, and images from different gas breathing techniques were quantitatively compared. 19F UTE MR imaging was then quantitatively compared to 19F gradient echo imaging in both healthy volunteers and in a resolution phantom. A preliminary comparison to HP 3He MR imaging is also presented, along with preliminary 19F measurements of the apparent diffusion coefficient (ADC) and iv gravitational gradients of ventilation in healthy volunteers. The potential of inert fluorinated gas MRI in detecting pulmonary diseases was further explored by performing ventilation mapping in animal models of inflammation and fibrosis. Overall, interest in pulmonary 19F MRI of inert fluorinated gases is increasing, and numerous sites around the world are now interested in developing this technique. This work may help to demonstrate that inert fluorinated gas MRI has the potential to be a viable clinical imaging modality that can provide useful information for the diagnosis and management of chronic respiratory diseases

Protein-carbohydrate and protein-protein interactions: using models to better understand and predict specific molecular recognition

Any molecular recognition event results in a change in the free energy of the system. The extent of this change is related to the association constant, such that the more negative the free energy change is, the tighter the interaction between receptor and ligand. Protein-carbohydrate interactions play a critical role in signal transduction, innate immunity, and metabolism. Modeling these interactions is somewhat complicated by the inherent flexibility of carbohydrates as well as their relatively large number of functional groups. An empirical scoring function for docking carbohydrates to proteins, specifically tailored to predict both the correct binding orientation and free energy of binding of the carbohydrate-ligand/protein-receptor complex, will be presented. This new scoring function can predict free energies of binding to within 1.1 kcal/mol residual standard error, a definite improvement over existing scoring functions that result in standard errors well over 2 kcal/mol. Application of automated docking methodology to determine carbohydrate recognition specificity of the C-type lectin, human surfactant protein D, will also be presented. In the second part of the thesis, the role of pi-stacking interactions (e.g. between Tyr side chains) in stabilizing protein folds will be discussed. A 17-residue peptide derived from the naturally occurring anti-microbial peptide tachyplesin I was investigated using NMR spectroscopy. NOE cross-peaks were observed, confirming the existence of this interaction in solution. In the final part of the thesis, a quantitative NMR investigation into the self-association behavior of the regulatory domains of several Tec family member kinases will be presented. Of particular interest, self-association within Bruton\u27s tyrosine kinase (Btk) regulatory domains occurs through the formation of an asymmetric homodimer. Together this work demonstrates the importance of rigorous biophysical characterization of biomolecular recognition events and the interdependence of computational modeling and experimentation