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Previous Research

Direction of causality between chronic pain and hypertension and non-pharmacological approaches to reducing cardiovascular morbidity

Chronic pain is associated with elevated arterial blood pressure (BP) and hypertension (HTN). However, the mechanisms involved remain unclear. Among healthy individuals, there is an association between elevated resting BP and hypoalgesia that involves sympathetic activation and enhanced descending pain inhibition. The alteration of normal interactions between cardiovascular and pain regulatory systems may impair buffering of BP and contribute to the development of HTN and cardiovascular morbidity. We have demonstrated that peripheral symapthetic nerve activity can be transiently reduced following epidural spinal cord stimulation in patients with chronic pain. In addition, comorbidities associated with alterations in sympathetic outflow, such as anxiety and depression, are highly prevalent among patients with chronic pain and affect the same brain network tasked with pain perception and cardiovascular control. Studies have examined the extent to which anxiety influences sympathetic outflow, which have prepared the foundation for ongoing investigations into impairment in descending pain inhibition among patients with chronic pain and anxiety. Additionally, ongoing studies have a specific focus on sex differences in the BP-pain sensitivity relationship, given the female predominance of common pain conditions, and our recent data showing greater BP reductions following epidural spinal cord stimulation for chronic pain among women compared with men. The overarching goal is to uncover the potential for non-pharmacological therapies to reduce the prevalence of cardiovascular disease among patients with chronic pain and identify and improve functional interactions between cardiovascular and pain regulatory systems.

  • Holwerda SW, Holland MT, Green AL, Pearson ACS, Pierce GL. Dissociation between reduced pain and arterial blood pressure following epidural spinal cord stimulation in patients with chronic pain: A retrospective study. Clin Auton Res. doi.org/10.1007/s10286-020-00690-5. 2020. PMID: 32323062
  • Holwerda SW, Holland MT, Reddy CG, Pierce GL. Femoral vascular conductance and peroneal muscle sympathetic nerve activity responses to acute epidural spinal cord stimulation in humans. Exp Physiol 103(6):905-915, 2018. PMCID: PMC5984152


Sympathetic support of vascular tone and blood pressure

Sympathetic vascular transduction involves competing dilatory signals that interact with and alter the ability of sympathetic activity to decrease vascular conductance. In my postdoctoral training, The PI has been part of numerous projects investigating the extent to which spontaneous bursts of muscle sympathetic nerve activity (MSNA) mediate decreases in vascular conductance. Spontaneous MSNA bursts evoke significant beat-by-beat decreases in brachial artery vascular conductance that are exclusively mediated via α-adrenergic receptors. Findings also suggest that spontaneously occurring MSNA bursts do not directly influence conduit arteries (e.g., common femoral) with local vasoconstriction, but rather induce a systemic pressor response that appears to passively increase conduit artery diameter. Thus, in healthy subjects with normal levels of resting MSNA, spontaneously occurring MSNA bursts appear to have a minimal effect to constrict upstream conduit arteries, while the same stimulus efficiently reduces downstream limb vascular conductance. These findings contrast with previous studies demonstrating decreases in conduit artery diameter during marked sympatho-excitation.

  • Holwerda SW, Luehrs RE, DuBose L, Collins MT, Wooldridge NA, Stroud AK, Fadel PJ, Abboud FM, Pierce GL. Elevated muscle sympathetic nerve activity contributes to central artery stiffness in young and middle-age/older adults. Hypertension. 73(5):1025-1035. 2019. PMCID: PMC6937199
  • Holwerda SW, Restaino RM, Fadel PJ. Adrenergic and non-adrenergic control of active skeletal muscle blood flow: Implications for blood pressure regulation during exercise. Auton Neurosci. 188:24-31, 2015. PMID: 25467222
  • Fairfax ST, Holwerda SW, Credeur DP, Zuidema MY, Medley JH, Dyke PC 2nd, Wray DW, Davis MJ, Fadel PJ. The role of α-adrenergic in mediating beat-by-beat sympathetic vascular transduction in the forearm of resting man. J Physiol. 591(Pt 14):3637-49, 2013. PMCID: PMC3731619
  • Fairfax ST, Padilla J, Vianna LC, Holwerda SW, Davis MJ, Fadel PJ. Influence of spontaneously occurring bursts of muscle sympathetic nerve activity on conduit artery diameter. Am J Physiol Heart Circ Physiol 305(6):H867-74, 2013. PMCID: PMC3761336


Neural mechanisms contributing to greater cardiovascular mortality in patients with type 2 diabetes

Type 2 diabetes patients exhibit exaggerated increases in arterial blood pressure during exercise, such as during moderate intensity handgrip that is like many activities of daily living (i.e., carrying groceries, etc.). This is important because exaggerated increases in blood pressure are related to adverse cardiovascular and cerebrovascular events. Indeed, the incidence of cardiovascular and cerebrovascular events is significantly elevated among type 2 diabetes patients. Diabetes and obesity are strongly correlated with anxiety and depression, and my postdoctoral training has focused on the role of anxiety on sympathetic activation. In my Ph.D. training, I led several projects that focused on both peripheral and central mechanisms that may be contributing to greater cardiovascular mortality observed in patients with type 2 diabetes. Given the vital contribution of the muscle metaboreflex to the blood pressure response to exercise, we examined the blood pressure and sympathetic nerve responses (microneurography) to isolated metaboreflex activation using post-handgrip exercise ischemia in patients with type 2 diabetes, and found significantly greater blood pressure and sympathetic nerve responses to muscle metaboreflex activation in type 2 diabetes patients compared to healthy controls. These findings indicate that muscle metaboreflex activation contributes, in part, to augmented pressor and sympathetic responses to exercise in this patient population.

Additional studies examining neural mechanisms that may be contributing to hypertension and cardiovascular risk among patients with type 2 diabetes have included arterial baroreflex control of sympathetic nerve activity and heart rate. Because of the elevated risk of stroke, we examined dynamic cerebral autoregulation at rest in patients with type 2 diabetes. The rate of regulation among patients with type 2 diabetes was significantly blunted at rest and during low- and high-intensity handgrip compared to healthy controls, and these differences were related to total reactive oxygen species and superoxide levels. These finding suggest that dynamic cerebral autoregulation is blunted among patients with type 2 diabetes, placing this patient population at greater risk for cerebral events during such activities. Moreover, these findings parallel the results of studies were performed in African American adults. Using dihydroethidium fluorescence to measure superoxide production and western blot to assess angiotensin II type 1 receptor (AT1R)and NADPH oxidase subunit, gp91phox, we demonstrated that young African American men exhibit greater resting peripheral blood mononuclear cell-derived superoxide production via an up-regulation of the AT1R-NADPH oxidase pathway. Thus, the AT1R-NADPH oxidase pathway likely contributes to elevations in systemic oxidative stress among African Americans and may partly explain the extremely high prevalence of hypertension among African Americans with type 2 diabetes.

  • Holwerda SW, Restaino RM, Fisher JP, Fadel PJ. Augmented pressor and sympathetic responses to skeletal muscle metaboreflex activation in type 2 diabetes patients. Am J Physiol Heart Circ Physiol. 310(2):H300-9, 2016. PMCID: PMC5504388
  • Holwerda SW, Vianna LC, Young CN, Fadel PJ. Arterial baroreflex control of sympathetic nerve activity and heart rate in patients with type 2 diabetes. Am J Physiol Heart Circ Physiol. 311(5):H1170-H1179. 2016. PMCID: PMC5504388
  • Vianna LC, Deo SH, Jensen AK, Holwerda SW, Zimmerman MC, Fadel PJ. Impaired dynamic cerebral autoregulation at rest and during isometric exercise in type 2 diabetes patients. Am J Physiol Heart Circ Physiol. 308(7):H681-7, 2015. PMCID: PMC4385994
  • Deo SH, Holwerda SW, Keller DM, Fadel PJ. Elevated peripheral blood mononuclear cell-derived superoxide production in healthy young black men. Am J Physiol Heart Circ Physiol. 308(5):H548-52, 2015. PMCID: PMC4346764


Impact of reduce physical activity and insulin sensitivity on control of the circulation

Reductions in physical activity contribute significantly to impaired glycemic control, insulin resistance and impairment in autonomic function. Insulin-stimulated muscle blood flow accounts for up 40% of glucose uptake. Also, cardiac baroreflex sensitivity is critically important for beat-to-beat blood pressure regulation, and impairment in cardiac baroreflex sensitivity is associated with chronic hyperglycemia and increases risk for cardiovascular morbidity and mortality. We performed several studies to examine the impact of reductions in insulin sensitivity via short-term reductions in physical activity (5 days) in young, active men on muscle blood flow and on cardiac baroreflex control of the heart following elevations plasma glucose and insulin. Findings demonstrated that acutely elevated plasma glucose and insulin reduced cardiac baroreflex sensitivity in normally active young men, but that acute reduction in physical activity and insulin sensitivity did not impact cardiac baroreflex sensitivity or muscle blood flow responses to acutely elevated plasma glucose and insulin. We also performed experiments to examine the influence of prolonged sitting (6 hrs) on lower and upper limb dilator function via flow mediated dilation. Findings demonstrated that there is a marked vulnerability of the vasculature in the lower and upper limbs to prolonged sitting and highlight the importance of physical activity in restoring vascular function.

  • Brooks VL, Shi Z, Holwerda SW, Fadel PJ. Obesity-induced increases in sympathetic nerve activity: Sex matters. Auton Neurosci. 187:18-26, 2014. PMCID: PMCID: PMC4786002
  • Holwerda SW, Reynolds LJ, Credeur DP, Leidy HJ, Thyfault JP, Fadel JP. The influence of reduced insulin sensitivity via short-term reductions in physical activity on cardiac baroreflex sensitivity during acute hyperglycemia. J Appl Physiol. 15;119(12):1383-92, 2015. PMCID: PMC5504388
  • Reynolds LJ, Credeur DP, Holwerda SW, Leidy HJ, Fadel PJ, Thyfault JP. Acute inactivity impairs glycemic control but not blood flow to glucose ingestion. Med Sci Sports and Exerc. 47(5):1087-94. 2015. PMCID: PMC4362863
  • Restaino RM, Holwerda SW, Credeur DP, Fadel PJ, Padilla J. Impact of prolonged sitting on lower and upper limb micro- and macrovascular dilator function. Exp Physiol. 100(7):829-38, 2015. PMCID: PMC4956484
Last modified: Oct 29, 2020
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