Age-related diastolic dysfunction occurs in the absence of disease in men and mice, limiting maximum oxygen consumption and increasing congestive heart failure risk. The pathogenesis of age-related diastolic dysfunction is unknown, but two hypotheses have emerged: (1) Age-related Arterial Stiffening (AS) increases cardiac work, stimulating hypertrophy which results in diastolic dysfunction; (2) Progressive myocyte death (apoptosis and/or necrosis) stimulates hypertrophy in the remaining myocytes. We will address the roles of these two processes in the genesis of age-related diastolic dysfunction in control and transgenic mice. Age-related AS and diastolic dysfunction occur in the 30 month B6D2 mouse. Our data suggest a role for arterial smooth muscle tone rather than structural proteins changes including glucose-mediated cross-linking.
Our specific aims are: (1) to measure effects of genetically modifying individual components of AS (vascular tone and structural proteins) with age in the mouse on the development of diastolic dysfunction using, a) smooth muscle a-actin null mice (little vascular smooth muscle tone), b) Glucose Transporter (Glut 4) overexpressor (low serum glucose), c) matrix gla +1- (accelerated vascular calcification); (2) to measure effects of inhibiting myocyte death on the development of diastolic dysfunction with a) cardiac-specific Bcl-2 overexpressor (decreased apoptosis), and b) HSP-70 overexpressor (increased resistance to ischemia). We will perform serial non-invasive studies over the mouse lifespan measuring AS and cardiac function in situ, invasive studies of AS (and aortic impedance) and cardiac function, and terminal studies of apoptosis, myocyte size and function, calcium uptake and gene and protein expression for the """"""""aging phenotype."""""""" An elucidation of the genesis of age-associated diastolic dysfunction will be accomplished by information provided by the individual models. With this knowledge, preventative approaches can then be developed for the normal mouse and human.
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| Hartley, Craig J; Reddy, Anilkumar K; Taffet, George E (2008) In-vitro evaluation of sensors and amplifiers to measure left ventricular pressure in mice. Conf Proc IEEE Eng Med Biol Soc 2008:965-8 |
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