Orthostatic Changes in Hemodynamics and Cardiovascular Biomarkers in Dysautonomic Patients

PLOS ONE, Dec 2019

Background Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained. Methods Six-hundred-and-seventy-one patients (299 males; 55±22 years) with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1st (reference) with 4th quartile of 3 min and maximal ΔSBP/ΔHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively. Results Higher resting CT-proET-1 predicted BP fall at 3min (Odds ratio (OR) per 1 SD: 1.62, 95%CI 1.18–2.22; p = 0.003), and max BP fall during HUT (1.82, 1.28–2.61; p = 0.001). Higher resting CT-proAVP predicted BP fall at 3min (1.33, 1.03–1.73; p = 0.03), which was also associated with increase in CT-proAVP (1.86, 1.38–2.51; p = 0.00005) and epinephrine (1.47, 1.12–1.92; p = 0.05) during HUT. Lower resting MR-proANP predicted tachycardia at 3min (0.37, 0.24–0.59; p = 0.00003), and max tachycardia during HUT (0.47, 0.29–0.77; p = 0.002). Further, tachycardia during HUT was associated with increase in epinephrine (1.60, 1.15–2.21; p = 0.005), and norepinephrine (1.87, 1.38–2.53; p = 0.005). Conclusions Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT-proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine.

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Orthostatic Changes in Hemodynamics and Cardiovascular Biomarkers in Dysautonomic Patients

June Orthostatic Changes in Hemodynamics and Cardiovascular Biomarkers in Dysautonomic Patients David Nilsson 0 1 2 Richard Sutton 0 1 2 Widet Tas 0 1 2 Philippe Burri 0 1 2 Olle Melander 0 1 2 Artur Fedorowski 0 1 2 0 1 Department of Clinical Sciences, Lund University, Clinical Physiology and Nuclear Medicine Unit, Skåne University Hospital, Malmö, Sweden, 2 National Heart and Lung Institute, Imperial College, St Mary's Hospital Campus , London , United Kingdom , 3 Department of Clinical Sciences, Lund University, Hypertension and Cardiovascular Disease Group, Clinical Research Centre, Skåne University Hospital, Malmö, Sweden, 4 Department of Cardiology, Skåne University Hospital , Malmö , Sweden 1 Funding: This study was supported by grants from the European Research Council (StG 282225), Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malmö University Hospital, the Albert Påhlsson Research Foundation, the Crafoord Foundation, the Ernhold Lundströms Research Foundation, the Region Skåne, the Hulda and Conrad Mossfelt Foundation, the King Gustaf V and Queen Victoria Foundation, the Wallenberg Foundation, the Lennart Hanssons Memorial 2 Academic Editor: Peyman Björklund, Uppsala University , SWEDEN - Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained. Six-hundred-and-seventy-one patients (299 males; 55±22 years) with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1st (reference) with 4th quartile of 3 min and maximal ΔSBP/ΔHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively. Higher resting CT-proET-1 predicted BP fall at 3min (Odds ratio (OR) per 1 SD: 1.62, 95% CI 1.18–2.22; p = 0.003), and max BP fall during HUT (1.82, 1.28–2.61; p = 0.001). Higher resting CT-proAVP predicted BP fall at 3min (1.33, 1.03–1.73; p = 0.03), which was also associated with increase in CT-proAVP (1.86, 1.38–2.51; p = 0.00005) and epinephrine (1.47, 1.12–1.92; p = 0.05) during HUT. Lower resting MR-proANP predicted tachycardia at 3min (0.37, 0.24–0.59; p = 0.00003), and max tachycardia during HUT (0.47, 0.29–0.77; p = 0.002). Further, tachycardia during HUT was associated with increase in epinephrine (1.60, 1.15–2.21; p = 0.005), and norepinephrine (1.87, 1.38–2.53; p = 0.005). Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT-proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine. “Orthostatic intolerance” refers to a group of clinical conditions in which symptoms induced by upright posture are ameliorated by recumbency[1]. On standing, the gravitational volume shift causes a redistribution of circulating blood by pooling within the capacitance vessels below the diaphragm [2]. A normal hemodynamic response to changes in posture requires normal function of the cardiovascular, endocrine, and autonomic nervous systems [3]. In cardiovascular dysautonomic states, the circulatory redistribution may lead to hypotension and/or tachycardia, thus compromising cerebral blood flow with symptoms such as blurred vision, fatigue, dizziness, and, in the most extreme cases, syncope[4]. Two main variants of orthostatic intolerance, orthostatic hypotension (OH) and postural tachycardia syndrome (POTS), distinctly differ from syncope due to classical vasovagal reflex [5]. In classical reflex syncope, cardiovascular reflexes become transiently inappropriate while in orthostatic hypotension (OH) sympathetic efferent activity may be chronically impaired. The etiology of POTS, which shares features of a chronic disorder with OH, remains under debate. Some studies have indicated that neuropeptides may play an important role in cardiovascular dysautonomia and syncope [6]. We have previously reported that suppression of atrial natriuretic peptide is associated with vasovagal reflex syncope, whereas increased endothelin-1 can be found in OH [7]. Further, a study measuring circulating vasopressin and epinephrine during head-up tilt test (HUT) has shown that these neurohormones are elevated prior to reflex syncope, while norepinephrine changes little [8]. The aim of this study was to explore how circulating levels of the most impor (...truncated)


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David Nilsson, Richard Sutton, Widet Tas, Philippe Burri, Olle Melander, Artur Fedorowski. Orthostatic Changes in Hemodynamics and Cardiovascular Biomarkers in Dysautonomic Patients, PLOS ONE, 2015, 6, DOI: 10.1371/journal.pone.0128962