Biomechanics of Central Artery Stiffening and its Role in Cardiovascular Disease Progression

Central artery stiffness has emerged over the past 15 years as a clinically significant indicator of cardiovascular function and initiator of disease. Loss of elastic fiber integrity is one of the primary contributors to increased arterial stiffening in normal aging and in pathologic conditions such as hypertension and aortic aneurysms. Competent elastic fibers endow the arterial wall with the compliance and resilience that are fundamental to the primary mechanical function of central arteries in all vertebrates. That is, by enabling elastic energy to be stored in the wall during systole and then to be used to work on the blood during diastole, elastic fibers decrease ventricular workload and augment distal blood flow within the pulsatile circulatory system. This dissertation examines the effects of altered elastic fiber integrity on central artery biomechanical function, systemic hemodynamic, and left ventricular function.;Blood vessels in vivo are stretched axially due to somatic growth and are distended circumferentially under the action of blood pressure. Therefore, we used consistent experimental methods for biaxial biomechanical testing in vitro, with the goal of measuring the functionality of excised arterial samples. In the analysis of biaxial data, we found it to be advantageous to use a four-fiber family constitutive relation for quantifying passive arterial behaviors, to employ the elastic stored energy as a convenient scalar metric of the associated material stiffness, and to adopt appropriate linearizations of the nonlinear, anisotropic biomechanical relations. Such methods were used to compare behaviors from common carotid arteries having graded degrees of elastic fiber integrity, caused by either genetic modifications or acute enzymatic degradation. Among the genetically modified models, carotids from mice lacking fibulin-5 - a glycoprotein involved in the regulation of elastic fiber assembly during development - showed the most severe biomechanical phenotypes. Hence, we explored regional variations in biomechanical properties due to loss of fibulin-5 by comparing five central arteries: the ascending thoracic aorta, descending thoracic aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and one common carotid artery. Our primary finding was that fibulin-5 null arteries maintain the intrinsic material stiffness nearly constant, while showing a marked decrease in elastic energy storage in all regions. At the microstructural level, such loss of function was mirrored by a generalized fragmentation of elastic fibers and a parallel increase in collagen content. Subsequently, we performed physiological measurements to assess vascular and cardiac function in wild-type and fibulin-5 null mice. We found that loss of elastic fiber integrity causes a loss of ascending aortic function, increased central pulse pressure, and increased pulse wave velocity. Despite some differences between male and female mice, diastolic function was significantly decreased in all fibulin-5 null animals, consistent with an accelerated aging phenotype.;In summary, the fundamental function of central arteries is to store elastic energy during cardiac systole and return it as work on. the blood during diastole. In this dissertation, we showed how loss of this key arterial feature - clinically referred to as increased arterial stiffness - increases the risk of diastolic heart failure, by altering systemic hemodynamics and ventricular-vascular mechanical coupling.