Evaluation of stroke volume estimation during orthostatic stress: the utility of Modelflow.

Advanced blood pressure monitoring devices contain algorithms that permit estimation of stroke volume (SV). Modelflow (Finapres Medical Systems) is one common method to non-invasively estimate beat-to-beat SV. However, Modelflow accuracy during profound reductions in SV is unclear. We aimed to compare SV estimation by Modelflow and echocardiography, at rest and during orthostatic challenge. We tested 13 individuals (age 24 ±â€…2 years; 7 female) using combined head-up tilt and graded lower body negative pressure, continued until presyncope. SV was derived by both Modelflow and echocardiography on multiple occasions while supine, during orthostatic stress, and at presyncope. SV index (SVI) was determined by normalising SV for body surface area. Bias and limits of agreement were determined using Bland-Altman analyses. Two one-sided tests (TOST) examined equivalency. Across all timepoints, Modelflow estimates of SV (73.2 ±â€…1.6 ml) were strongly correlated with echocardiography estimates (66.1 ±â€…1.3 ml) (r = 0.56, P  < 0.001) with a bias of +7.1 ±â€…21.1 ml. Bias across all timepoints was further improved when SV was indexed (+3.6 ±â€…12.0 ml.m -2 ). Likewise, when assessing responses relative to baseline, Modelflow estimates of SV (-23.4 ±â€…1.4%) were strongly correlated with echocardiography estimates (-19.2 ±â€…1.3%) (r = 0.76, P  < 0.001), with minimal bias (-4.2 ±â€…13.1%). TOST testing revealed equivalency to within 15% of the clinical standard for SV and SVI, both expressed as absolute values and relative to baseline. Modelflow can be used to track changes in SV during profound orthostatic stress, with accuracy enhanced with correction relative to baseline values or body size. These data support the use of Modelflow estimates of SV for autonomic function testing.

Pain associated with intravascular instrumentation reduces orthostatic tolerance and predisposes to vasovagal reactions in healthy young adults without needle phobia: a randomised controlled study.

PURPOSE: Vasovagal syncope (VVS), or fainting, is frequently triggered by pain, fear, or emotional distress, especially with blood-injection-injury stimuli. We aimed to examine the impact of intravenous (IV) instrumentation on orthostatic tolerance (OT; fainting susceptibility) in healthy young adults. We hypothesized that pain associated with IV procedures would reduce OT. METHODS: In this randomised, double-blind, placebo-controlled, cross-over study, participants (N = 23; 14 women; age 24.2 ± 4.4 years) underwent head-up tilt with combined lower body negative pressure to presyncope on three separate days: (1) IV cannulation with local anaesthetic cream (EMLA) (IV + EMLA); (2) IV cannulation with placebo cream (IV + Placebo); (3) sham IV cannulation with local anaesthetic cream (Sham + EMLA). Participants rated pain associated with IV procedures on a 1-5 scale. Cardiovascular (finger plethysmography and electrocardiogram; Finometer Pro), and forearm vascular resistance (FVR; brachial Doppler) responses were recorded continuously and non-invasively. RESULTS: Compared to Sham + EMLA (27.8 ± 2.4 min), OT was reduced in IV + Placebo (23.0 ± 2.8 min; p = 0.026), but not in IV + EMLA (26.2 ± 2.2 min; p = 0.185). Pain was increased in IV + Placebo (2.8 ± 0.2) compared to IV + EMLA (2.0 ± 2.2; p = 0.002) and Sham + EMLA (1.1 ± 0.1; p < 0.001). Orthostatic heart rate responses were lower in IV + Placebo (84.4 ± 3.1 bpm) than IV + EMLA (87.3 ± 3.1 bpm; p = 0.007) and Sham + EMLA (87.7 ± 3.1 bpm; p = 0.001). Maximal FVR responses were reduced in IV + Placebo (+ 140.7 ± 19.0%) compared to IV + EMLA (+ 221.2 ± 25.9%; p < 0.001) and Sham + EMLA (+ 190.6 ± 17.0%; p = 0.017). CONCLUSIONS: Pain plays a key role in predisposing to VVS following venipuncture, and our data suggest this effect is mediated through reduced capacity to achieve maximal sympathetic activation during orthostatic stress. Topical anaesthetics, such as EMLA, may reduce the frequency and severity of VVS during procedures requiring needles and intravascular instrumentation.

Exaggerated postural sway improves orthostatic cardiovascular and cerebrovascular control.

Introduction: Healthy individuals with poor cardiovascular control, but who do not experience syncope (fainting), adopt an innate strategy of increased leg movement in the form of postural sway that is thought to counter orthostatic (gravitational) stress on the cardiovascular system. However, the direct effect of sway on cardiovascular hemodynamics and cerebral perfusion is unknown. If sway produces meaningful cardiovascular responses, it could be exploited clinically to prevent an imminent faint. Methods: Twenty healthy adults were instrumented with cardiovascular (finger plethysmography, echocardiography, electrocardiogram) and cerebrovascular (transcranial Doppler) monitoring. Following supine rest, participants performed a baseline stand (BL) on a force platform, followed by three trials of exaggerated sway (anterior-posterior, AP; mediolateral, ML; square, SQ) in a randomized order. Results: All exaggerated postural sway conditions improved systolic arterial pressure (SAP, p = 0.001) responses, while blunting orthostatic reductions in stroke volume (SV, p < 0.01) and cerebral blood flow (CBFv, p < 0.05) compared to BL. Markers of sympathetic activation (power of low-frequency oscillations in SAP, p < 0.001) and maximum transvalvular flow velocity (p < 0.001) were reduced during exaggerated sway conditions. Responses were dose-dependent, with improvements in SAP (p < 0.001), SV (p < 0.001) and CBFv (p = 0.009) all positively correlated with total sway path length. Coherence between postural movements and SAP (p < 0.001), SV (p < 0.001) and CBFv (p = 0.003) also improved during exaggerated sway. Discussion: Exaggerated sway improves cardiovascular and cerebrovascular control and may supplement cardiovascular reflex responses to orthostatic stress. This movement provides a simple means to boost orthostatic cardiovascular control for individuals with syncope, or those with occupations that require prolonged motionless standing.

Faintly tired: a systematic review of fatigue in patients with orthostatic syncope.

BACKGROUND: Orthostatic syncope (transient loss of conscious when standing-fainting) is common and negatively impacts quality of life. Many patients with syncope report experiencing fatigue, sometimes with "brain fog", which may further impact their quality of life, but the incidence and severity of fatigue in patients with syncope remain unclear. In this systematic review, we report evidence on the associations between fatigue and conditions of orthostatic syncope. METHODS: We performed a comprehensive literature search of four academic databases to identify articles that evaluated the association between orthostatic syncope [postural orthostatic tachycardia syndrome (POTS), vasovagal syncope (VVS), orthostatic hypotension (OH)] and fatigue. Studies were independently screened using a multi-stage approach by two researchers to maintain consistency and limit bias. RESULTS: Our initial search identified 2797 articles, of which 13 met our inclusion criteria (POTS n = 10; VVS n = 1; OH n = 1; VVS and POTS n = 1). Fatigue scores were significantly higher in patients with orthostatic syncope than healthy controls, and were particularly severe in those with POTS. Fatigue associated with orthostatic syncope disorders spanned multiple domains, with each dimension contributing equally to increased fatigue. "Brain fog" was an important symptom of POTS, negatively affecting productivity and cognition. Finally, fatigue was negatively associated with mental health in patients with POTS. CONCLUSION: In conditions of orthostatic syncope, fatigue is prevalent and debilitating, especially in patients with POTS. The consideration of fatigue in patients with orthostatic disorders is essential to improve diagnosis and management of symptoms, thus improving quality of life for affected individuals.

The effect of water temperature on orthostatic tolerance: a randomised crossover trial.

PURPOSE: Bolus water drinking, at room temperature, has been shown to improve orthostatic tolerance (OT), probably via sympathetic activation; however, it is not clear whether the temperature of the water bolus modifies the effect on OT or the cardiovascular responses to orthostatic stress. The aim of this study was to assess whether differing water temperature of the water bolus would alter time to presyncope and/or cardiovascular parameters during incremental orthostatic stress. METHODS: Fourteen participants underwent three head-up tilt (HUT) tests with graded lower body negative pressure (LBNP) continued until presyncope. Fifteen minutes prior to each HUT, participants drank a 500 mL bolus of water which was randomised, in single-blind crossover fashion, to either room temperature water (20 °C) (ROOM), ice-cold water (0-3 °C) (COLD) or warm water (45 °C) (WARM). Cardiovascular parameters were monitored continuously. RESULTS: There was no significant difference in OT in the COLD (33 ± 3 min; p = 0.3321) and WARM (32 ± 3 min; p = 0.6764) conditions in comparison to the ROOM condition (31 ± 3 min). During the HUT tests, heart rate and cardiac output were significantly reduced (p < 0.0073), with significantly increased systolic blood pressure, stroke volume, cerebral blood flow velocity and total peripheral resistance (p < 0.0054), in the COLD compared to ROOM conditions. CONCLUSIONS: In healthy controls, bolus cold water drinking results in favourable orthostatic cardiovascular responses during HUT/LBNP without significantly altering OT. Using a cold water bolus may result in additional benefits in patients with orthostatic intolerance above those conferred by bolus water at room temperature (by ameliorating orthostatic tachycardia and enhancing vascular resistance responses). Further research in patients with orthostatic intolerance is warranted.

Evaluating the Impact of Orthostatic Syncope and Presyncope on Quality of Life: A Systematic Review and Meta-Analysis.

PURPOSE: Syncope (transient loss of consciousness and postural tone) and presyncope are common manifestations of autonomic dysfunction that are usually triggered by orthostasis. The global impact of syncope on quality of life (QoL) is unclear. In this systematic review, we report evidence on the impact of syncope and presyncope on QoL and QoL domains, identify key factors influencing QoL in patients with syncopal disorders, and combine available data to compare QoL between syncopal disorders and to population normative data. METHODS: A comprehensive literature search of academic databases (MEDLINE (PubMed), Web of Science, CINAHL, PsycINFO, and Embase) was conducted (February 2021) to identify peer-reviewed publications that evaluated the impact of vasovagal syncope (VVS), postural orthostatic tachycardia syndrome (POTS), or orthostatic hypotension (OH) on QoL. Two team members independently screened records for inclusion and extracted data relevant to the study objectives. RESULTS: From 12,258 unique records identified by the search, 36 studies met the inclusion criteria (VVS: n = 20; POTS: n = 13; VVS and POTS: n = 1; OH: n = 2); 12 distinct QoL instruments were used. Comparisons of QoL scores between patients with syncope/presyncope and a control group were performed in 16 studies; significant QoL impairments in patients with syncope/presyncope were observed in all studies. Increased syncopal event frequency, increased autonomic symptom severity, and the presence of mental health disorders and/or comorbidities were associated with lower QoL scores. CONCLUSION: This review synthesizes the negative impact of syncope/presyncope on QoL and identifies research priorities to reduce the burden of these debilitating disorders and improve patient QoL.

Reliance on vascular responses for the maintenance of blood pressure in healthy older adults - Insights from the Valsalva maneuver.

Effective baroreflex-mediated cardiac and vascular resistance responses are crucial for homeostatic blood pressure control. We investigated the impacts of age and sex on arterial blood pressure regulation during a standard supine Valsalva maneuver (40 mmHg, 20s) in 46 healthy young and 25 healthy older adults. Noninvasive, continuous cardiovascular parameters were recorded. In older adults, cardiac output (older: -58.4 ± 2.4%; young: -40.8 ± 1.4%; p < 0.001) and stroke volume (older: -63.6 ± 2.6%; young: -48.7 ± 1.9%; p < 0.001) fell more than in young adults and was compensated by augmented vascular resistance responses (older: +189.8 ± 17.6%; young: +105.8 ± 6.7; p < 0.001); heart rate responses were attenuated in older adults. Male and female responses were comparable in their respective age groups.

Forearm vascular resistance responses to the Valsalva maneuver in healthy young and older adults.

PURPOSE: Effective end-organ peripheral vascular resistance responses are critical to blood pressure control while upright, and prevention of syncope (fainting). The Valsalva maneuver (VM) induces blood pressure decreases that evoke baroreflex-mediated vasoconstriction. We characterized beat-to-beat forearm vascular resistance (FVR) responses to the VM in healthy adults, evaluated the impact of age and sex on these responses, and investigated their association with orthostatic tolerance (OT; susceptibility to syncope). We hypothesized that individuals with smaller FVR responses would be more susceptible to syncope. METHODS: Healthy young (N = 36; 19 women; age 25.4 ± 4.6 years) and older (N = 21; 12 women; age 62.4 ± 9.6 years) adults performed a supine 40 mmHg, 20 s VM. Graded 60° head-up-tilt with combined lower body negative pressure continued to presyncope was used to determine OT. Non-invasive beat-to-beat blood pressure and heart rate (finger plethysmography) were recorded continuously. FVR was calculated as mean arterial pressure (MAP) divided by brachial blood flow velocity (Doppler ultrasound) relative to baseline. RESULTS: The VM produces a distinctive FVR pattern that peaks (+137.1 ± 11.6%) in phase 2B (17.5 ± 0.3 s) as the baroreflex responds to low-pressure perturbations. This response increased with age overall (p < 0.001) and within male (p = 0.030) and female subgroups (p < 0.001). Maximum FVR during the VM was significantly correlated with maximal tilt FVR (r = 0.364; p = 0.0153) and with OT when expressed relative to the MAP decrease in phase 2A (Max FVR (%)/MAP2A-1; r = 0.337; p = 0.0206). CONCLUSION: This is the first characterization of FVR responses to the VM. The VM elicits large baroreflex-mediated increases in FVR; small FVR responses to the VM may indicate susceptibility to syncope.

Pubertal Hormonal Changes and the Autonomic Nervous System: Potential Role in Pediatric Orthostatic Intolerance.

Puberty is initiated by hormonal changes in the adolescent body that trigger physical and behavioral changes to reach adult maturation. As these changes occur, some adolescents experience concerning pubertal symptoms that are associated with dysfunction of the autonomic nervous system (ANS). Vasovagal syncope (VVS) and Postural Orthostatic Tachycardia Syndrome (POTS) are common disorders of the ANS associated with puberty that are related to orthostatic intolerance and share similar symptoms. Compared to young males, young females have decreased orthostatic tolerance and a higher incidence of VVS and POTS. As puberty is linked to changes in specific sex and non-sex hormones, and hormonal therapy sometimes improves orthostatic symptoms in female VVS patients, it is possible that pubertal hormones play a role in the increased susceptibility of young females to autonomic dysfunction. The purpose of this paper is to review the key hormonal changes associated with female puberty, their effects on the ANS, and their potential role in predisposing some adolescent females to cardiovascular autonomic dysfunctions such as VVS and POTS. Increases in pubertal hormones such as estrogen, thyroid hormones, growth hormone, insulin, and insulin-like growth factor-1 promote vasodilatation and decrease blood volume. This may be exacerbated by higher levels of progesterone, which suppresses catecholamine secretion and sympathetic outflow. Abnormal heart rate increases in POTS patients may be exacerbated by pubertal increases in leptin, insulin, and thyroid hormones acting to increase sympathetic nervous system activity and/or catecholamine levels. Given the coincidental timing of female pubertal hormone surges and adolescent onset of VVS and POTS in young women, coupled with the known roles of these hormones in modulating cardiovascular homeostasis, it is likely that female pubertal hormones play a role in predisposing females to VVS and POTS during puberty. Further research is necessary to confirm the effects of female pubertal hormones on autonomic function, and their role in pubertal autonomic disorders such as VVS and POTS, in order to inform the treatment and management of these debilitating disorders.

Intermittent calf compression reverses lower limb pooling and improves cardiovascular control during passive orthostasis.

When upright, venous pooling and capillary filtration reduce the effective circulating volume and are key contributors to susceptibility to syncope (fainting). Recurrent syncope has a devastating impact on quality of life. Static calf compression garments are frequently prescribed for patients with syncope, but have questionable efficacy. Intermittent calf compression, which mimics the skeletal muscle pump to minimize pooling and filtration, is a potential alternative that holds promise for the management of syncope. We aimed to evaluate use of intermittent calf compression compared to commonly prescribed compression stockings, and determine the optimal intermittent calf compression paradigm, for improvement of orthostatic fluid shifts and cardiovascular control. We evaluated heart rate, blood pressure, stroke volume, cardiac output and peripheral resistance (finger plethysmography with Modelflow™) and calf pooling and filtration (calf circumference; strain gauge plethysmography) during a series of 10-min head-upright tilts. We first compared (protocol one) low (ICLF; 4 s on, 11 s off) and high (ICHF; 4 s on, 6 s off) frequency 0-100 mm Hg intermittent calf compression with static elastic and inelastic compression stockings and a placebo condition (n = 19, 5 males, aged 23.5 ±â€¯0.1 years). We then compared (protocol two) ICLF applied at 0-40 mm Hg, 0-60 mm Hg, 0-80 mm Hg and 0-100 mm Hg as well as a placebo condition (n = 15, 5 males, aged 22.7 ±â€¯0.5 years). The intervention order was randomized. In protocol one, all compression conditions significantly reduced calf circumference (p < 0.001) compared to placebo after 10-min upright; however, this reduction was greater in ICLF (-0.88 ±â€¯0.18%) and ICHF (-1.14 ±â€¯0.21%) conditions than both elastic (+0.49 ±â€¯0.17%) and inelastic (-0.01 ±â€¯0.19%) compression (p < 0.001). ICLF and ICHF, but not elastic or inelastic compression, were associated with improved stroke volume (p ≤ 0.001), allowing cardiac output to be maintained at a reduced heart rate (p < 0.001) without increases in vascular resistance responses, increasing hemodynamic reserve. ICHF showed no significant benefit over ICLF, evidenced by the lack of significant difference between ICLF and ICHF in any parameter measured. In protocol two, 0-60 mm Hg ICLF was considered the optimal intermittent compression because it was the lowest pressure that abolished the increase in calf circumference during orthostasis, while improving SV (p = 0.002), and reducing HR (p < 0.001) throughout tilt. Intermittent calf compression from 0 to 60 mm Hg ICLF is the optimal intermittent compression paradigm to ameliorate orthostatic fluid shifts and improve hemodynamic control. Commonly prescribed static calf compression garments do not improve orthostatic cardiovascular responses.

Intermittent Calf Compression Delays the Onset of Presyncope in Young Healthy Individuals.

Orthostatic fluid shifts reduce the effective circulating volume and thus contribute to syncope susceptibility. Recurrent syncope has a devastating impact on quality of life and is challenging to manage effectively. To blunt orthostatic fluid shifts, static calf compression garments are often prescribed to patients with syncope, but have questionable efficacy. Intermittent calf compression, which mimics the skeletal muscle pump to minimize pooling and filtration, holds promise for the management of syncope. We aimed to evaluate the effectiveness of intermittent calf compression for increasing orthostatic tolerance (OT; time to presyncope). We conducted a randomized single-blind crossover study, in which participants (n = 21) underwent three graded 60° head-up-tilt tests to presyncope with combined lower body negative pressure on separate days. Low frequency intermittent calf compression (ICLF; 4 s on and 11 s off) at 0-30 and 0-60 mmHg was applied during two tests and compared to a placebo condition where the garment was fitted, but no compression applied. We measured continuous leg circumference changes (strain gauge plethysmography), cardiovascular responses (finger plethysmography; Finometer Pro), end tidal gases (nasal cannula), and cerebral blood flow velocity (CBFv, transcranial Doppler). The 0-60 mmHg ICLF increased OT (33 ± 2.2 min) compared to both placebo (26 ± 2.4 min; p < 0.001) and 0-30 mmHg ICLF (25 ± 2.7 min; p < 0.001). Throughout testing 0-60 mmHg ICLF reduced orthostatic fluid shifts compared to both placebo and 0-30 mmHg ICLF (p < 0.001), with an associated improvement in stroke volume (p < 0.001), allowing blood pressure to be maintained at a reduced heart rate (p < 0.001). In addition, CBFv was higher with 0-60 mmHg ICLF than 0-30 mmHg ICLF and placebo (p < 0.001). Intermittent calf compression is a promising novel intervention for the management of orthostatic intolerance, which may provide affected individuals renewed independence and improved quality of life.

Genomic structure and promoter activity of the human testis lactate dehydrogenase gene.

The structure of the gene encoding the human testis-specific isozyme of lactate dehydrogenase (LDH) has been characterized and a regulatory region identified by promoter activity. The single-copy ldh-c gene has two alternative 5' noncoding exons and seven coding exons comprising an approximately 40-kb locus. The gene does not contain the canonical TATA or CAAT promoter sequences, and ribonuclease protection experiments suggest multiple transcription start sites. In the present study an immortalized murine germ cell line was used to detect promoter activity driven by 5' sequence of human ldh-c with lacZ as the reporter gene. Reporter gene activity was nondetectable when promoter constructs were transfected into nongerminal cells.