Download WOUTER VVSPARTiiFINALRS - Spiral

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WOUTER 17 OCTOBRE revision of WW dd octobre 11 2016 with final track
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changes
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Guideline Heart Rhythm : Reviews 6000 words including references, legends
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and tables. 8 Figures/ Tables allowed
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WOUTER dd octobre 16th
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TOTAL WORD count 7536 - 21 (legends counted twice) = 7421 – 472 = 6949
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Manuscript 3841 (about the same as 3683 in Part I)
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References 2378 (about 100, allowed by Heart Rhythm ?? )
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Legends 472 (legend figure 5 still missing)
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Table 416
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The pathophysiology of the vasovagal response
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David L Jardine 1, Wouter Wieling 2 , Michele Brignole 3 , Jacques W.M. Lenders 4, ,
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Richard Sutton 5, Julian Stewart
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1 Department
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Christchurch, New Zealand
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2
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Amsterdam, The Netherlands
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3 Department
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Italy
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4 Department
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The Netherlands and Department of Internal Medicine III, Technical University
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Dresden, Germany
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5 National
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6 Departments
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Valhalla, NY 10595
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Running title: the four phases of the vasovagal response
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of General Medicine, Christchurch Hospital, University of Otago,
Departments of Internal Medicine, Academic Medical Centre, University of
of Cardiology, Arrhythmologic Centre, Ospedali del Tigullio, Lavagna,
of Internal Medicine, Radboud University Medical Centre, Nijmegen,
Heart & Lung institute, Imperial College, London, United Kingdom
of Pediatrics, Physiology and Medicine. New York Medical College.
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Manuscript with references, legends and Table ????? words; Abstract ????
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5 Figures, 1 Table
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Conflict of interest: None
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Corresponding author W Wieling. Academic Medical Centre.
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Meibergdreef 9 1105 AZ Amsterdam, The Netherlands
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Tel +31 20-5668224, Email: [email protected]
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Abstract
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Introduction
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The classical literature (1920-1980) concerning the mechanisms underlying
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vasovagal syncope was recently reviewed in Heart Rhythm [1=Wieling 2016]. It was
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concluded that interpretation of data from the early reports was severely hampered
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by the inability to record rapid hemodynamic changes. Furthermore, when blood
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pressure is rapidly falling, the exact timing of measurements is crucial: the distinction
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between measurements made just before syncope as opposed to during fully
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developed syncope (loss of consciousness) is paramount and key to understanding
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the sequence of hypotensive mechanisms responsible. Vasodilatation was
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suggested by Lewis to be the defining mechanism of vasovagal syncope, and
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Barcoft’s obervations during fully developed “heroic” faints supported this view.
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However, we argued that vasodilatation may not be the main hypotensive
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mechanism [1].
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After 1980, techniques became available to monitor rapid hemodynamic changes
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continuously and noninvasively. Penaz and Wesseling introduced the Finapres or
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volume clamp method that allowed continuous noninvasive measurement of finger
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arterial pressure [2=Wesseling 1995, 3=Imholz 1998]. The Modelflow algorithm has
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subsequently allowed the computation of stroke volume (SV) from the area under the
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systolic pulse curve, and thereby calculation of cardiac output (CO) and systemic
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vascular resistance (SVR) [4=Wesseling 1993, 5=Harms1999]. These extraordinary
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scientific developments enabled clinicians and researchers to study noninvasively the
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hemodynamics of vasovagal syncope on a beat-to-beat basis during laboratory
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induced vasovagal syncope [6=Westerhof 2015].
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Several other recently developed techniques have been introduced to monitor other
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physiological parameters during vasovagal syncope. Impedance measurements
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provide qualitative and directional changes of segmental volume induced by
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gravitational stress [7=Matzen 1991, 8=Stewart 2004]. Direct recordings of muscle
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sympathetic nerve activity (MSNA) using the microneurographic technique allows
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continuous monitoring of efferent muscle vasoconstrictor sympathetic activity
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[9=Wallin 1982]. Measurements of venous plasma norepinephrine concentrations
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have been used for a long time as an indirect global index of sympathetic activity.
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However, without taking into account systemic and organ clearance of
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catecholamines, venous levels of norepinephrine are not an accurate measure of
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total body sympathetic activity. By contrast, venous plasma epinephrine levels can be
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used as a reliable estimate of the adrenomedullary sympathetic activity, because
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epinephrine is exclusively derived from the adrenal medulla [10=Esler 1990,
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11=Goldstein 2003].
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On the basis of the advances described above we find it relevant to extend our first
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review on the mechanisms underlying vasovagal syncope and include studies
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published over the last 35 years. We analysed studies of healthy male and female
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subjects and patients with recurrent vasovagal syncope who were monitored using
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modern noninvasive continuous monitoring technology in various experiments to
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model orthostatic vasovagal syncope. We focused on results that might help us
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explain whether development of hypotension during vasovagal syncope is dominated
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by arterial vasodilatation or a decrease in cardiac output.
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Methods
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Referenced papers were selected manually from our own databases. For subject and
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author searches, Pubmed was used as the preferred database. All available studies
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were checked for relevance to the present review. For the mechanisms involved in
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orthostatic BP control in healthy subjects we refer to standard texts [12=Rowell 1993,
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13=Wieling 2008]. The capabilities and limitations of the different continuous non-
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invasive monitoring techniques will not be covered.
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The four phases of the vasovagal response
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Careful analysis of continuous BP recordings (and other derived variables) during
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orthostatic stress allows us to divide the sequence of hemodynamic events leading to
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vasovagal syncope into 4 phases: phase 1: early stabilisation, phase 2: circulatory
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instability (early presyncope) phase 3: terminal hypotension (late presyncope) and
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syncope, phase 4: recovery. Figure 1 provides an example of a subject progressing
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through the 4 phases during a tilt test combined with lower body negative pressure
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(LBNP)
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Figure 1 about here
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Phase
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Legend. Vasovagal response monitored in a 48-year-old healthy male (author WW)
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without a fainting history using Finapres technology and thoracic impedance (TI). An
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increase in TI documents a decrease in central blood volume (CBV) i.e. the reservoir
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of blood available in the four cardiac chambers and in the pulmonary and great
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thoracic vessels. Fainting was induced by a combination of head-up tilt with -20
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mmHg followed by -40 mm Hg lower body negative pressure enabling a large shift of
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blood to the lower body in a controlled and reproducible way [14=El-Bedawi 1994]. 4
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phases can be distinguished: 1, early stabilisation (first 22 minutes), 2, circulatory
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instability (28-32 min), 3, terminal hypotension and syncope, and 4, recovery (38-42
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min)(Wieling unpublished). Abbreviations: BP= blood pressure, MAP = mean blood
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pressure, TI= thoracic impedance, HR= heart rate, SV= stroke volume, CO = cardiac
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output, SVR = systemic vascular resistance
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Phase 1. Early stabilisation: The adjustments from supine to head up tilt at 0-2
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minutes show a rapid increase in TI (decrease in CBV) resulting in decreases in SV
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and CO despite an increase in HR. MAP is maintained by an increase in SVR. By this
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mechanism, MAP remains stable for over 20 minutes despite a progressive fall in
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CO.
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Phase 2. Circulatory instability (or early presyncope): At 28-32 minutes, the addition
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of -20 mm Hg LBNP to head-up tilt causes further decreases in CBV and CO.
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Systolic blood pressure and pulse pressure decrease, and BP variability increases
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markedly indicating increased sympathetic activity (see below). However, MAP is
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maintained by a further increase in SVR.
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Phase 3. Terminal hypotension (or late presyncope): At 38-40 min, increasing LBNP
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further to -40 mmHg induces a fall in HR and CO. Although SVR decreases, it
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remains far above supine control, BP variability virtually disappears (see below) and
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a classical vasovagal faint occurs.
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Phase 4. Recovery: After tilt-down and cessation of LBNP, there is a rapid recovery
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of BP to baseline levels followed by an overshoot.
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Further analyses of tilt and LBNP studies (similar to that shown in figure 1) indicates
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that the timing and duration of the 4 phases differ between healthy subjects and
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patients, but the order of events is consistent and generally accepted by researchers
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despite varying terminologies [15=Julu 2003, 16=Hainsworth 2004, 17=Verheyden
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2008, 18=Jardine 2013 19=Stewart 2013, 20=Stewart 2017]. A similar sequence has
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also been demonstrated during hemorrhage in humans [21=Barcroft 1944,22=
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Secher 2004] and animals [23Schadt 1991].
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Phase 1. Early phase of stabilization of tilt/standing and low levels of LBNP
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A change of posture induces a rapid and large gravitational blood volume shift. The
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bulk of venous pooling occurs within the first 10s. The transfer of blood is almost
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complete within 2- 3 min of orthostatic stress. About 500-1000 cc of blood (10-20% of
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the total blood volume) is transferred from the central thoracic blood volume into
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vascular bed below the diaphragm (Figure 2). Intravascular blood volume may
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decrease further following transcapillary filtration of fluid into the interstitial spaces in
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the legs [24=Smit 1999, 8=Stewart 2004].
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The figure demonstrates representative changes in thoracic, splanchnic, pelvic, and
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leg impedances induced by head-up tilt (dotted lines) in a healthy adolescent in the
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upper panels. Impedance changes correspond to calculated fractional changes in
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regional blood volumes in lower panels. Impedance scales are not all the same.
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Thoracic impedance increases (central blood volume decreases) while other
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segmental impedances decrease (regional blood volumes increase) with tilt up and
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revert towards control when tilted down (revised after Stewart 2004=8 )
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LBNP (up to the level of the iliac crest in the horizontal position) has been used to
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simulate loss of CBV as a model for hemorrhage 25=[Johnson 2014]. Recent studies,
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however, suggest that LBNP does not reproduce splanchnic pooling observed during
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actual orthostasis (standing or head-up tilting). Thus, LBNP without head-up tilt may
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simulate haemorrhage but not orthostasis [26=Taneja 2007, 27=Wieling 2014 ].
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Since 1980, many studies of subjects with recurrent vasovagal syncope have
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documented normal hemodynamic and MSNA levels both at baseline and during
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early tilt [28=Morillo 1997,29= Jardine 1998, 30=Kamyia 2005, 31=Fu 2012]. The
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rapid decrease in CBV results in a fall in CO of 10-20%, because the increase in HR
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does not compensate for the fall in SV (Figure 1) [32=Hainsworth 2000]. MAP is
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maintained by an increase in SVR. There is considerable variation between subjects
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in changes in CO and SVR in the early phase of stabilization [17=Verheyden 2008,
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33=Fu 2003, 34=Fuca 2006, 35=Nigro 2012]. In children, teenagers and young
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adults with recurrent vasovagal syncope, the early phase of stabilisation is different.
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There is a more pronounced postural tachycardia and an attenuated increase in SVR
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as early as 1 minute after upright tilt/ standing [36=Dambrink 1991, 37=ten Harkel
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1993 ,38=de Jong-de Vos van Steenwijk 1995,]. Some studies have suggested there
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may be a variant group with low-normal resting BP, mild postural hypotension and
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variable MSNA responses to tilt [39=Mosqueda-Garcia 1997, 40=Vadaadi 2011]
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SVR is mediated by sympathetic stimulation of alpha receptors causing
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vasoconstriction of skeletal muscle and richly innervated visceral beds in response
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to unloading of the carotid baroreceptors [12=Rowell 1993]. The present view is that
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arteriolar vasoconstriction is “designed” to divert blood away from the splanchnic
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capacitance vessels as soon as orthostatic stress is applied. Splanchnic arteriolar
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constriction effectively limits excessive filling of capacitance vessels by allowing
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passive venous recoil to direct blood back to the heart [41=Hirsch 1989, 12=Rowell
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1993, 42=Hainsworth 2005, 43=Gelman 2004, 44=Gelman2008]. Active
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venoconstriction may also contribute [45=Roth 1986, 46=Roth1990]. Although the
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splanchnic vasculature contains approximately 25% of blood volume and
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vasoconstricts by about 40% during severe orthostatic stress, we know very little
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about the sympathetic control of this mechanism in humans [12=Rowell 1993,
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42=Hainsworth 2005]. On the other hand, sympathetic control of vasoconstriction in
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skeletal muscle has been extensively documented [47=Jacobsen 1992, 29=Jardine
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1998, 48=Fu 2006, 49=Ryan 2012]. In muscles (unlike the viscera), sympathetic
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venous innervation is sparse and active venoconstriction does not occur during
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baroreflex unloading. Venous filling here is totally controlled by arterial
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vasoconstriction, passive venous recoil and the muscle pump [12= Rowell 1993,
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50=Stewart 2001]. During orthostasis induced by active standing or tilt, a static
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increase in skeletal muscle tone opposes pooling of blood in limb veins. Increases in
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skeletal muscle tone are a key factor in orthostatic adjustment [12=Rowell 1993,
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13Wieling 2008]. Accordingly, in recent years it has been shown that physical
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counter-pressure maneuvers such as lower body muscle tensing can abort an
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impending vasovagal faint [51=Krediet 2005, 52=Wieling 2015].
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Phase 2. Circulatory instability
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After normal early adjustments to orthostasis, patients and controls destined to faint
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during tilt, standing or LBNP enter into phase 2. This phase refers to circulatory
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instability (or early presyncope) [16=Hainsworth 2004, 18=Jardine 2013]. Continuous
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BP records have demonstrated increased variability at this time, mainly because of
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oscillations in the 0.1 Hz frequency domain, known as Mayer waves (Figures 1 and
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3) [37=Ten Harkel 1993, 53=Furlan 2000, 15=Julu 2003, 54=Hausenloy 2009,
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55=Barbic 2015] and further increases in HR, especially in young subjects. The
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increase in 0.1 Hz blood pressure oscillations indicate reduced central blood volume,
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intact sympathetic baroreflex loops, and increased sympathetic activity directed to the
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blood vessels.. Despite these adjustments, there is usually a gradual fall in MAP
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(approximately 20 mmHg) in Phase 2 over a variable time (2- 5 minutes). (Figs 1 and
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3).
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Figure 3 somewhere here.
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Blood pressure (BP), muscle sympathetic nerve recordings (MSNA) and cardiac
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output (CO) measurements during the 4 phases of syncope in a tilted patient. During
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Phase 1, BP is maintained by a rapid increase in MSNA and vasoconstriction. Note
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the Mayer waves in the BP tracing (0.1Hz). CO falls despite a minor increase in HR.
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During phase 2 there is a progressive, gradual fall in BP and CO despite further
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increases in HR and MSNA. (Note the disappearance of the Mayer waves). During
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the last minute of Phase 3, BP falls more rapidly whereas slowing of HR and MSNA
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burst frequency occur only seconds before syncope. During recovery, MSNA is
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maintained despite a rapid increase in BP (from Jardine, unpublished.]
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In phase 2 the progressive increase in SVR is mediated by further vasoconstriction
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of visceral and skeletal vessels, although as in phase 1, increased sympathetic nerve
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activity has only been demonstrated in skeletal muscle [ 56=Vissing 1989, 57=Rea
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1989, 58=Joyner 1990, 47=Jacobsen 1992, 59=Jardine 1997, 28=Morillo 1997,
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29=Jardine 1998, 60=Brown 2000, 30=Kamiya 2004, 31=Fu 2012]. Furthermore
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vasoconstriction is not universal. In a subgroup of children, teenagers and some
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younger adult subjects there is significant systemic vasodilatation [37=ten Harkel
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1993, 38=de Jong-de Vos van Steenwijk 1995, 61=Thomas 2010, 31=Fu 2012,
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62=Stewart 2016]. The mechanism for this is uncertain, but may relate to increased
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secretion of adrenaline (a circulating vasodilator) in younger patients [63=Benditt
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2012].
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During phase 2, in addition to the gradual fall in MAP, there is also a modest fall in
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cerebral blood flow velocity and therefore calculated cerebrovascular resistance
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remains constant despite an increase in ventilation [64=Schondorf 1997, 65=Carey
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2001]. Consistent with this, a relatively early fall in cerebral perfusion has also been
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demonstrated using near-infrared spectroscopy (NIRS), a noninvasive measure of
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cerebral oxygenation [66=Colier 1997]. These changes are not associated with any
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hypotensive symptoms [67=Szufladowicz 2004].
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Phase 3. Terminal hypotension and Syncope
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Terminal hypotension refers to “late presyncope” or the rapid fall in SBP [by about 50
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mmHg] over the final 30-60 seconds before syncope. This rapid fall is usually
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symptomatic. When absolute SBP falls below 50- 60 mmHg at heart level, syncope
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(loss of consciousness) occurs [68=Wieling 2009].
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We retrieved 8 studies that addressed the course of BP, HR, SV, CO, and SVR using
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pulse wave analysis during tilt-induced vasovagal syncope in healthy controls and
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patients with suspected vasovagal syncope [see table].
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Table 1 somewhere here
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The values for baseline and early stabilization after tilt [phase 1] are normal and
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consistent between studies. Some of the variability of the hemodynamic changes
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during phases II and III may be explained by study design: for example time of onset
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of presyncope was usually based on when BP fell below an arbitrary level and
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patients reported prodromal symptoms; tilt effects were augmented by GTN spray in
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some studies [34=Fuca 2006, 17=Verheyden 2008, 35=Nigro 2012] and by tilt +
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LBNP in others [61=Thomas 2010]. Sampling intervals at syncope ranged from less
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than 20s [34=Fuca 2006, 61=Thomas 2010, 35=Nigro 2012, 31=Fu 2012,
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20=Stewart 2017, 69=Schwarz 2013, ] up to 60s 38=de Jong 1995,70= de Jong
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1997, 17=Verheyden 2008]. Although precise statistical analysis is inappropriate
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here, we suggest there are clear patterns in this table that relate primarily to the
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average age of the study groups. Therefore we have divided the table into younger
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(mean age<30yrs) and older groups (mean age>30yrs). During presyncope, HR
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tended to be higher in the younger group: range 86-110 bpm [38=de Jong 1995,
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70=de Jong 1997, 20=Stewart 2017, 61=Thomas 2010, 31=Fu 2012] versus 73-93
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bpm [.Verheyden 17=2008, 34=Fuca 2006, 35=Nigro 2012]. At syncope, HR
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decreased irrespective of age, but only after a pronounced fall in BP from
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presyncope levels, consistent with other studies [71=Alboni P 2002, 72=Galleta
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2004, 73=Tellez 2009, 74=Schroeder 2011 ]. During late presyncope, the fall in CO
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(from baseline levels) tended to be greater in the older group: range 35-48% versus
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13-30%. SVR increased in the older group: (range 12- 44%) but was largely
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unchanged in the younger group: (range -8 to +15. Therefore in older subjects, the
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fall in CO was the dominant hypotensive mechanism, because all of the studies
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demonstrated that SVR remained above baseline levels. The data support our
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previous conclusion that in the classical Barcroft papers, major vasodilatation (about
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40%) has been “over-called” as the dominant hypotensive mechanism of vasovagal
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syncope [Wieling 2015?]. We emphasise that in some younger patients,
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vasodilatation is present (Figure 4) [38=de Jong 1995,70=1997, 20=Stewart 2016 ??,
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62=2017]. Therefore collective analysis of syncope patients irrespective of age may
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be misleading.
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FIGURE 4 somewhere here
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Legend Figure 4. From top down arterial blood pressure, (BP), mean arterial pressure
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(MAP), thoracic impedance (TI) heart rate (HR), stroke volume (SV) cardiac output
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(CO) estimated from ModelFlow, and systemic vascular resistance (SVR), estimated
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from MAP/CO, are shown in an 18-year- old patient with VVS during a 70o upright tilt.
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There is a modest increase in TI associated with a fall in stroke volume and an
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increase in HR. SVR is initially similar to baseline which is somewhat unusual and then
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falls steadily throughout orthostasis in parallel with MAP and inversely related to CO.
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The spike of SVR at the BP minimum reflects a precipitous fall in CO as fainting
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supervenes.
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In order to address this problem, patients have been divided into groups based on
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CO and SVR changes during presyncope [34=Fuca 2006, 61=Thomas 2010, 31=Fu
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2012, 20=Stewart 2017?]. For example, 3 haemodynamic profiles were described by
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Stewart [fig 4] [20=Stewart 2017?] showing marked hemodynamic differences during
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circulatory instability and terminal hypotension
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Figure 5 somewhere here
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LEGEND:
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The inference from these studies is that there are separate hemodynamic
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mechanisms which start several minutes before patients become symptomatic during
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terminal hypotension. It should come as no surprise that classification systems based
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on changes in HR during terminal hypotension (eg VASIS) 74=[Brignole 2000], bear
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no relationship to these mechanisms.
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Two studies (31=Verheyden 2008, 35=Nigro 2012) addressed the VASIS
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classification. Similar levels of vasodilatation were seen in cardio-inhibitory VVS
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(VASIS types 2a and 2b). Furthermore, in VASIS type 3 patients (designated as pure
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vasodepressor) SVR did not fall significantly below baseline supine or early tilt levels,
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while CO fell by 30% in both studies. Based on these hemodynamic results, we
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conclude that VASIS cannot classify “pure” vasodepressor type VVS because it
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does not exist. .
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There is also uncertainty about the mechanism for vasodilatation [or loss of
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vasoconstrictor tone] during phase 3. Limited vasodilatation has been demonstrated
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in the upper limbs during syncope (loss of consciousness) [76=Dietz 1997,
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18=Jardine 2013], but to date, not in the lower limbs or the splanchnic circulation.
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Some withdrawal of vasoconstrictor activity [MSNA] has been demonstrated in the
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lower limbs, but not in all studies [77=Vadaadi 2011,49= Ryan 2012, 18=Jardine
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2013]. The sympathetic control of splanchnic blood flow and capacitance during VVS
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is likely to be crucial but to date has not been demonstrated [44=Gelman 2004,
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Stewart 2004, Stewart 2016]. Epinephrine, secreted by the adrenals is usually a
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powerful vasoconstrictor of splanchnic vessels (via alpha1 and 2 receptors), however
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it may also have vasodilatory effects (via beta receptors) and its levels are rapidly
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increased [up to 10-fold] at syncope [44=Gelman 2004,11= Goldstein 2003]. At
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present it is uncertain if this surge is a cause or an effect of terminal hypotension
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[78=Benditt 2003]. Failure to vasoconstrict despite a progressive fall in central blood
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volume and BP also suggests a transient malfunction of sympathetic baroreflex
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control [Samniah 2004]. The neural (central) limb of the reflex is affected first,
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resulting in loss of BP-MSNA coupling during phase 2 and is marked by loss of the
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0.1 Hz oscillations in BP. [79Schwartz 2013]. The peripheral limb (the effect of MSNA
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bursts on vascular tone) is lost later during phase 3 [80=Iwase 2002, 30=Kamiya
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2005]. The cardiovagal reflex control of HR is also affected, becoming progressively
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weaker as BP declines and ventilation increases during phase 2 [81=Zhang 2000,
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82=Ocon 2010,]. The tendancy for younger adults to become severely bradycardic
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during phase 3 is probably secondary to vagal stimulation via other (non-baroreflex)
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pathways when brainstem perfusion reaches a critical nadir [83=Brignole 1992].
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Traditionally, the explanation for transient baroreflex failure has been the Bezold-
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Jarisch reflex, [hypothesised by Sharpey-Schaffer] which involves inhibitory impulses
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from the heart acting on the brainstem during central hypovolaemia [84=Oberg 1970,
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85=Sharpey-Schafer 1956]. A simpler explanation might be that it occurs in response
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to impaired brainstem perfusion and loss of cerebral autoregulation when BP falls
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below arteriolar closing pressure [65=Carey 2001, 86=Hainsworth 2003].
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Phase 4. Recovery
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In nearly all patients, BP recovers within 30s of tilt-back to the horizontal position or
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reversal of LBNP. Recovery may even include transient “overshoot” of BP (Figures
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1, 3 ) [18=Jardine 2013, 87=Wieling 2006, 68=2009
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The mechanism for the rapid increase in BP is primarily cardiac. As the subject
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becomes supine there is a rapid transfusion of blood from capacitance vessels in the
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legs and abdomen back into the central veins and right heart. Increased venous
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return results in rapid recovery of preload, SV and CO, secondary to the Frank-
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Starling mechanism 45=[Roth 1986,33= Fu 2003, 88=Truijen 2010]. It has been
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argued that withdrawal of inhibitory reflex mechanisms may also contribute to BP
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recovery, but as discussed in phase 3, it may not be necessary to invoke another
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mechanism here. [89=Weissler 1957,51= Krediet 2005]. Therefore, recovery of
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MSNA and HR towards baseline levels is most likely secondary to the reversal of the
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changes in phase 3, namely restored brainstem perfusion and correction of
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baroreflex dysfunction (Figure 3).
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Not all patients recover their BP rapidly, and some experience “prolonged post-faint
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hypotension” (PPFH). They remain pale, unwell, bradycardic (HR < 60 bpm) and
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hypotensive (SBP < 80 mmHg) for up to 5 minutes or even longer, with
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gastrointestinal symptoms [90=Wieling 2011a, 91=Wieling 2011b]. Pronounced
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bradycardia in combination with abdominal discomfort and nausea is consistent with
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increased vagal outflow from the nucleus ambiguous to the heart and from the dorsal
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nucleus to the stomach. Surprisingly, the mechanism for this prolonged reaction has
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been demonstrated to be delayed recovery of SV and CO due to decreased cardiac
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contractility, not sympathetic withdrawal and protracted vasodilatation
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[92=Rozenberg 2012]. Decreased cardiac contractility has been attributed to a
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combination of excess vagal activity and decreased sympathetic neural outflow to the
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heart [93=Casadei 2001, 94=Coote 2013]. During PPFH, the arterial baroreflex is
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unloaded and the persistent inappropriately low HR and BP are consistent with a
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sustained central suppression of excitatory mechanisms. We postulate that
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diminished capacity to activate the central sympathetic pathways and thereby
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overcome exaggerated vagal activity is a key abnormality in patients with PPFH This
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concept is supported by the observation that all the time-honored remedies for
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ameliorating a severe faint (including dynamic exercise, slapping the face, splashing
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the face with cold water and administering smelling salts), are all stimulatory in nature
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[95=Zitnik 1969].
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Conclusion
1) Laboratory studies performed since 1980 using noninvasive continuous
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monitoring technology have included subjects and patients over a much wider
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age range than the classical studies. Detailed vasovagal responses to head-
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up tilt/ standing and LBNP have included continuous monitoring of BP, HR,
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sympathetic vasoconstrictor activity, cerebral blood flow and regional blood
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volumes.
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2) The use of continuous monitoring has allowed us to divide vasovagal syncope
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into 4 phases which are present in all subjects although there is huge variation
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between individuals with regard to the duration of each phase and the
410
mechanisms underlying circulatory adjustments.
411
3) Vasovagal syncope is a complex reaction and although much of the variation
412
between individuals may relate to study methods, age is most important. For
413
example during phase 2, CO falls in nearly all patients whereas vasodilatation
414
only occurs in younger patients. .
415
4) The mechanism for circulatory instability in younger patients is variable: for
416
example some have splanchnic pooling resulting in decreased venous return
417
and stroke volume. In older adults the mechanism is unknown.
418
419
5) In all patients, the mechanism for terminal hypotension is a fall in cardiac
output, with or without a fall in systemic resistance.
18
420
6) The mechanism for recovery is more likely the effect of increased venous
421
return on stroke volume [Frank-Starling relationship] than the reversal of a
422
cardio-inhibitory reflex
423
424
19
425
References 2429 WORDS
426
1) Wieling W, Jardine D, de Lange F, Brignole M, Nielsen H, Stewart J, Sutton R. Cardiac
427
output and vasodilatation in the vasovagal response: an analysis of the classical papers.
428
Heart Rhythm 2016;13:798-805.
429
430
2) Wesseling KH. Continuous non-invasive recording of arterial pressure. Homeostasis
1995;36:50-66.
431
3) Imholz BPM, Wieling W, Montfrans GA van, Wesseling KH. Fifteen-years-experience
432
with finger arterial pressure monitoring: Assessment of the technology. Cardiovasc Res
433
1998;38:605-616.
434
4) Wesseling K, Jansen J, Settels J, Schreude rJ. Computation of aorticflow from pressure
435
in humans using a nonlinear, three-element model. J Appl Physiol 1993;74:2566-
436
2573.
437
5) Harms MP. Wesseling KH, Pott F, Jenstrup M, van Goudoever J, Secher NH, van
438
Lieshout JJ. Continuous stroke volume monitoring by modelling blood flow from non-
439
invasive measurement of arterial pressure in humans under orthostatic stress. Clin
440
Sci 1999;97:291-301.
441
6) Westerhof BE, Settels JJ, Bos WJ, Karemaker JM, Wieling W, van Montfrans GA, van
442
Lieshout JJ. Bridging cardiovascular physics, physiology, and clinical practice: Karel
443
Wesseling, pioneer of continuous noninvasive hemodynamic monitoring. Am J
444
Physiol-Heart Circ Physiol 2015;308:H153-156)
445
7) Matzen S, Perko G, Groth S, Friedman DB, Secher NH. Blood volume distribution
446
during head-up tilt induced central hypovolaemia in man. Clin Physiol 1991;11:411-
447
422.
448
8) Stewart JM, Mcloed KJ, Sanyal S, Hezberg G, Montglomery LD. Relation of postural
449
vasovagal syncope to splanchnic hypervolemia in adolescents. Circulation
450
2004;110:2575-2581.
451
452
9) Wallin G. Sympathetic outflow to muscles during vasovagal syncope. J Auton Nerv
Syst 1982;6:287-291
453
10) Esler M, Jennings G, Lambert G, Meredith I, Horne M and Eisenhofer G. Overflow of
454
catecholamine neurotransmitters to the circulation: source, fate, and functions.
455
Physiol Rev 1990;70:963-985.
20
456
11) Goldstein DS, Holmes C, Frank SM, Naqibuddin M, Snaders S, Calkin H.
457
Sympathoadrenal imbalance before neurocardiogenic syncope. Am J Cardiol
458
2003;91:53-58.
459
12)Rowell LB. Human Cardiovascular Control. Oxford, Oxford University Press. 1993.
460
13)Wieling W, van Lieshout JJ. Maintenance of postural normotension in humans. In:
461
Low PA, Benarroch EE, eds. Clinical Autonomic Disorders: evaluation and manage-
462
ment. 3rd ed. Boston, Massachusetts: Little, Brown and Company; 2008:57-68.
463
464
465
14)El-Bedawai K, Hainsworth R. Combined tilt and lower body suction: a test of
orthostatic tolerance. Clin Autonom Res 1994;4:41-47.
15) Julu POO, Cooper VL, Hansen S, Hainsworth R. Cardiovascular regulation in the
466
period preceding vasovagal syncope in conscious humans. J Physiol. 2003;549:299-
467
311.
468
469
470
16) Hainsworth R Pathophysiology of syncope. [Review]. Clin Autonom Res 2004; 14
Suppl 1: 18-24
17)Verheyden Bart, Liu Jiexin, van Dijk Nynke, Westerhof Berend E., Reybrouck Tony,
471
Aubert André E., Wieling Wouter: Steep fall in cardiac output is main determinant of
472
hypotension during drug-free and nitroglycerine-induced orthostatic vasovagal
473
syncope. Heart Rhythm 2008;5:1695-1701.
474
475
476
477
478
18)Jardine DL. Vasovagal Syncope. New Physiological Insights. Cardiology Clinics
2013;31:75-67.
19)Stewart. Common syndromes of orthostatic intolerance. Pediatrics 2013;131:968980.
20)Stewart J, Medow M, Sutton R, Visintainer P, Jardine D, Wieling W. Mechanisms of
479
vasovagal syncope in the young: reduced systemic vascular resistance versus reduced
480
cardiac output. JAHA Revison 2017
481
482
483
484
485
486
21)Barcroft H, McMichael J, Edholm OG, Sharpey-Schafer EP. Post-haemorrhagic
fainting. Study by cardiac output and forearm flow. Lancet 1944;1:489-491.
22)Secher NH, van Lieshout JJ Normovolaemia defined by central blood volume and
venous oxygen saturation. Clin Exp Pharmacol Physiol. 2005;32:901-910
23)Schadt JC, Ludbrook J. Hemodynamic and neurohormonal responses to acute
hypovolemia in conscious mammals. Am J Physiol 1991;29:H305-H318.
21
487
488
24)Smit AAJ, Halliwill JR, Low PA, Wieling W. Topical Review. Pathophysiological basis of
orthostatic hypotension in autonomic failure. J Physiol 1999; 519: 1-10.
489
25)Johnson BD, van Helmond N, Curry TB, van Buskirk CM, Convertino VA, Joyner MJ.
490
Reductions in Central Venous Pressure by Lower Body Negative Pressure or Blood
491
Loss Elicit Similar Hemodynamic Responses. J Appl Physiol 2014;117:131-141.
492
26)Taneja I, Moran C, Medow MS, Glover JL, Montgomry LD, Stewart JM. Differential
493
effects of lower body negative pressure and upright tilt on splanchnic blood volume.
494
Am. J. Physiol. Heart Circ. Physiol 2007;292, H420-H426.
495
496
27) Wieling W, de Lange FJ, Jardine DL. The heart cannot pump blood that it does not
receive. Front Physiol 2014;5:360
497
28)Morillo CA, Eckberg DL, Ellenbogen KA, Beightol LA, Hoag JB, Tahvanainen KUO,
498
Kuusela TA, Diedrich A. Vagal and sympathetic mechanisms in patients with
499
orthostatic vasovagal syncope. Circulation 1997;96:2509-13.
500
501
502
29)Jardine DL, Ikram H, Frampton CM, Frethey R, Bennett SI, Crozier IG. The autonomic
control of vasovagal syncope. Am J Physiol Heart Circ Physiol 1998;274:H2110-H2115.
30)Kamiya A, Hayano J, Kawada T, Michikami D, Yamamoto K, Ariumi H, Shimizu S,
503
Uemura K, Miyamoto T, Aiba T, Sunagawa K, Sugimachi M. Low-frequency oscillation
504
of sympathetic nerve activity decreases during development of tilt-induced syncope
505
preceding sympathetic withdrawal and bradycardia. Am J Physiol Heart Circ Physiol
506
2005;289:H1758-H1769.
507
31)Fu Q, Verheyden B, Wieling W, Levine BD. Cardiac output and sympathetic
508
vasoconstrictor responses during upright tilt to presyncope in healthy humans. J
509
Physiol 2012;590:1839-1848.
510
32)Hainsworth R. Heart rate and orthostatic stress. Clin Autonom Res 2000;10:323-325
511
33)Fu Q, Arbab-Zedah A, Pderhonen M, Zhang R, Zuckerman J, Levine B. Hemodynamics
512
of orthostatic intolerance: implications of gender differences. Am J Physiol Heart Circ
513
Physiol 2003;286:H449-H457.
514
34)Fuca G, Dinelli M, Suzzani P, Scarfo S, Tassinari F, Alboni P. The venous system is the
515
main determinant of hypotension in patients with vasovagal syncope. Europace
516
2006;8:839-845.
22
517
35)Nigro G, Russo V, Rago A, Iovino M, Arena G, Golino P, Russo M, Calabro R. The main
518
determinant of hypotension in nitroglycerine tilt-induced vasovagal syncope. Pacing
519
Clin Electrophysiol 2012; 35: 739-748.
520
36) Dambrink JHA, Imholz BPM, Karemaker JM, Wieling W. Circulatory adaptation to
521
orthostatic stress in healthy 10-14 year old children investigated in a general practice.
522
Clin Sci 1991; 81: 51-58.
523
37) ten Harkel ADJ, van Lieshout JJ, Karemaker JM, Wieling W. Differences in circulatory
524
control in normal subjects who faint and who do not faint during orthostatic stress. Clin
525
Autonom Res 1993; 3: 11-124.
526
38) de Jong-de Vos van Steenwijk CCE, Wieling W, Johannes JM, Harms MPM, Kuis W,
527
Wesseling KH. Incidence and hemodynamics of near-fainting in healthy 6-16 year old
528
subjects. J Am Col Cardiol 1995; 25:1615-21.
529
39)Mosqueda-Garcia R, Furlan R, Fernandez-Violante R, Desai T, Snell M, Jarai Z,
530
Ananthram V, Robertson RM, Robertson D. J Clin Invest. Sympathetic and
531
baroreceptor reflex function in neurally mediated syncope evoked by tilt.1997; 99:
532
2736-44.
533
40)Vadaadi G, Guo L, Esler M, Socratous F, Schlaich M, Chopra R, Eikelis N, Lambert G,
534
Trauer T, Lambert E. Recurrent postural vasovagal syncope. Sympathetic nervous
535
system phenotypes. Circ Arrhyth Electrophysiol 2011;4:711-718.
536
41)Hirsch A, Levenson D, Cutler S, Dzau V, Creager M. Regional vascular responses to
537
prolonged lower body negative pressure in normal subjects. Am J Physiol Heart Circ
538
Physiol 1989;257:H219-H225.
539
540
541
542
543
544
545
546
42)Hainsworth R. Vascular capacitance: Its control and importance. Reviews of
Physiology, Biochemistry and Pharmacology 2005;105:101-173.
43)Gelman S. Venous Function and Central Venous Pressure. Anesthesiology 2008;
108:735–48
44)Gelman S, Mushin PS. Catecholamine-induced changes in the splanchnic circulation
affecting systemic hemodynamics. Anesthesiology 2004; 100:434–439.
45)Roth CF. Physiology of venous return. An unexpected boost to the heart. Arch Intern
Med 1986; 146: 977-982.
23
547
548
549
46)Roth CF, Gaddis MI. Autoregulation of cardiac output by passive elastic
characteristics of the vascular capacitance system. Circulation 1990; 81:360-368
47)Jacobsen T, Nielsen H, Kassis E, Amtorp O. Subcutaneous and skeletal muscle vascular
550
responses in human limbs to lower body negative pressure. Acta Phys Scand
551
1992;144:247-252.
552
48)Fu Q, Shook RP, Okazaki K, Hastings JL, Shibata S, Conner CL, Palmer MD, Levine BD.
553
Vasomotor sympathetic neural control is maintained during sustained upright
554
posture in humans. J Physiol 2006; 577: 679-687.
555
49)Ryan K, Rickards C, Hinojosa-Laborde C, Cooke W, Convertino V. Sympathetic
556
responses to central hypovolemia: new insights from microneurographic recordings.
557
Front Physiol 2012; 3: 1-14.
558
559
560
50)Stewart JM, Lavin J, Weldon A. Orthostasis fails to produce active limb
venoconstriction in adolescents. J Appl Physiol 2001; 91: 1723-1729.
51)Krediet P, de Bruin I, Ganzeboom K, Linzer M, van Lieshout J, Wieling W. Leg crossing,
561
muscle tensing, squatting and the crash position are effective against the vasovagal
562
reaction solely through increases in cardiac output. J Appl Physiol 2005; 99: 1697-
563
1703.
564
565
566
52)Wieling W, van Dijk N, Thijs RD, de Lange FJ, Krediet CTP, Halliwill JR. Physical
countermeasures to increase orthostatic tolerance. J Intern Med 2015; 277: 69-82.
53)Furlan R, Porta A, Costa F, Tank J, Baker L, Schiavi R, Robertson D, Malliani A,
567
Mosqueda-Garcia R. Oscillatory patterns in sympathetic neural discharge and
568
cardiovascular variables during orthostatic stimulus. Circulation 2000; 101: 886-892.
569
54)Hausenloy DJ, Arhi C, Chandra N, Franzen-McManus A-C, Meyer A, Sutton R. Blood
570
pressure oscillations during tilt testing as a predictive marker of vasovagal syncope.
571
Europace 2009; 11:1696-1701.
572
55)Barbic F, Hensse K, Marchin A, Zamuner R, Gauger P, Tank J, Dietrich A, Robertson D,
573
Dipaola F, Achenza S, Porat A, Furlan R. Cardiovascular parameters and neural
574
sympathetic discharge variability before orthostatic syncope: role of sympathetic
575
baroreflex control to vessels. Physiol Meas 2015; 36: 633-641.
576
56)Vissing S, Scherrer U, Victor R. Relation between sympathetic outflow and vascular
577
resistance in the calf during perturbations in central venous pressure. Circ Res 1989;
578
65: 1710-1717.
24
579
580
57) Rea RF, Wallin BG. Sympathetic nerve activity in arm and leg muscles during lower
body negative pressure in humans. J Appl Physiol 1989; 66: 2778-2781.
581
58) Joyner M, Shepherd J, Seals D. Sustained increase in sympathetic outflow during
582
prolonged lower body negative pressure in humans. J Appl Physiol 1990; 68: 1104-
583
1109.
584
59)Jardine DL, Melton IC, Crozier IG, Bennett S, Donald R, Ikram H. Neurohormonal
585
response to head-up tilt and its role in vasovagal syncope. Am J Cardiol
586
1997;79:1302-1306.
587
60)Brown CM, Hainsworth R. Forearm vascular responses during orthostatic stress in
588
control subjects and patients with posturally related syncope. Clin Autonom Res
589
2000; 10: 57-61.
590
61)Thomas KN, Galvin SD, Williams MJA, Willie CK, AInsley PN. Identical pattern of
591
cerebral hypoperfusion during different types of syncope. J Hum Hypertens 2010;
592
24: 458-466.
593
62)Stewart JM, Suggs M, Merchant S, Sutton R, Terilli C, Visintrainer P, Medow MS.
594
Post-synaptic alpha1-adrenergic vasoconstriction is impaired in young patients
595
with vasovagal syncope and is corrected by nitric oxide synthase inhibition.
596
? CIRCAE/2015?003828R3.In Press 2016
597
598
63)Benditt DG, Deeloff BL, Adkisson WO, Lu F, Sakaguchi S, Schussler S, Austin E, Chen L.
599
Age dependence of relative change in circulating epinephrine and norepinephrine
600
concentrations during tilt induced vasovagal syncope. Heart Rhythm 2012;9:1847-
601
1852.
602
603
64)Schondorf R, Benoit J, Wein T. Cerebrovascular and cardiovascular measurements
604
during neutrally mediated syncope induced by head-up tilt. Stroke 1997;28:1564-
605
1568.
606
65)Carey B, Eames P, Panerai R, Potter J. Carbon dioxide, critical closing pressure and
607
cerebral haemodynamics prior to vasovagal syncope in humans. Clin Sci 2001; 101:
608
351-358.
25
609
66)Colier W, Binkhorst R, Hopman M, Oeseberg B. Cerebral and circulatory
610
haemodynamics before vasovagal syncope induced by orthostatic stress. Clin Physiol
611
1997; 17: 83-94.
612
67)Szufladowicz E, Maniewski R, Zbiec A, Nosek A, Walczak F. Near inra-red
613
spectroscopy of cerebral oxygenation during vasovagal syncope. Physiol Meas 2004;
614
25: 823-836.
615
68)Wieling W, Thijs RD, van Dijk N, Wilde AA, Benditt DG, van Dijk JG. Symptoms and
616
signs of syncope: a review of the link between physiology and clinical clues. Brain
617
2009; 132: 2630-2642.
618
69)Schwartz CE, Lambert E, Medow M, Stewart J. Disruption of phase synchronization
619
between blood pressure and muscle sympathetic activity in postural vasovagal
620
syncope. Am J Physiol Heart Circ Physiol 2013; 305: H1238-H1245
621
70) Jong-de Vos van Steenwijk CCE, Wieling W, Harms MPM, Wesseling KH. Variability of
622
near-fainting esponses in healthy 6-16-year-old subjects. Clin Sci 1997; 93: 205-211.
623
71)Alboni P, Dinelli M, Gruppillo P, Bondanelli M, Bettiol K, Marchi P, Urbeti E.
624
Haemodynamic changes early in the prodromal symptoms of vasovagal syncope.
625
Europace 2002 ;4: 333-338.
626
72)Galetta F, Franzoni F, Femina F, Prattichizzo F, Bartolomucci F, Santoro G, Carpi A.
627
Response to tilt test in young and elderly patients with syncope of unknown origin.
628
Biomed and Pharmacol 2004; 58: 443-446.
629
73) Tellez M, Norcliffe-Kaufman L, Lenina S, Voustianiouk A, Kaufman H. Usefulness of
630
head-up tilt induced heart rate changes in the differential diagnosis of vasovagal
631
syncope and chronic autonomic failure. Clin Auton Res 2009; 19: 375-380.
632
74)Schroeder C, Tank J, Heusser K, Diedrich A, Luft F, Jordan J. Physiological
633
phenomenology of neurally-mediated syncope with management of complications.
634
PloS One 2011 ;6: 1-8.
635
75)Brignole M, Menozzi C, Del rosso A, Costa S, Gaggioli G, Bottoni N, Bartoli P, Sutton R.
636
New classification of haemodynamics of vasovagal syncope: beyond the VASIS
637
classification. Europace 2000; 2: 66-67.
638
76)Dietz NM, Halliwill JR, Spielmann JM, Lawler LA, Papouchado BG, Eickhoff TJ, Joyner
639
MJ. Sympathetic withdrawal and forearm vasodilation during vasovagal syncope in
640
humans. J Appl Physol 1997; 82: 1785-1793.
26
641
642
643
77)Vadaadi G, Esler MD, Dawood T, Lambert E. Persistence of muscle sympathetic nerve
activity during vasovagal syncope. Eur Heart J 2010; 31: 2027-2033
78)Benditt DG, Ermis C, Padanilam B, Samniah N, Sakaguchi. Catecholamine response
644
during haemodynamically stable upright posture in individuals with and without tilt-
645
table induced vasovagal syncope. Europace 2003; 5: 65-70.
646
647
79)Samniah N, Sakaguchi S, Ermis C, Lurie K, Benditt D. Transient modification of
baroreceptor response during tilt-induced syncope. Europace 2004; 6: 48-54.
648
80) Iwase S, Mano T, Kamiya A, Niimi Y, Fu Qi, Suzumura A. Syncopal attack alters the burst
649
properties of muscle sympathetic nerve activity in humans. Auton Neurosci 2002; 95:
650
141-145.
651
81)Zhang R, Behbehani K, Crandall C, Zuckerman J, Levine B. Dynamic regulation of heart
652
rate during acute hypotension: new insight into baroreflex function. Am J Physiol Heart
653
Circ Physiol 2000; 280: H407-H419.
654
82)Ocon A, Medow M, Taneja I, Stewart J. Respiration drives phase synchronization
655
between blood pressure and RR interval following loss of cardiovagal baroreflex
656
during vasovagal syncope. Am J Physiol Heart Circ Physiol 2010; 300: H527-H540.
657
83)Brignole M, Menozzi C, Gianfranchi L, Bottini N, Lolli G. The clinical and prognostic
658
significance of the asystolic response during head-up tilt. Eur J Card Pacing
659
1992;2:109-113.
660
84)Oberg B, White S. The role of vagal cardiac nerves and arterial baroreceptors in the
661
circulatory adjustments to hemorrhage in the cat. Acta Physiol Scand 1970; 80: 395-
662
403.
663
664
85)Sharpey-Schafer E. Emergencies in general practice: syncope. B Med J 1956; 1: 506509.
665
86)Hainsworth R. Syncope: what is the trigger? Heart 2003; 89: 123-124.
666
87)Wieling W, Krediet CT, Wilde AA. Flush after syncope: not always an arrhythmia.
667
668
Cardiovasc Electrophysiol 2006; 17: 804-805.
88)Truijen J, Bundgaard-Nielsen M, van Lieshout J. A definition of normovolaemia and
669
consequences for cardiovascular control during orthostasis and environmental stress.
670
Eur J Appl Physiol 2010; 109: 141-157.
671
89)Weissler A, Warren J, Estes E, McIntosh H, Leonard J. Vasodepressor syncope. Factors
27
672
673
influencing cardiac output. Circulation 1957; 15: 875-882.
90)Wieling W, Rozenberg J, Schon IK, Karemaker JM, Westerhof B, Jardine DJ.
674
Hemodynamic mechanisms underlying prolonged postfaint hypotension. Clin Auton
675
Res. 2011; 21: 405-413a
676
91)Wieling W, Rozenberg J, Schon IK, Karemaker JM, Westerhof B, Jardine DJ. prolonged
677
postfaint hypotension can be reversed by dynamic tension. Clin Auton Res. 2011; 21:
678
415-418b
679
680
681
682
92)Rozenberg J, Wieling W, Schon IK, Westerhof B, Frampton C, Jardine D. MSNA during
prolonged post-faint hypotension. Clin Auton Res. 2012; 22: 167-73.
93)Casadei B. Vagal control of myocardial contractility in humans. Exp Physiol 2001; 86:
817-823.
683
94)Coote JH. Myths and realities of the cardiac vagus. J Physiol 2013; 591: 4073-4085
684
95) Zitnik R, Burchell H, Shepherd J. Hemodynamic effects of inhalation of ammonia in
685
man. Am J Cardiol 1969; 24: 187-190.
686
687
688
689
Jardine DL Melton IC, Crozier IG, English S, Bennett SI, Frampton CM, Ikram H. Decrease in
690
cardiac output and sympathetic activity during vasovagal syncope. Am J Physiol Heart Circ
691
Physiol 2002; 282: H1804-H1809.
692
28
693
Figure legends (474 WORDS)
694
695
Figure 1. The four phases of the vasovagal response
696
Vasovagal response monitored in a 48-year-old healthy male (author WW) without a fainting
697
history using Finapres technology and thoracic impedance (TI). An increase in TI documents a
698
decrease in central blood volume (CBV) i.e. the reservoir of blood available in the four
699
cardiac chambers and in the pulmonary and great thoracic vessels. Fainting was induced by a
700
combination of head-up tilt with -20 mmHg followed by -40 mm Hg lower body negative
701
pressure enabling a large shift of blood to the lower body in a controlled and reproducible
702
way [El-Bedawi 1994]. 4 phases can be distinguished: 1, early stabilisation (first 22 minutes),
703
2, circulatory instability (early presyncope) (28-32 min), 3, terminal hypotension (late
704
presyncope) and syncope, and 4, recovery (38-42 min)(Wieling unpublished). Abbreviations:
705
BP= blood pressure, MAP = mean blood pressure, TI= thoracic impedance, HR= heart rate,
706
SV= stroke volume, CO = cardiac output, SVR = systemic vascular resistance
707
708
709
Figure 2
710
The figure demonstrates representative changes in thoracic, splanchnic, pelvic, and leg
711
impedances induced by head-up tilt (dotted lines) in a healthy adolescent in the upper
712
panels. Impedance changes correspond to calculated fractional changes in regional blood
713
volumes in lower panels. Impedance scales are not all the same. Thoracic impedance
714
increases (central blood volume decreases) while other segmental impedances decrease
715
(regional blood volumes increase) with tilt up and revert towards control when tilted down
716
(revised after Stewart 2004)
717
718
29
719
Figure 3
720
Blood pressure (BP), muscle sympathetic nerve recordings (MSNA) and cardiac output (CO)
721
measurements during the 4 phases of syncope in a tilted patient. During Phase 1, BP is
722
maintained by a rapid increase in MSNA and vasoconstriction. Note the Mayer waves in the
723
BP tracing (0.1Hz). CO falls despite a minor increase in HR. During phase 2 there is a
724
progressive, gradual fall in BP and CO despite further increases in HR and MSNA. (Note the
725
disappearance of the Mayer waves). During the last minute of Phase 3, BP falls more rapidly
726
whereas slowing of HR and MSNA burst frequency occur only seconds before syncope.
727
During recovery, MSNA is maintained despite a rapid increase in BP. (from Jardine,
728
unpublished]
729
730
731
Figure 4
732
From top down arterial blood pressure, (BP), mean arterial pressure (MAP), thoracic
733
impedance (TI) heart rate (HR), stroke volume (SV) cardiac output (CO) estimated from
734
ModelFlow, and systemic vascular resistance (SVR), estimated from MAP/CO, are shown in
735
an 18-year-old patient with VVS during a 70o upright tilt. There is a modest increase in TI
736
associated with a fall in stroke volume and an increase in HR. SVR is initially similar to
737
baseline which is somewhat unusual and then falls steadily throughout orthostasis in parallel
738
with MAP and inversely related to CO. The spike of SVR at the BP minimum reflects a
739
precipitous fall in CO as fainting supervenes.
740
741
Figure 5
742
743
30
744
31