I. Patterns and Determinants of Arterial Aging: A. Longitudinal insight into the complex nature of arterial aging Findings from the Baltimore Longitudinal Study on Aging (BLSA) revealed a non-linear, longitudinal increase in pulse wave velocity (PWV) with aging (AlGhatrif et al., 2013). Analysis of longitudinal data from SardiNIA project showed similar results, but in addition it showed an interesting separation between the longitudinal trajectories of PWV and SBP in men with advancing age (Scuteri 2014); To test the hypothesis that aortic dilatation contributes to the separation between PWV and SBP in men, preliminary analysis of data from BLSA confirmed the separation between SBP and PWV in older men, and showed greater rates of longitudinal aortic dilatation among men, which supports our hypothesis; these results were presented as an oral presentation during the at the American Heart Association Scientific Sessions, 2013, Dallas, TX. We analyzed data on carotid diameter from the SardiNIA project, we found earlier decline in distensibility between the age of 30 to 50 is a result of impaired recoil rather than restricted expansion. These interesting findings support our working hypothesis of major role of age-associated process that is independent from other traditional cardiovascular risk factors. B. Genetic and Environmental Underpinnings of Accelerated Cardiovascular Aging -Genetic determinates: Earlier results from the SardiNIA study have revealed a potential role of the Col4A1 gene (Tarasov 2009) and a second genetic element located in a desert region of the genome (Mitchell 2012), findings which have been confirmed in replication studies and larger Consortia-based analysis. Work is in progress to examine genetic determinants of the longitudinal change in PWV. -Environmental determinants: We have previously found a minimal role of traditional cardiovascular risk factors in the progression of arterial stiffness(AlGhatrif et al., 2013). Central obesity might introduce bias to PWV measurements (Canepa et al. 2014). In addition, vitamin D modulates the association of circulating insulin-like growth factor-1 with carotid artery intima-media thickness (Ameri et al. 2014). We have also found that bone mineral density plays a role in the inverse relationship between body size and aortic calcification (Canepa et 2014). II. Advanced CV phenotyping: To further examine the complex nature of arterial aging, we have initiated a program focused on advanced mathematical analysis of cardiovascular physiological signals including pressure, flow, and geometry signals to derive parameters that better represent the functional status of the CV in a given person and how it changes with aging. We recruited a post-doctoral fellow with training in biomedical engineering and established collaborations with international experts to develop advanced software to analyze CV traits collected from BLSA and SardiNIA participants. Great efforts have been made to compile raw data from echocardiography, Doppler, and applanation tonometry. Variables generated include derived central blood pressures, wave reflection parameters, aortic and carotid characteristic impedance, carotid geometric phenotype, carotid total, systolic, and diastolic flow rates, and CV mechanical power and efficiency. III. The impact of arterial aging on cardiac geometry and function: We have previously shown an early contribution of arterial wave reflection on myocardial diastolic dysfunction before the progression of hypertension (Canepa, AlGhatrif, et al., 2013). A more extensive analysis will be performed once the arterial phenotypic evaluation is completed. Preliminary analyses of data analyzed so far have shown a decline in cardiac energy efficiency with aging and that it was negatively associated with early arrival of the reflected wave and positively with the reflection index. This data has been submitted for presentation at the American Heart Association meeting 2015. IV. The Impact of arterial aging on end organs.. a. A new collaboration has been established with the Laboratory of Behavioral Neuroscience to examine the association between arterial parameters and measures of cognitive function in addition to brain structural changes evaluated by MRI. We are currently performing analysis relating pulse wave velocity to brain amyloid assessed by MRI. A more extensive analysis will be performed once the advanced CV phenotypic analysis is performed. b. To better understand the relationship between central arterial aging and end organ damage, efforts are aimed at evaluating distal flow. Currently, and via collaboration with the Johns Hopkins Wilmer Eye Institute, we are testing a new technology aimed at evaluating retinal capillary flow using a new technology that captures high resolution images down to 6-8 microns and at 20ms intervals. This allows detailed mapping of the retinal arterial tree with vessel-specific flow velocities. This provides a unique opportunity on terminal flow, its alterations with age, and the role central arterial changes in these alterations. The goal is to implement this technology in a sub-sample of the BLSA that also receives brain MRI and PET scan testing. V. Clinical Trials to Prevent and retard Arterial stiffness Resveratrol, a natural compound in grapes and red wine with antioxidant and anti-inflammatory properties, has been associated with improved health and prolonged lifespan in mice. There is evidence that acute and chronic use of resveratrol is associated with improved endothelial dysfunction. A Phase 1 and 2 double-blind randomized study is in progress aiming to examine the effect of resveratrol on PWV in 90 overweight /obese subjects beyond the age of 50. VI. Translational studies: efforts are being direct to conduct bidirectional translational research through 1) examining the clinical relevance of some the bench-side discoveries at the LCS such as those related to the role of marinobufagenin in arterial stiffness, and 2) to develop basic science experiments to test hypothesis generated from data observed in human studies, for example designing animal experiments to test mathematical models that described the cardiovascular system based on advanced phenotyping of human data.
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