The long range objective of the studies proposed in this application is to elucidate the quantitative contributions of the specific passive and active properties of both left atrium (LA) and left ventricle (LV) to the indices of diastolic function. This information will establish a physiological and biophysical basis for the interpretation of clinical data. We propose to study anesthetized open-chest dogs with the experimental methods unique to this laboratory: 1) LV systolic volume clamping; 2) LV diastolic volume clamping; and 3) LA controlled filling. The first and second are accomplished by a custom designed computer controlled aortic clamp and prosthetic mitral valve capable of controlling the onset and the cessation of ventricular ejection and filling, thus clamping the LV at different volumes. The third is achieved by controlling pulmonary venous flow with a computer controlled pulmonary venous clamp. These techniques, combined with the measurements of flow (ultrasonic and electromagnetic), pressure (micromanometer), LV dimensions (ultrasonic , LV volume (conductance catheter), and with echocardiographic and Doppler velocity measurements, are capable of providing new and important information regarding the mechanics of diastole and the dynamics of filling. We will quantify the changes in the LV and LA parameters during normal physiological variations, as well as during acute interventions: myocardial stunning and ischemia, atrial fibrillation, mitral stenosis and mitral regurgitation. The LV and LA passive pressure-volume relationships will be described with emphasis on the equilibrium volume, the volume parameter based on our new description of the diastolic pressure-volume relation. We will characterize the following specific mechanical and functional properties of the LV and LA:1. passive elastic (tensile and compressive), viscoelastic and geometrical LV properties, LV relaxation and the role of the mitral valve apparatus in determining LV chamber properties; 2. LA reservoir, conduit and pump functions. Data will be utilized to address the following specific questions: Does inotropic state, heart rate or afterload influence LV diastolic elastic restoring and viscous forces? Is systolic function influenced independently by both end-diastolic volume (fiber length) and process of filling (fiber lengthening)? What is the effect of afterload increase on the LV relaxation and filling; What is the role of elastic recoil forces and diastolic LV shape in creating regional pressure differences within the ventricle? What diastolic properties of the LV are influenced by the mitral valve apparatus? How are the end-systolic and end-diastolic P-V relations normalized to account for difference in heart size? What is the effect of acute myocardial ischemia and stunning on LV elastic recoil, viscous properties and relaxation? How do HR, LA volume and LA compliance affect LA function during LV filling? What are the contributions of different LA functions during atrial fibrillation, in mitral regurgitation and mitral stenosis? We will also incorporate the findings of the physiological studies into a computational model to provide a comprehensive analysis of the relations between the mechanical properties of the LV and LA, and the characteristics of diastolic filling.
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