Melissa Witman | University of Delaware (original) (raw)

Papers by Melissa Witman

American Journal of Physiology - Heart and Circulatory Physiology, 2015

The consequence of elevated oxidative stress on exercising skeletal muscle blood flow, 49 and the... more The consequence of elevated oxidative stress on exercising skeletal muscle blood flow, 49 and the transport and utilization of oxygen (O 2 ) in patients with chronic obstructive pulmonary 50 disease (COPD) is not well understood. This study examined the impact of an oral antioxidant 51 cocktail (AOC) on leg blood flow (LBF) and O 2 consumption during dynamic exercise in 16 52 patients with COPD and 16 healthy subjects. Subjects performed submaximal (3W, 6W, and 53 9W) single-leg knee extensor exercise (KE) while LBF (Doppler ultrasound), mean arterial 54 blood pressure, leg vascular conductance (LVC), arterial O 2 saturation, leg arterial-venous O 2 55 difference, and leg O 2 consumption (direct Fick) were evaluated under control conditions 56 (CTRL) and after AOC administration. AOC administration increased LBF (3W: 1604±100 vs 57 1798±128; 6W: 1832±109 vs 1992±120; 9W: 2035±114 vs 2187±136 ml/min, P<0.05, CTRL vs 58 AOC, respectively), LVC, and leg O 2 consumption (3W: 173±12 vs 210±15; 6W: 217±14 vs 59 237±15; 9W: 244±16 vs 260±18 ml O 2 /min, P<0.05, CTRL vs AOC, respectively) during 60 exercise in COPD, while no effect was observed in the healthy subjects. In addition, the AOC 61 afforded a small, but significant, improvement in arterial O 2 saturation only in the patients with 62 COPD. Thus, these data demonstrate a novel, beneficial role of AOC administration on 63 exercising LBF, O 2 consumption, and arterial oxygen saturation in patients with COPD, 64 implicating oxidative stress as a potential therapeutic target for impaired exercise capacity in this 65 population. 66 67 Word Count: 228 68 69 70

International Journal of Cardiology, 2015

Background: The complex pathophysiology of heart failure (HF) creates a challenging paradigm to d... more Background: The complex pathophysiology of heart failure (HF) creates a challenging paradigm to differentiate the role of central and peripheral hemodynamic dysfunction during conventional exercise. Adopting a novel reductionist approach with potential clinical relevance, we studied the central and peripheral contributors to both continuous and single passive leg movement (PLM)-induced hyperemia in 14 HF patients with reduced ejection fraction (HFrEF) and 13 controls. Methods: Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and femoral artery blood flow (FBF) were recorded during PLM. Results: The FBF response (area under the curve; AUC) to 60 s of continuous PLM was attenuated in the HFrEF (25 ± 15 ml AUC) compared to controls (199 ± 34 ml AUC) as were peak changes from baseline for FBF, leg vascular conductance (LVC), CO, and HR. During single PLM, increases in CO and HR were smaller and no longer different between groups, supporting the use of this modality to assess groups with disparate central hemodynamics. Interestingly, single PLM-induced hyperemia, likely predominantly driven by flow-mediated vasodilation due to minimal vessel deformation, was essentially nonexistent in the HFrEF (−9 ± 10 ml AUC) in contrast to the controls (43 ± 25 ml AUC). Conclusions: These data fail to support a HFrEF-associated exaggeration in the mechanoreceptor driven component of the exercise pressor response. In fact, by exhibiting limited central hemodynamic responses compared to the controls, the observed attenuation in movement-induced FBF in HFrEF appears largely due to peripheral vascular dysfunction, particularly flow-mediated vasodilation.

American journal of physiology. Heart and circulatory physiology, Jan 15, 2012

This study sought to characterize the role of free radicals in regulating central and peripheral ... more This study sought to characterize the role of free radicals in regulating central and peripheral hemodynamics at rest and during exercise in patients with heart failure (HF). We examined cardiovascular responses to dynamic handgrip exercise (4, 8, and 12 kg at 1 Hz) following consumption of either a placebo or acute oral antioxidant cocktail (AOC) consisting of vitamin C, E, and α-lipoic acid in a balanced, crossover design. Central and peripheral hemodynamics, mean arterial pressure, cardiac index, systemic vascular resistance (SVR), brachial artery blood flow, and peripheral (arm) vascular resistance (PVR) were determined in 10 HF patients and 10 age-matched controls. Blood assays evaluated markers of oxidative stress and efficacy of the AOC. When compared with controls, patients with HF exhibited greater oxidative stress, measured by malondialdehyde (+36%), and evidence of endogenous antioxidant compensation, measured by greater superoxide dismutase activity (+83%). The AOC incre...

$Research paper thumbnail of Hemodynamic responses to small muscle mass exercise in heart failure patients with reduced ejection fraction$

American journal of physiology. Heart and circulatory physiology, Jan 15, 2014

To better understand the mechanisms responsible for exercise intolerance in heart failure with re... more To better understand the mechanisms responsible for exercise intolerance in heart failure with reduced ejection fraction (HFrEF), the present study sought to evaluate the hemodynamic responses to small muscle mass exercise in this cohort. In 25 HFrEF patients (64 ± 2 yr) and 17 healthy, age-matched control subjects (64 ± 2 yr), mean arterial pressure (MAP), cardiac output (CO), and limb blood flow were examined during graded static-intermittent handgrip (HG) and dynamic single-leg knee-extensor (KE) exercise. During HG exercise, MAP increased similarly between groups. CO increased significantly (+1.3 ± 0.3 l/min) in the control group, but it remained unchanged across workloads in HFrEF patients. At 15% maximum voluntary contraction (MVC), forearm blood flow was similar between groups, while HFrEF patients exhibited an attenuated increase at the two highest intensities compared with controls, with the greatest difference at the highest workload (352 ± 22 vs. 492 ± 48 ml/min, HFrEF vs...

Nutrition Research, 2012

Quercetin (Q) reduces blood pressure (BP) in hypertensive individuals, but the mechanism is unkno... more Quercetin (Q) reduces blood pressure (BP) in hypertensive individuals, but the mechanism is unknown. We hypothesized that acute Q aglycone administration reduces BP in hypertensive men by decreasing angiotensin-converting enzyme (ACE) activity and/or by lowering the ratio of circulating endothelin-1 (ET-1) to nitric oxide and that these alterations will improve endothelial function. Using a double-blind, placebo-controlled, crossover design Q or placebo (P) was administered to normotensive men (n = 5; 24 ± 3 years; 24 ± 4 kg/m 2 ) and stage 1 hypertensive men (n = 12; 41 ± 12 years; 29 ± 5 kg/m 2 ). As anticipated, ingesting 1095 mg Q did not affect BP in normotensive men but resulted in maximal plasma Q (2.3 ± 1.8 μmol/L) at approximately 10 hours, with Q returning to baseline concentrations (0.4 ± 0.08 μmol/L) by approximately 17 hours. Results from this study provided rationale for determining end-points of interest in stage 1 hypertensive men 10 hours after ingesting Q or P. In stage 1 hypertensive individuals, plasma Q increased(0.6 ± 0.4 vs. 0.05 ± 0.02 μmol/L), and mean BP decreased (103 ± 7 vs 108 ± 7 mm Hg; both P < .05) 10 hours after Q vs P, respectively. Plasma ACE activity (16 ± 10 vs 18 ± 10 U/L), ET-1 (1.6 ± 0.9 vs 1.6 ± 0.8 pg/ml), nitrites (57.0 ± 3.0 vs 56.7 ± 2.6 μmol/L), and brachial artery flow-mediated dilation (6.2 ± 2.9 vs. 6.3 ± 3.2%) were unaffected by Q. A single dose of Q aglycone reduces BP in hypertensive men through a mechanism that is independent of changes in ACE activity, ET-1, or nitric oxide bioavailability and without affecting vascular reactivity.

Journal of Neurology, 2011

Multiple sclerosis (MS) is a debilitating disease with an assumed autoimmune etiology which may l... more Multiple sclerosis (MS) is a debilitating disease with an assumed autoimmune etiology which may lead to elevated oxidative stress, vascular dysfunction, and subsequent predisposition to cardiovascular disease. Therefore, the primary aim of this study was to evaluate vascular function and the potential role of oxidative stress in patients diagnosed with MS compared to healthy controls (C). Fourteen patients with relapsing-remitting MS (47 ± 3 years) and 13 age-and activity-matched controls (44 ± 5 years) underwent brachial artery flow-mediated dilation (FMD) and reactive hyperemia testing using ultrasound Doppler. Venous blood was analyzed for C-reactive protein (CRP), lipid hydroperoxides (LH), the ferric reducing ability of plasma (FRAP), superoxide dismutase (SOD), and catalase activity. CRP [1.8 ± 0.5 mg/L (MS), 1.0 ± 0.5 mg/L (C)] and LH [1.2 ± 0.2 lmol/L (MS), 1.1 ± 0.1 lmol/L (C)] were not different between MS patients and controls. FMD [8.0 ± 1.2% (MS) and 9.2 ± 1.6% (C)] and reactive hyperemia [380 ± 61 mL (MS) and 402 ± 69 mL (C)] were also not different between groups. Vascular function, as assessed by both FMD and reactive hyperemia, was not impaired in patients with MS compared to controls. Further, there was no evidence of elevated systemic inflammation or oxidative stress in these patients, who were currently all in remission. These findings suggest that impaired vascular function, elevated inflammation and oxidative stress are not an obligatory accompaniment to MS.

Experimental Physiology, 2011

Heat and cold exposure can decrease and increase total peripheral resistance, respectively, in hu... more Heat and cold exposure can decrease and increase total peripheral resistance, respectively, in humans. With unique access to human skeletal muscle feed arteries, we sought both to characterize these vessels and to determine the interaction between temperature and α 1adrenergic receptor responsiveness. We hypothesized that α 1 -mediated vasocontraction of human feed arteries would be attenuated in response to 39 or 35 • C. Skeletal muscle feed arteries were harvested from thirty-two human volunteers and studied using isometric techniques. Vessel function was assessed using KCl, sodium nitroprusside (SNP), phenylephrine (PE) and ACh dose-response curves to characterize non-receptor-and receptor-mediated vasocontraction and vasorelaxation. Single doses of PE (1 mm) and KCl (100 mm) were administered at 37 • C and then, in a balanced design, repeated at both 35 and 39 • C. The KCl and PE dose-response curves elicited significant vasocontraction (2009 ± 407 and 1974 ± 508 mg developed tension, respectively), whereas SNP and ACh induced the expected vasorelaxation (102 ± 6 and 73 ± 10% relaxation, respectively). Altering the temperature had no effect on inherent smooth muscle function (KCl response), but both a reduction (35 • C) and an increase in temperature (39 • C) decreased the vasocontractile response to 1 mm PE (37 • C, 1478 ± 338 mg; 35 • C, 546 ± 104 mg; and 39 • C, 896 ± 202 mg; P < 0.05) or across PE dose (P < 0.05, 35 and 39 versus 37 • C). Despite clear heterogeneity between both the human volunteers and the feed arteries themselves, this novel approach to the procurement of human vessels revealed a robust 'inverted U' response to altered temperature, such that α 1 -mediated vasocontraction was attenuated with either warming or cooling.

AJP: Heart and Circulatory Physiology, 2011

intact animal to the cellular, subcellular, and molecular levels. It is published 12 times a year... more intact animal to the cellular, subcellular, and molecular levels. It is published 12 times a year (monthly) by the American lymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the publishes original investigations on the physiology of the heart, blood vessels, and AJP -Heart and Circulatory Physiology on December 16, 2011 ajpheart.physiology.org Downloaded from

AJP: Heart and Circulatory Physiology, 2013

Previous studies have determined that premenopausal women exhibit an attenuated metaboreflex; how... more Previous studies have determined that premenopausal women exhibit an attenuated metaboreflex; however, little is known about sex specificity of the mechanoreflex. Thus, we sought to determine if sex differences exist in the central and peripheral hemodynamic responses to passive limb movement. Second-by-second measurements of heart rate, stroke volume, cardiac output (CO), mean arterial pressure, and femoral artery blood flow (FBF) were recorded during 3 min of supine passive knee extension in 24 young healthy subjects (12 women and 12 men). Normalization of CO and stroke volume to body surface area, expressed as cardiac index and stroke index, eliminated differences in baseline central hemodynamics, whereas, peripherally, basal FBF and femoral vascular conductance were similar between the sexes. In response to passive limb movement, women displayed significantly attenuated peak central hemodynamic responses compared with men (heart rate: 9.0 ± 1 vs. 14.8 ± 2% change, stroke index: 4.5 ± 0.6 vs. 7.8 ± 1.2% change, cardiac index: 9.6 ± 1 vs. 17.2 ± 2% change, all P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), whereas movement induced similar increases in peak FBF (167 ± 32 vs. 193 ± 17% change) and femoral vascular conductance (172 ± 31 vs. 203 ± 16% change) in both sexes (women vs. men, respectively). Additionally, there was a significant positive relationship between individual peak FBF and peak CO response to passive movement in men but not in women. Thus, although both sexes exhibited similar movement-induced hyperemia and peripheral vasodilatory function, the central hemodynamic response was blunted in women, implying an attenuated mechanoreflex. Therefore, this study reveals that, as already recognized with the metaboreflex, there is likely a sex-specific attenuation of the mechanoreflex in women.

International Journal of Cardiology, 2014

Objective: To better understand the hemodynamic and autonomic reflex abnormalities in heart-failu... more Objective: To better understand the hemodynamic and autonomic reflex abnormalities in heart-failure patients (HF), we investigated the influence of group III/IV muscle afferents on their cardiovascular response to rhythmic exercise. Methods: Nine HF-patients (NYHA class-II, mean left ventricular ejection-fraction: 27 ± 3%) performed single leg knee-extensor exercise (25/50/80% peak-workload) under control conditions and with lumbar intrathecal fentanyl impairing μ-opioid receptor-sensitive muscle afferents. Results: Cardiac-output (Q) and femoral blood-flow (Q L ) were determined, and arterial/venous blood samples collected at each workload. Exercise-induced fatigue was estimated via pre/post-exercise changes in quadriceps strength. There were no hemodynamic differences between conditions at rest. During exercise, Q was 8-13% lower with Fentanyl-blockade, secondary to significant reductions in stroke volume and heart rate. Lower norepinephrine spillover during exercise with Fentanyl revealed an attenuated sympathetic outflow that likely contributed to the 25% increase in leg vascular conductance (p b 0.05). Despite a concomitant 4% reduction in blood pressure, Q L was 10-14% higher and end-exercise fatigue attenuated by 30% with Fentanyl-blockade (p b 0.05). Conclusion/practice/implications: Although group III/IV muscle afferents play a critical role for central hemodynamics in HF-patients, it also appears that these sensory neurons cause excessive sympatho-excitation impairing Q L which likely contributes to the exercise intolerance in this population.