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Brian Stauffer, MD
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Sex/Gender Differences in Cardiac Growth and Heart Failure
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Clinical heart failure substantially decreases the quality of life in many individuals. There appear to be differences in the development of this disease between men and women. The etiology of these differences is unknown; however, estrogen and testosterone have been postulated to contribute. My laboratory is interested in evaluating the role of these sex hormones in cardiac growth and the development of heart failure. Human hypertrophic cardiac disease has been observed to have a sex specific phenotypic variation in the development of hypertrophy and progression to heart failure. Both sexes appear to develop left ventricular (LV) hypertrophy initially, however, once clinical end-stage disease develops women tend to have preserved LV function and men tend to develop chamber dilation and wall thinning. In spite of these differences, mortality is equally significant in both groups. Our lab has a hypertrophic cardiomyopathy (HCM) mouse expressing a mutant myosin heavy chain transgene in a cardiac specific manner. Transgene expression causes sex specific phenotypic variation similar to that noted above in humans. Both sexes initially develop similar degrees of LV hypertrophy. The male mice subsequently develop LV chamber dilation and wall thinning in contrast to the female mice, which continue the progression of LV wall thickness. We hypothesized that sex hormones contribute to gender differences in the LV structural and functional changes associated with HCM. During the course of characterizing this model of heart failure we discovered the diet is a novel modifier of the cardiac disease, promoting cardiac growth and preventing the dilated cardiomyopathy in the male mice. My laboratory is investigating the interaction between sex hormones and diet and molecular pathways known to influence cardiac growth. We strive to characterize the molecular alterations that are responsible for cardiac adaptation at a physiologic level. In doing so we incorporate molecular and physiologic measures, in an attempt to understand how changes at a subcellular level influence a clinical disease process at the systemic level.
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Principal Investigator
Brian Stauffer, MD, Assistant Professor, Medicine/Cardiology
Laboratory: BRB 1st floor, Rm: 143
Office: BRB 1st floor, Rm: 143C
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Obesity/Insulin Resistance, Vitamin C and Endothelin-1
Sex/Gender Differences in Cardiac Growth and Heart Failure
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There is evidence that endotheliopathy is intrinsic to obesity/insulin resistance and, in turn, type 2 diabetes. Alterations in vasomotor function, specifically an imbalance between vasodilation and vasoconstriction, occurring in the obese/insulin resistant prediabetic stage is thought to contribute to the accelerated rates of atherosclerotic vascular disease in type 2 diabetes. Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. In addition to its effects on vascular tone, ET-1 has been linked to the initiation and development of atherosclerosis. Importantly, oxidative stress is associated with obesity/insulin resistance, impaired endothelium-dependent vasodilation and increased ET-1 production and activity. The specific aims of the present proposal will be to determine: 1) whether the vasoconstrictor activity of endogenous ET-1 is increased in obese/insulin resistant adult humans; 2) if oral vitamin C supplementation reduces endogenous ET-1 vasoconstrictor activity in obese/insulin resistant adults as much or more than regular aerobic exercise; and 3) if oral vitamin C supplementation improves endotheliumdependent vasodilation in obese/insulin resistant adult humans as much or more than regular aerobic exercise; and to determine whether improvements in endothelial vasodilation is due, at least in part, to reduced ET-1 vasoconstrictor activity. To address these aims, 252 middle-aged and older obese/insulin resistant and lean/insulin sensitive adult humans will be studied. Endogenous ET-1 vasoconstrictor activity will be assessed by changes in forearm blood flow (plethysmography) in response to intra-arterial infusion of selective and nonselective ET-1 receptor antagonists as well as exogenous ET-1. In addition, the vasodilator response to both acetylcholine and sodium nitroprusside will be determined in the absence and presence of ET-1 receptor blockade. Endogenous ET-1 vasoconstrictor activity will also be assessed before and after a 12-week intervention of either oral vitamin C supplementation (500 mg/d) or aerobic exercise training in obese/insulin resistant adults. The results of the proposed study should provide clinically important information regarding the activity of the ET-1 system with obesity/insulin resistance; and the efficacy of vitamin C supplementation in reducing ET-l-mediated vasoconstriction and, in turn, improving endothelial vasomotor regulation in obese/insulin resistant adults.
This grant is a subcontract of a University of Colorado at Boulder grant.
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Principal Investigator
Christopher DeSouza, PhD; Associate Professor, Integrative Physiology
Professional Research Assistants
Jared Greiner
Yoli Casas
Heather Irmiger
Research associates
Greta Hoetzer, PhD
Graduate Students
Gary Van Guilder (doctoral)
Jeremy Stoner (masters)
Chris Westby
Medical Director
Brian Stauffer, MD; Assistant Professor, Medicine/Cardiology
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Aging, Exercise, and Endothelin-1 Vasoconstrictor Tone
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| Integrative Vascular Biology Laboratory |
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Impaired vascular vasomotor function plays an essential role in the pathogenesis and prognosis of cardiovascular disease. The endothelium is central to the regulation of vascular tone through the synthesis and release of opposing vasoactive substances, particularly nitric oxide (NO) and endothelin-1 (ET-1). It has been suggested that a disruption in the balance between the opposing effects of these vasoactive substances, favoring constriction, contributes to the age-related decline in vasomotor regulation. To date, however, the vast majority of studies (in humans) have focused on age-associated changes in NO bioavailability, there is currently very little information regarding the effects of aging on ET-1 vasoconstrictor activity and its potential impact on vasomotor function. This represents a critical void in our understanding of the regulation of vascular tone with human aging. Moreover, increased ET-1-dependent vasoconstriction has been linked to the etiology of a number of age-related pathologies including hypertension, vasospasm, heart failure and coronary artery disease. The specific aims of the present proposal will be to determine if : 1) endogenous ET-1 vasoconstrictor activity increases with age in healthy adult humans and, if so, whether the increase is progressive with age from young adulthood and are mediated by both ET-1 receptor subtypes; 2) the vascular vasoconstrictor response to ET-1 is altered with age; 3) increased ET-1 vasoconstrictor activity contributes to the age-related impairment in endothelial vasodilator function observed in healthy, sedentary adult humans; and 4) a program of regular aerobic exercise reduces ET-1-mediated vasoconstriction in previously sedentary middle-aged and older adults. To address these aims, forearm vascular responses to selective and nonselective ET-1 receptor antagonists as well as exogenous ET-1 will be determined in healthy adult humans (20-79 yr). In addition, the vasodilator response to acetylcholine and sodium nitroprusside will be determined in the absence and presence of ET-1 receptor blockade. ET-1 vasoconstrictor activity will also be assessed before and after a 12-week aerobic exercise training program. The proposed study should provide new and clinically useful information regarding the influence of age on the activity of the ET-1 system and its impact on vasomotor regulation as well as the potential benefical effects of exercise in reducing ET-1 vasoconstrictor tone.
This grant is a subcontract of a University of Colorado at Boulder grant.
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Principal Investigator
Christopher DeSouza, PhD; Associate Professor, Integrative Physiology
Professional Research Assistants
Jared Greiner
Yoli Casas
Heather Irmiger
Graduate Students
Gary Van Guilder (doctoral)
Jeremy Stoner (masters)
Chris Westby
Medical Director
Brian Stauffer, MD; Assistant Professor, Medicine/Cardiology
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CU Boulder:
Carlson 108
Boulder Satellite General Clinical Research Center: Wardenburg Health Center
UCD:
4200 East 9th Ave, BRB 1st Floor
Denver, CO 80262
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