WOUTER 17 OCTOBRE revision of WW ddoctobre 11 2016 with final track changes
Guideline Heart Rhythm : Reviews 6000 words including references, legends and tables. 8 Figures/ Tables allowed
WOUTER ddoctobre16th
TOTAL WORD count 7536 - 21 (legends counted twice) = 7421 – 472 = 6949
Manuscript 3841 (about the same as 3683 in Part I)
References 2378 (about 100, allowed by Heart Rhythm ??)
Legends 472 (legend figure 5 still missing)
Table 416
The pathophysiology of the vasovagal response
David L Jardine 1, WouterWieling2 , Michele Brignole3 , Jacques W.M. Lenders 4, , Richard Sutton 5, Julian Stewart 6
1Department of General Medicine, Christchurch Hospital, University of Otago, Christchurch, New Zealand
2 Departments of Internal Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands
3Department of Cardiology, Arrhythmologic Centre, Ospedali del Tigullio, Lavagna, Italy
4Department of Internal Medicine, RadboudUniversity Medical Centre, Nijmegen, The Netherlands and Department of Internal Medicine III, Technical University Dresden, Germany
5National Heart & Lung institute, Imperial College, London, United Kingdom
6Departments of Pediatrics, Physiology and Medicine. New York Medical College. Valhalla, NY 10595
Running title: the four phases of the vasovagal response
Manuscript with references, legends and Table ????? words; Abstract ????
5 Figures, 1 Table
Conflict of interest: None
Corresponding author W Wieling. Academic Medical Centre.
Meibergdreef 9 1105 AZ Amsterdam, The Netherlands
Tel +31 20-5668224, Email:
Abstract
Introduction
The classical literature (1920-1980) concerningthe mechanisms underlyingvasovagal syncope was recently reviewed in Heart Rhythm [1=Wieling 2016]. It was concluded that interpretation of data from the early reports was severely hampered by the inability to record rapid hemodynamic changes. Furthermore, when blood pressure is rapidly falling, the exact timing of measurements is crucial: the distinction between measurements made just before syncope as opposed to during fully developed syncope (loss of consciousness) is paramount and key to understanding the sequence of hypotensive mechanisms responsible. Vasodilatation was suggested by Lewis to be the defining mechanism of vasovagal syncope,and Barcoft’s obervations during fully developed “heroic” faints supported this view. However, we argued that vasodilatation may not be the main hypotensive mechanism [1].
After 1980, techniques became available to monitor rapid hemodynamic changes continuously and noninvasively. Penaz and Wesseling introduced the Finapres or volume clamp method that allowed continuous noninvasive measurement of finger arterial pressure [2=Wesseling 1995, 3=Imholz 1998]. The Modelflow algorithm has subsequently allowed the computation of stroke volume (SV) from the area under the systolic pulse curve, and thereby calculation of cardiac output (CO) and systemic vascular resistance (SVR)[4=Wesseling 1993, 5=Harms1999].These extraordinary scientific developments enabled clinicians and researchers to study noninvasivelythe hemodynamics of vasovagal syncope on a beat-to-beat basis during laboratory induced vasovagal syncope [6=Westerhof 2015].
Several other recently developed techniques have been introduced to monitor other physiological parameters during vasovagal syncope. Impedance measurements providequalitative and directional changes of segmental volume induced by gravitational stress [7=Matzen 1991, 8=Stewart 2004]. Direct recordings of muscle sympathetic nerve activity (MSNA) using themicroneurographic techniqueallows continuous monitoring of efferent muscle vasoconstrictor sympathetic activity[9=Wallin 1982]. Measurements of venous plasma norepinephrine concentrations have been used for a long time as an indirect global index of sympathetic activity. However, without taking into account systemic and organ clearance of catecholamines, venous levels of norepinephrine are not an accurate measure of total body sympathetic activity. By contrast, venous plasma epinephrine levels can be used as a reliable estimate of the adrenomedullary sympathetic activity, because epinephrine is exclusively derived from the adrenal medulla [10=Esler 1990, 11=Goldstein 2003].
On the basis of the advances described above we find it relevant to extendour first review on the mechanisms underlying vasovagal syncope and includestudiespublished over the last 35 years. We analysed studiesofhealthy male and female subjects and patients with recurrent vasovagal syncope who were monitored using modernnoninvasive continuous monitoring technology in various experiments to model orthostatic vasovagalsyncope. We focused on results that might help us explain whether development of hypotension during vasovagal syncope is dominated by arterial vasodilatation or a decrease in cardiac output.
Methods
Referenced papers were selected manually from our own databases. For subject and author searches,Pubmed was used as the preferred database. All available studies were checked for relevance to the present review. For the mechanisms involved in orthostatic BP control in healthy subjects we refer to standard texts [12=Rowell 1993, 13=Wieling 2008].The capabilities and limitations of the different continuous non-invasive monitoring techniques will not be covered.
The four phases of the vasovagal response
Careful analysis of continuous BP recordings (and other derived variables) during orthostatic stress allows us to divide the sequence of hemodynamic events leading to vasovagal syncope into 4 phases: phase 1: early stabilisation, phase 2: circulatory instability(early presyncope) phase 3: terminal hypotension(late presyncope) and syncope, phase 4: recovery. Figure 1provides an example of a subject progressing through the 4 phases during a tilt test combined with lower body negative pressure (LBNP)
Figure 1 about here
Phase1 234
Legend. Vasovagal response monitored in a 48- year-old healthy male (author WW) without a fainting history using Finapres technology and thoracic impedance (TI). An increase in TI documents a decrease in central blood volume (CBV) i.e. the reservoir of blood available in the four cardiac chambers and in the pulmonary and great thoracic vessels.Fainting was induced by a combination of head-up tilt with -20 mmHg followed byand -40 mm Hg lower body negative pressure enabling a large shift of blood to the lower body in a controlled and reproducible way[14=El-Bedawi 1994]. 4 phases can be distinguished: 1,early stabilisation (first 22 minutes), 2,circulatory instability (28-32 min), 3,terminal hypotension and syncope, and 4,recovery (38-42 min)(Wieling unpublished). Abbreviations: BP= blood pressure, MAP = mean blood pressure, TI= thoracic impedance, HR= heart rate,SV= stroke volume, CO = cardiac output, SVR = systemic vascular resistance
Phase 1. Early stabilisation:The adjustments from supine to head up tilt at 0-2 minutes show a rapid increase in TI (decrease in CBV) resulting in decreases in SV and CO despite an increase in HR. MAP is maintained by an increase in SVR. By this mechanism, MAP remains stable for over 20 minutes despite a progressive fall in CO.
Phase 2. Circulatory instability (or early presyncope): At 28-32 minutes, the addition of -20 mm Hg LBNP to head-up tilt causes further decreases in CBV and CO. Systolic blood pressure and pulse pressure decrease, and BP variability increases markedly indicating increased sympathetic activity (see below). However,MAP is maintained by a further increase in SVR.
Phase 3. Terminal hypotension (or late presyncope): At 38-40 min, increasing LBNP further to -40 mmHg induces a fall in HR and CO. AlthoughSVR decreases, it remains far above supine control, BP variability virtually disappears(see below) anda classical vasovagal faint occurs.
Phase 4. Recovery: After tilt-down and cessation of LBNP, there is a rapid recovery of BP to baseline levels followed by an overshoot.
Further analyses of tilt and LBNP studies (similar to that shown in figure 1)indicates that the timing and duration of the 4 phases differ between healthy subjects and patients, but the order of events is consistentand generally accepted by researchers despite varying terminologies [15=Julu2003, 16=Hainsworth 2004, 17=Verheyden 2008, 18=Jardine 2013 19=Stewart 2013,20=Stewart 2017]. A similar sequence has also been demonstrated during hemorrhage in humans [21=Barcroft 1944,22=Secher2004] andanimals [23Schadt1991].
Phase 1. Early phase of stabilization of tilt/standing and low levels of LBNP
A change of posture induces a rapid and large gravitational blood volume shift. The bulk of venous pooling occurs within the first 10s. The transfer of blood is almost complete within 2- 3 min of orthostatic stress. About 500-1000 ccof blood (10-20% of the total blood volume) is transferred from the central thoracic blood volume into vascular bed below the diaphragm (Figure 2). Intravascular blood volume may decrease further following transcapillary filtration of fluid into the interstitial spaces in the legs [24=Smit 1999, 8=Stewart 2004].
The figuredemonstrates representative changes in thoracic, splanchnic, pelvic, and leg impedances induced by head-up tilt (dotted lines) in a healthy adolescent in the upper panels. Impedance changes correspond to calculated fractional changes in regional blood volumes in lower panels. Impedance scales are not all the same. Thoracic impedance increases (central blood volume decreases) while other segmental impedances decrease (regional blood volumes increase) with tilt up and revert towards control when tilted down (revised after Stewart 2004=8 )
LBNP (up to the level of the iliac crest in the horizontal position) has been used to simulate loss of CBV as a model for hemorrhage25=[Johnson 2014]. Recent studies, however, suggest that LBNP does not reproduce splanchnic pooling observed during actual orthostasis (standing or head-up tilting). Thus, LBNPwithout head-up tiltmay simulate haemorrhage but not orthostasis [26=Taneja 2007, 27=Wieling 2014 ].
Since 1980, many studies of subjects with recurrent vasovagal syncope have documented normal haemodynamic and MSNA levels both at baseline and during early tilt [28=Morillo 1997,29=Jardine 1998, 30=Kamyia 2005, 31=Fu 2012]. The rapid decrease in CBV results in a fall in CO of 10-20%, because the increase in HR does not compensate for the fall in SV(Figure 1) [32=Hainsworth 2000]. MAP is maintained by an increase in SVR. There is considerable variation between subjects in changes in CO and SVR in the early phase of stabilization [17=Verheyden 2008, 33=Fu 2003, 34=Fuca 2006,35=Nigro 2012].In children, teenagers and young adults with recurrentvasovagal syncope, the early phase of stabilisation is different. There is a more pronounced postural tachycardia and an attenuated increase in SVR as early as 1 minute after upright tilt/ standing [36=Dambrink1991, 37=ten Harkel 1993 ,38=deJong-de Vos van Steenwijk 1995,].Some studies have suggested there may be a variant group with low-normal resting BP, mild postural hypotension and variable MSNA responses to tilt [39=Mosqueda-Garcia 1997, 40=Vadaadi 2011]
SVR is mediated by sympathetic stimulation of alpha receptors causing vasoconstrictionof skeletal muscle and richly innervated visceral beds in response to unloadingof the carotid baroreceptors [12=Rowell 1993].The present view is that arteriolar vasoconstriction is “designed” to divert blood away from the splanchnic capacitance vessels as soon as orthostatic stress is applied. Splanchnic arteriolar vasoconstriction effectively limits excessive filling of capacitance vessels by allowing passive venous recoil to direct blood back to the heart [41=Hirsch 1989, 12=Rowell 1993, 42=Hainsworth 2005, 43=Gelman 2004, 44=Gelman2008]. Active venoconstriction may also contribute [45=Roth 1986, 46=Roth1990]. Although the splanchnic vasculature contains approximately 25% of blood volume and vasoconstricts by about 40% during severe orthostatic stress, we know very little about the sympathetic control of this mechanism in humans[12=Rowell 1993, 42=Hainsworth 2005]. On the other hand, sympathetic control of vasoconstriction in skeletal muscle has been extensively documented [47=Jacobsen 1992, 29=Jardine 1998, 48=Fu 2006, 49=Ryan 2012].In muscles (unlike the viscera), sympathetic venous innervation is sparse and activevenoconstrictiondoes not occur during baroreflex unloading.Venous filling here is totally controlled by arterial vasoconstriction, passive venous recoil and the muscle pump[12= Rowell 1993, 50=Stewart 2001].Duringorthostasis induced by active standing or tilt, astatic increase in skeletal muscle tone opposes pooling of blood in limb veins.Increases in skeletal muscle tone are a key factor in orthostatic adjustment [12=Rowell 1993, 13Wieling 2008].Accordingly, in recent years it has been shown that physical counter-pressure maneuvers such as lower body muscle tensing can abort an impending vasovagal faint [51=Krediet 2005,52=Wieling 2015].
Phase 2. Circulatory instability
After normal early adjustments to orthostasis, patients and controls destined to faint during tilt, standing or LBNP enter into phase 2. This phase refers to circulatory instability(or early presyncope)[16=Hainsworth 2004, 18=Jardine 2013]. Continuous BP records have demonstrated increased variability at this time, mainly because of oscillations in the 0.1 Hz frequency domain, known as Mayer waves(Figures 1 and 3) [37=Ten Harkel 1993, 53=Furlan 2000, 15=Julu 2003, 54=Hausenloy 2009, 55=Barbic 2015] andfurtherincreases in HR, especially in young subjects. The increase in 0.1 Hz blood pressure oscillations indicate reduced central blood volume, intact sympathetic baroreflex loops, and increased sympathetic activity directed to the blood vessels.. Despite these adjustments, there is usually a gradual fall in MAP(approximately 20 mmHg) in Phase 2 over a variable time (2- 5 minutes). (Figs1and3).
Figure 3 somewhere here.
Blood pressure (BP), muscle sympathetic nerve recordings (MSNA) and cardiac output (CO) measurements during the 4 phases of syncope in a tilted patient. During Phase 1, BP is maintained by a rapid increase in MSNA and vasoconstriction. Note the Mayer waves in the BP tracing (0.1Hz). CO falls despite a minor increase in HR. During phase 2 there is a progressive, gradual fall in BP and CO despite further increases in HR and MSNA. (Note the disappearance of the Mayer waves). During the last minute of Phase 3, BP falls more rapidly whereas slowing of HR and MSNA burst frequency occur only seconds before syncope. During recovery, MSNA is maintained despite a rapid increase in BP (from Jardine, unpublished.]
Inphase 2 the progressive increase in SVR is mediated by further vasoconstriction of visceral and skeletal vessels, although as in phase 1, increased sympathetic nerve activity has only been demonstrated in skeletal muscle [ 56=Vissing 1989, 57=Rea 1989, 58=Joyner 1990, 47=Jacobsen 1992, 59=Jardine 1997, 28=Morillo 1997, 29=Jardine 1998, 60=Brown 2000, 30=Kamiya 2004, 31=Fu 2012]. Furthermore vasoconstriction is not universal. Ina subgroup of children, teenagers and some younger adult subjectsthere is significant systemic vasodilatation [37=ten Harkel 1993, 38=de Jong-de Vos van Steenwijk 1995, 61=Thomas 2010, 31=Fu 2012, 62=Stewart 2016].The mechanism for this is uncertain, but may relate to increased secretion of adrenaline (a circulating vasodilator) in younger patients [63=Benditt 2012].
During phase 2, in addition to the gradual fall in MAP, there is also a modest fall in cerebral blood flow velocity andtherefore calculated cerebrovascular resistance remains constant despite an increase in ventilation [64=Schondorf 1997, 65=Carey 2001]. Consistent with this, a relatively early fall in cerebral perfusionhas also been demonstrated using near-infrared spectroscopy (NIRS), a noninvasive measure of cerebral oxygenation[66=Colier 1997].These changes are not associated with any hypotensive symptoms [67=Szufladowicz 2004].
Phase 3. Terminal hypotension and Syncope
Terminal hypotension refers to “late presyncope” or the rapid fall in SBP [by about 50 mmHg] over the final 30-60 seconds before syncope. This rapid fall is usually symptomatic. When absolute SBP falls below 50- 60 mmHg at heart level, syncope(loss of consciousness) occurs [68=Wieling 2009].
-We retrieved 8 studies that addressed the course of BP, HR, SV, CO, and SVR using pulse wave analysis during tilt-induced vasovagal syncope in healthy controls and patients with suspected vasovagal syncope [see table].
-
-Table 1 somewhere here
-The values for baseline and early stabilization after tilt [phase 1] are normal and consistent between studies. Some of the variability of the haemodynamic changes during phases II and III may be explained by study design: for example time of onset of presyncope was usually based on when BP fell below an arbitrary level andpatients reported prodromal symptoms; tilt effects were augmented by GTN spray in some studies [34=Fuca 2006, 17=Verheyden 2008, 35=Nigro 2012] and bytilt + LBNP in others [61=Thomas 2010]. Sampling intervals at syncope ranged from less than 20s [34=Fuca 2006, 61=Thomas 2010, 35=Nigro 2012, 31=Fu 2012, 20=Stewart 2017, 69=Schwarz 2013, ] up to 60s 38=de Jong 1995,70= de Jong 1997,17=Verheyden 2008]. Although precise statistical analysis is inappropriate here, we suggest there are clear patterns in this table that relate primarily to the average age of the study groups. Therefore we have divided the table into younger (mean age<30yrs) and older groups (mean age>30yrs).During presyncope, HR tended to be higher in the younger group: range 86-110 bpmeats/min[38=de Jong 1995, 70=de Jong 1997, 20=Stewart 2017, 61=Thomas 2010, 31=Fu 2012]versus 73-93 bpmeats/min [.Verheyden17=2008, 34=Fuca 2006,35=Nigro 2012]. At syncope, HR decreased irrespective of age, but only after a pronounced fall in BP from presyncope levels, consistent with other studies [71=Alboni P 2002, 72=Galleta 2004, 73=Tellez 2009, 74=Schroeder 2011 ].During late presyncope,the fall in CO(from baseline levels)tended to be greater in the older group: range 35-48% versus 13-30%.SVR increasedin the older group: (range 12- 44%) but was largely unchanged l in the younger group: (range -8 to +15. Therefore in older subjects, the fall in CO was the dominant hypotensive mechanism, because all of the studies demonstrated that SVR remained above baseline levels. The data support our previous conclusion that in the classical Barcroft papers, major vasodilatation (about 40%) has been “over-called” as the dominant hypotensive mechanism of vasovagal syncope [Wieling 2015?6]. We emphasise that insome younger patients, vasodilatation is present (Figure 4) [38=de Jong 1995,70=1997, 20=Stewart 2016 ??, 62=2017]. Therefore collective analysis of syncope patients irrespective of age may be misleading.
-
-FIGURE 4 somewhere here
-
-Legend Figure 4. From top down arterial blood pressure, (BP), mean arterial pressure (MAP), thoracic impedance (TI) heart rate (HR), stroke volume (SV) cardiac output (CO) estimated from ModelFlow, and systemic vascular resistance (SVR), estimated from MAP/CO, are shown in an 18- year-r old patient with VVS during a 70o upright tilt. There is a modest increase in TIassociated with a fall in stroke volume and an increase in HR. SVR is initially similar to baseline which is somewhat unusual and then falls steadily throughout orthostasis in parallel with MAP and inversely related to CO. The spike of SVR at the BP minimum reflects a precipitous fall in CO as fainting supervenes.
-In order to address this problem,patients have been divided into groups based on CO and SVR changes during presyncope [34=Fuca 2006, 61=Thomas 2010, 31=Fu 2012, 20=Stewart 2017?]. For example, 3 haemodynamic profiles were described by Stewart [fig 4] [20=Stewart 2017?] showing marked haemodynamic differences during circulatory instability and terminal hypotension
-
-Figure 5 somewhere here
-