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Valsalva Maneuver in Pulmonary Arterial Hypertension: Susceptibility to Syncope and Autonomic Dysfunction.
Mar PL, Nwazue V, Black BK, Biaggioni I, Diedrich A, Paranjape SY, Loyd JE, Hemnes AR, Robbins IM, Robertson D, Raj SR, Austin ED
(2016) Chest 149: 1252-60
MeSH Terms: Adult, Autonomic Nervous System Diseases, Baroreflex, Blood Pressure, Case-Control Studies, Familial Primary Pulmonary Hypertension, Female, Heart Rate, Hemodynamics, Humans, Hypertension, Pulmonary, Male, Syncope, Valsalva Maneuver
Show Abstract · Added February 21, 2017
BACKGROUND - Patients with pulmonary arterial hypertension (PAH) are routinely instructed to avoid performing the Valsalva maneuver for fear of syncope or sudden cardiac death. The mechanism of this action has not been elucidated. We conducted a case-control trial of nine patients with PAH and 15 healthy control subjects to determine if systemic hemodynamic changes during the Valsalva maneuver in these patients invoke greater susceptibility to syncope than healthy control subjects. Metrics commonly employed in autonomic testing were used to assess the degree of autonomic failure.
METHODS - Common Valsalva parameters, including adrenergic baroreflex sensitivity, pressure recovery time, systolic BP (SBP) recovery, diastolic BP (DBP) recovery, mean arterial pressure recovery, and the Valsalva ratio, were calculated. Mann-Whitney U tests were used to compare continuous variables. The primary end point was adrenergic baroreflex sensitivity.
RESULTS - Patients with PAH had lower adrenergic baroreflex sensitivity (9.7 ± 4.6 mm Hg/s vs 18.8 ± 9.2 mm Hg/s; P = .005), longer pressure recovery time (3.6 ± 2.5 s vs 1.7 ± 0.8 s; P = .008), similar SBP recovery (-13 ± 11 mm Hg vs -12 ± 23 mm Hg; P = .640), less DBP recovery (-1 ± 12 mm Hg vs 13 ± 14 mmHg; P = .025), less mean arterial pressure recovery (-5 ± 11 mm Hg vs 5 ± 17 mm Hg; P = .048), and a decreased Valsalva ratio (1.25 ± 0.11 vs 1.60 ± 0.22; P < .001) compared with healthy control subjects.
CONCLUSIONS - Compared with healthy control subjects, patients with PAH are more susceptible to syncope during the Valsalva maneuver because of autonomic dysfunction causing cerebral hypoperfusion. These study patients with PAH exhibited a degree of susceptibility to syncope similar to a spectrum of patients with intermediate autonomic failure who typically experience a SBP drop of 10 to 30 mm Hg with standing.
Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Norepinephrine transporter variant A457P knock-in mice display key features of human postural orthostatic tachycardia syndrome.
Shirey-Rice JK, Klar R, Fentress HM, Redmon SN, Sabb TR, Krueger JJ, Wallace NM, Appalsamy M, Finney C, Lonce S, Diedrich A, Hahn MK
(2013) Dis Model Mech 6: 1001-11
MeSH Terms: Animals, Baroreflex, Behavior, Animal, Biological Transport, Catecholamines, Disease Models, Animal, Female, Gene Knock-In Techniques, Humans, Methoxyhydroxyphenylglycol, Mice, Mutant Proteins, Norepinephrine, Norepinephrine Plasma Membrane Transport Proteins, Postural Orthostatic Tachycardia Syndrome, Telemetry
Show Abstract · Added June 2, 2014
Postural orthostatic tachycardia syndrome (POTS) is a common autonomic disorder of largely unknown etiology that presents with sustained tachycardia on standing, syncope and elevated norepinephrine spillover. Some individuals with POTS experience anxiety, depression and cognitive dysfunction. Previously, we identified a mutation, A457P, in the norepinephrine (NE; also known as noradrenaline) transporter (NET; encoded by SLC6A2) in POTS patients. NET is expressed at presynaptic sites in NE neurons and plays a crucial role in regulating NE signaling and homeostasis through NE reuptake into noradrenergic nerve terminals. Our in vitro studies demonstrate that A457P reduces both NET surface trafficking and NE transport and exerts a dominant-negative impact on wild-type NET proteins. Here we report the generation and characterization of NET A457P mice, demonstrating the ability of A457P to drive the POTS phenotype and behaviors that are consistent with reported comorbidities. Mice carrying one A457P allele (NET(+/P)) exhibited reduced brain and sympathetic NE transport levels compared with wild-type (NET(+/+)) mice, whereas transport activity in mice carrying two A457P alleles (NET(P/P)) was nearly abolished. NET(+/P) and NET(P/P) mice exhibited elevations in plasma and urine NE levels, reduced 3,4-dihydroxyphenylglycol (DHPG), and reduced DHPG:NE ratios, consistent with a decrease in sympathetic nerve terminal NE reuptake. Radiotelemetry in unanesthetized mice revealed tachycardia in NET(+/P) mice without a change in blood pressure or baroreceptor sensitivity, consistent with studies of human NET A457P carriers. NET(+/P) mice also demonstrated behavioral changes consistent with CNS NET dysfunction. Our findings support that NET dysfunction is sufficient to produce a POTS phenotype and introduces the first genetic model suitable for more detailed mechanistic studies of the disorder and its comorbidities.
1 Communities
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16 MeSH Terms
Nitric oxide and regulation of heart rate in patients with postural tachycardia syndrome and healthy subjects.
Gamboa A, Okamoto LE, Raj SR, Diedrich A, Shibao CA, Robertson D, Biaggioni I
(2013) Hypertension 61: 376-81
MeSH Terms: Adult, Autonomic Nervous System, Baroreflex, Blood Pressure, Enzyme Inhibitors, Female, Heart Rate, Humans, Male, Nitric Oxide, Nitric Oxide Synthase, Phenylephrine, Postural Orthostatic Tachycardia Syndrome, omega-N-Methylarginine
Show Abstract · Added December 10, 2013
The objective is to study the role of nitric oxide (NO) on cardiovascular regulation in healthy subjects and postural tachycardia syndrome (POTS) patients. Reduced neuronal NO function, which could contribute to a hyperadrenergic state, and increased NO-induced vasodilation, which could contribute to orthostatic intolerance, have been reported in POTS. In protocol 1, 13 healthy volunteers (33 ± 3 years) underwent autonomic blockade with trimethaphan and were administered equipressor doses of Nω-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor) and phenylephrine to determine the direct chronotropic effects of NO (independent of baroreflex modulation). In protocol 2, we compared the effects of L-NMMA in 9 POTS patients (31 ± 3 years) and 14 healthy (32 ± 2 years) volunteers, during autonomic blockade. During autonomic blockade, L-NMMA and phenylephrine produced similar increases in systolic blood pressure (27 ± 2 versus 27 ± 3 mm Hg). Phenylephrine produced only minimal heart rate changes, whereas L-NMMA produced a modest, but significant, bradycardia (-0.8 ± 0.4 versus -4.8 ± 1.2 bpm; P=0.011). There were no differences between POTS and healthy volunteers in the systolic blood pressure increase (22 ± 2 and 28 ± 5 mm Hg) or heart rate decrease (-6 ± 2 and -4 ± 1 bpm for POTS and controls, respectively) produced by L-NMMA. In the absence of baroreflex buffering, inhibition of endogenous NO synthesis results in a significant bradycardia, reflecting direct tonic modulation of heart rate by NO in healthy individuals. We found no evidence of a primary alteration in NO function in POTS. If NO dysfunction plays a role in POTS, it is through its interaction with the autonomic nervous system.
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14 MeSH Terms
Sympathetic activation and nitric oxide function in early hypertension.
Gamboa A, Okamoto LE, Diedrich A, Choi L, Robertson D, Farley G, Paranjape S, Biaggioni I
(2012) Am J Physiol Heart Circ Physiol 302: H1438-43
MeSH Terms: Adolescent, Adult, Aging, Baroreflex, Blood Pressure, Enzyme Inhibitors, Female, Heart Rate, Humans, Hypertension, Male, Middle Aged, Muscle Tonus, Muscle, Smooth, Vascular, Nicotinic Antagonists, Nitric Oxide, Nitric Oxide Synthase Type III, Receptors, Nicotinic, Smoking, Sympathetic Nervous System, Trimethaphan, Young Adult, omega-N-Methylarginine
Show Abstract · Added December 10, 2013
The purpose of this study was to determine if tonic restrain of blood pressure by nitric oxide (NO) is impaired early in the development of hypertension. Impaired NO function is thought to contribute to hypertension, but it is not clear if this is explained by direct effects of NO on vascular tone or indirect modulation of sympathetic activity. We determined the blood pressure effect of NO synthase inhibition with N(ω)-monomethyl-l-arginine (L-NMMA) during autonomic blockade with trimethaphan to eliminate baroreflex buffering and NO modulation of autonomic tone. In this setting, impaired NO modulation of vascular tone would be reflected as a blunted pressor response to L-NMMA. We enrolled a total of 66 subjects (39 ± 1.3 yr old, 30 females), 20 normotensives, 20 prehypertensives (blood pressure between 120/80 and 140/90 mmHg), 17 hypertensives, and 9 smokers (included as "positive" controls of impaired NO function). Trimethaphan normalized blood pressure in hypertensives, suggesting increased sympathetic tone contributing to hypertension. In contrast, L-NMMA produced similar increases in systolic blood pressure in normal, prehypertensive, and hypertensive subjects (31 ± 2, 32 ± 2, and 30 ± 3 mmHg, respectively), whereas the response of smokers was blunted (16 ± 5 mmHg, P = 0.012). Our results suggest that sympathetic activity plays a role in hypertension. NO tonically restrains blood pressure by ∼30 mmHg, but we found no evidence of impaired modulation by NO of vascular tone contributing to the early development of hypertension. If NO deficiency contributes to hypertension, it is likely to be through its modulation of the autonomic nervous system, which was excluded in this study.
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23 MeSH Terms
Altered systemic hemodynamic and baroreflex response to angiotensin II in postural tachycardia syndrome.
Mustafa HI, Raj SR, Diedrich A, Black BK, Paranjape SY, Dupont WD, Williams GH, Biaggioni I, Robertson D
(2012) Circ Arrhythm Electrophysiol 5: 173-80
MeSH Terms: Adolescent, Adult, Angiotensin II, Baroreflex, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Hemodynamics, Humans, Infusions, Intravenous, Middle Aged, Postural Orthostatic Tachycardia Syndrome, Retrospective Studies, Treatment Outcome, Vasoconstrictor Agents, Young Adult
Show Abstract · Added March 21, 2014
BACKGROUND - Postural tachycardia syndrome (POTS) is characterized by excessive orthostatic tachycardia and significant functional disability. We have previously found that patients with POTS have increases in plasma angiotensin II (Ang II) that are twice as high as healthy subjects despite normal blood pressures (BPs). In this study, we assess systemic and renal hemodynamic and functional responses to Ang II infusion in patients with POTS compared with healthy controls.
METHODS AND RESULTS - Following a 3-day sodium-controlled diet, we infused Ang II (3 ng/kg per minute) for 1 hour in patients with POTS (n=15) and healthy controls (n=13) in the supine position. All study subjects were women with normal BP. Ages were similar for patients with POTS and controls (mean±SEM, 30±2 versus 26±1 years; P=0.11). We measured the changes from baseline mean arterial pressure, renal plasma flow, plasma renin activity, aldosterone, urine sodium, and baroreflex sensitivity in both groups. In response to Ang II infusion, patients with POTS had a blunted increase compared with controls in mean arterial pressure (10±1 versus 14±1 mm Hg, P=0.01) and diastolic BP (9±1 versus 13±1 mm Hg, P=0.01) but not systolic BP (13±2 versus 15±2 mm Hg, P=0.40). Renal plasma flow decreased similarly with Ang II infusion in patients with POTS versus controls (-166±20 versus -181±17 mL/min per 1.73 kg/m(2), P=0.58). Postinfusion, the decrease in plasma renin activity (-0.9±0.2 versus -0.6±0.2 ng/mL per hour, P=0.43) and the increase in aldosterone (17±1 versus 15±2 pg/mL, P=0.34) were similar in both groups. The decrease in urine sodium excretion was similar in patients with POTS and controls (-49±12 versus -60±16 mEq/g creatinine, P=0.55). The spontaneous baroreflex sensitivity at baseline was significantly lower in patients with POTS compared with controls (10.1±1.2 versus 16.8±1.5 ms/mm Hg, P=0.003), and it was further reduced with Ang II infusion.
CONCLUSIONS - Patients with POTS have blunted vasopressor response to Ang II and impaired baroreflex function. This impaired vasoconstrictive response might be exaggerated with upright posture and may contribute to the subsequent orthostatic tachycardia that is the hallmark of this disorder. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00962949.
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16 MeSH Terms
Dysautonomia: perioperative implications.
Mustafa HI, Fessel JP, Barwise J, Shannon JR, Raj SR, Diedrich A, Biaggioni I, Robertson D
(2012) Anesthesiology 116: 205-15
MeSH Terms: Airway Management, Anesthesia, Baroreflex, Drug Interactions, Humans, Hyperventilation, Hypotension, Orthostatic, Infections, Perioperative Care, Postoperative Care, Primary Dysautonomias
Show Abstract · Added May 20, 2014
Severe autonomic failure occurs in approximately 1 in 1,000 people. Such patients are remarkable for the striking and sometimes paradoxic responses they manifest to a variety of physiologic and pharmacologic stimuli. Orthostatic hypotension is often the finding most commonly noted by physicians, but a myriad of additional and less understood findings also occur. These findings include supine hypertension, altered drug sensitivity, hyperresponsiveness of blood pressure to hypo/hyperventilation, sleep apnea, and other neurologic disturbances. In this article the authors will review the clinical pathophysiology that underlies autonomic failure, with a particular emphasis on those aspects most relevant to the care of such patients in the perioperative setting. Strategies used by clinicians in diagnosis and treatment of these patients, and the effect of these interventions on the preoperative, intraoperative, and postoperative care that these patients undergo is a crucial element in the optimized management of care in these patients.
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11 MeSH Terms
Brain-selective overexpression of angiotensin-converting enzyme 2 attenuates sympathetic nerve activity and enhances baroreflex function in chronic heart failure.
Xiao L, Gao L, Lazartigues E, Zucker IH
(2011) Hypertension 58: 1057-65
MeSH Terms: Angiotensin I, Angiotensin II, Angiotensin-Converting Enzyme 2, Animals, Baroreflex, Enzyme Induction, Heart Failure, Humans, Male, Medulla Oblongata, Mice, Mice, Knockout, Myocardial Ischemia, Nerve Tissue Proteins, Nitric Oxide, Norepinephrine, Organ Specificity, Peptide Fragments, Peptidyl-Dipeptidase A, Proto-Oncogene Proteins, Receptors, Angiotensin, Receptors, G-Protein-Coupled, Recombinant Fusion Proteins, Reflex, Abnormal, Sympathetic Nervous System
Show Abstract · Added August 5, 2014
Angiotensin-converting enzyme 2 (ACE2) has been suggested to be involved in the central regulation of autonomic function. During chronic heart failure (CHF), elevated central angiotensin II signaling contributes to the sustained increase of sympathetic outflow. This is accompanied by a downregulation of ACE2 in the brain. We hypothesized that central overexpression of ACE2 decreases sympathetic outflow and enhances baroreflex function in CHF. Transgenic mice overexpressing human ACE2 selectively in the brain (SYN-hACE2 [SA]) and wild-type littermates (WT) were used. CHF was induced by permanent coronary artery ligation. Four weeks after coronary artery ligation, both WT and SA mice exhibited a significant decrease in left ventricular ejection fraction (<40%). A slight decrease in mean arterial pressure was found only in SA mice. Compared with WT mice with CHF, brain-selective ACE2 overexpression attenuated left ventricular end-diastolic pressure; decreased urinary norepinephrine excretion; baseline renal sympathetic nerve activity (WT CHF: 71.6±7.6% max versus SA CHF: 49.3±6.1% max); and enhanced baroreflex sensitivity (maximum slope: WT sham: 1.61±0.16%/mm Hg versus SA CHF: 1.51±0.17%/mm Hg). Chronic subcutaneous blockade of mas receptor increased renal sympathetic nerve activity in SA mice with CHF (A779: 67.3±5.8% versus vehicle: 46.4±3.6% of max). An upregulation in angiotensin II type 1 receptor expression was detected in medullary nuclei in WT CHF mice, which was significantly attenuated in SA mice with CHF. These data suggest that central ACE2 overexpression exerts a potential protective effect in CHF through attenuating sympathetic outflow. The mechanism for this effect involves angiotensin (1-7) mas signaling, as well as a decrease in angiotensin II type 1 receptor signaling in the medulla.
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25 MeSH Terms
Portal osmopressor mechanism linked to transient receptor potential vanilloid 4 and blood pressure control.
McHugh J, Keller NR, Appalsamy M, Thomas SA, Raj SR, Diedrich A, Biaggioni I, Jordan J, Robertson D
(2010) Hypertension 55: 1438-43
MeSH Terms: Animals, Baroreflex, Blood Pressure Determination, Disease Models, Animal, Humans, Hypertension, Mice, Mice, Inbred C57BL, Mice, Knockout, Osmotic Pressure, Prazosin, Probability, Random Allocation, Statistics, Nonparametric, Sympathetic Nervous System, TRPV Cation Channels, Vagotomy, Vascular Resistance, Water, Water-Electrolyte Balance
Show Abstract · Added December 10, 2013
Human subjects with impaired baroreflex function cannot buffer rises or falls in blood pressure (BP), thus allowing BP effects of endogenous or environmental stimuli that previously escaped detection to emerge dramatically. Studies in these patients led us to discover that water ingestion induced a robust increase in BP and vascular resistance. Here, using a mouse model of baroreflex impairment, we show that the increase in blood pressure after water ingestion is mediated through sympathetic nervous system activation and that the osmosensitive transient receptor potential vanilloid 4 channel (Trpv4) is an essential component of the response. Although portal osmolality decreases after water ingestion in both wild-type and Trpv4(-/-) mice, only the wild-type animals show a pressor response. The same volume of physiological saline does not elicit an increase in BP, suggesting osmolality as the stimulus. The osmopressor response to water, and Trpv4 thus represent new factors now implicated in the physiology of BP regulation.
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20 MeSH Terms
'Labile hypertension' can be due to autonomic nervous system failure.
Raj SR, Luther JM, Sato K, Diedrich A
(2009) Kidney Int 75: 860; author reply 860-1
MeSH Terms: Autonomic Nervous System, Baroreflex, Humans, Hypertension
Added October 27, 2014
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4 MeSH Terms
The impact of blood pressure and baroreflex sensitivity on wind-up.
Chung OY, Bruehl S, Diedrich L, Diedrich A
(2008) Anesth Analg 107: 1018-25
MeSH Terms: Adrenergic alpha-2 Receptor Antagonists, Adult, Back Pain, Baroreflex, Blood Pressure, Case-Control Studies, Cross-Over Studies, Double-Blind Method, Female, Humans, Hypertension, Male, Pain Management, Placebos, Yohimbine
Show Abstract · Added March 5, 2014
BACKGROUND - Elevated resting blood pressure (BP) and spontaneous baroreflex sensitivity (BRS) are associated with hypoalgesia to acute pain. These associations are significantly altered in chronic pain. We investigated whether degree of wind-up (marker for central sensitization) is similarly influenced by BP and BRS, and whether these associations are altered by chronic pain.
METHODS - BP and BRS (sequence method) were assessed in 30 healthy and 26 chronic back pain subjects who then completed a standardized thermal stimulation protocol to assess wind-up. This protocol was performed under placebo and alpha-2 adrenergic (ADRA2) blockade with yohimbine in counterbalanced order to test for the influence of ADRA2 mechanisms.
RESULTS - 1) In healthy controls, higher systolic BP was associated with lower wind-up (P < 0.05) but this was reversed in chronic pain subjects (P < 0.05); 2) higher BRS was associated with lower wind-up in healthy controls (P < 0.05) but not in the chronic pain group; 3) higher systolic BP was associated with lower BRS only in the chronic pain group (P < 0.05); and 4) ADRA2 receptor blockade did not significantly affect wind-up.
CONCLUSIONS - These findings suggest that hypoalgesia associated with elevated resting BP and BRS in healthy individuals involves both diminished central sensitization (reflected in wind-up) and enhanced descending inhibition. The presence of chronic pain significantly alters the nature of these interactions. The reversal of normal interactions between overlapping systems modulating cardiovascular systems and pain in chronic pain patients may shift the healthy buffering of BP and heart rate toward instability and eventual higher BP and cardiovascular morbidity.
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15 MeSH Terms