Re: 갑작스러운 실신 -- 미주혈관성 실신

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The pathophysiology of vasovagal syncope: Novel insights

Author links open overlay panelJ. Gert van Dijk a, Ineke A. van Rossum a, Roland D. Thijs a b

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Abstract

The pathophysiology of vasovagal syncope (VVS) is reviewed, focusing on hemodynamic aspects. Much more is known about orthostatic than about emotional VVS, probably because the former can be studied using a tilt table test (TTT). Recent advances made it possible to quantify the relative contributions of the three factors that control blood pressure: heart rate (HR), stroke volume (SV) and total peripheral resistance (TPR). Orthostatic VVS starts with venous pooling, reflected in a decrease of SV. This is followed by cardioinhibition (CI), which is a decrease of HR that accelerates the ongoing decrease of BP, making the start of CI a literal as well as fundamental turning point.

The role of hormonal and other humoral factors, respiration and of psychological influences is reviewed in short, leading to the conclusion that a multidisciplinary approach to the study of the pathophysiology of VVS may yield new insights.

요약

혈관미주신경성 실신(VVS)의 병태생리학을 혈역학 측면에 초점을 맞추어 검토합니다.

기립성 VVS에 비해 정서성 VVS에 대해서는 훨씬 더 많은 것이 알려져 있는데,

아마도 전자는 틸트테이블 테스트(TTT)를 사용하여 연구할 수 있기 때문일 것입니다.

최근의 발전으로 인해 혈압을 조절하는 세 가지 요소인

심박수(HR),

stroke volue(SV),

총 말초 저항(TPR)의 상대적 기여도를 정량화할 수 있게 되었습니다.

기립성 혈관미주 실신은

정맥혈의 정체로 시작되어,

stroke volume(SV)의 감소로 반영됩니다.

그 다음에는

심박수 억제(CI)가 발생하는데,

심박수 감소로 인해 혈압의 지속적인 감소가 가속화되어,

CI의 시작이 문자 그대로 근본적인 전환점이 됩니다.

Orthostatic VVS starts with venous pooling, reflected in a decrease of SV.

This is followed by cardioinhibition (CI), which is a decrease of HR that accelerates the ongoing decrease of BP, making the start of CI a literal as well as fundamental turning point.

호르몬 및 기타 체액성 요인,

호흡,

심리적 영향의 역할에 대한 간략한 검토를 통해

VVS의 병태 생리학 연구에 대한 다학제적 접근이

새로운 통찰력을 얻을 수 있다는 결론을 내렸습니다.

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1. Introduction and normal blood pressure physiology

1.1. Scope of this chapter

Vasovagal syncope (VVS) is the most common form of Transient Loss of Consciousness: about one third of all people have at least one VVS spell in their lifetime (Brignole et al., 2018a), and 5% of all people have at least five VVS spells during their lifetime (Thijs et al., 2006). VVS has a negative impact on quality of life and is associated with psychological distress (Ng et al., 2019). In spite of these dual features of being very common and having negative consequences, the mechanisms behind VVS are still imperfectly known. This chapter discusses several aspects of the pathophysiology of VVS with a focus on hemodynamic events, as these are central to VVS. The loss of consciousness (LOC) in VVS is, as in any form of syncope, the result of cerebral hypoperfusion caused by low arterial blood pressure (BP).

We also reviewed other pathophysiological fields, with the intention of identifying other factors that may contribute to the understanding of the pathophysiology of VVS. We excluded the genetics of VVS, as these are discussed in another paper.

In the ESC classification (Brignole et al., 2018a), VVS is a form of ‘reflex syncope’, a category also known under the synonym ‘neurally mediated syncope’. The reflex in question is mediated by the autonomic nervous system. As the neural pathways of VVS are interwoven with the pathways of normal blood pressure (BP) control, the discussion of VVS will be preceded by a brief discussion of the baroreflex, the mainstay of BP control, and a discussion how hemodynamic measurements can be used to infer pathophysiological processes.

1. 소개 및 정상적인 혈압 생리학

1.1. 이 장의 범위

혈관미주신경성 실신(VVS)은

일시적 의식 상실의 가장 흔한 형태입니다:

모든 사람의 약 1/3이 일생에 적어도 한 번의

VVS 발작을 경험합니다(Brignole et al., 2018a),

그리고

모든 사람의 5%는 일생에

적어도 다섯 번의 VVS 발작을 경험합니다(Thijs et al., 2006).

VVS는

삶의 질에 부정적인 영향을 미치며,

심리적 고통과 관련이 있습니다(Ng et al., 2019).

매우 흔하고 부정적인 결과를 초래하는 이러한 이중적인 특징에도 불구하고,

VVS의 기전은 아직 불완전하게 알려져 있습니다.

이 장에서는

VVS의 중심에 있는 혈역학 사건에 초점을 맞추어

VVS의 병태 생리학의 여러 측면을 논의합니다.

VVS의 의식 상실(LOC)은

다른 형태의 실신과 마찬가지로

낮은 동맥 혈압(BP)으로 인한 대뇌 저관류로 인해 발생합니다.

또한 VVS의 병태 생리학에 기여할 수 있는 다른 요인을 파악하기 위해 다른 병태 생리학 분야도 검토했습니다. VVS의 유전학은 다른 논문에서 논의되므로 제외했습니다.

ESC 분류(Brignole et al., 2018a)에서 VVS는 '반사성 실신'의 한 형태이며, '신경 매개 실신'이라는 동의어로도 알려진 범주입니다. 이 반사는 자율 신경계에 의해 매개됩니다.

VVS의 신경 경로가

정상적인 혈압(BP) 조절 경로와 얽혀 있기 때문에,

VVS에 대한 논의에 앞서 BP 조절의 주축인 baroreflex에 대한 간단한 논의와 혈역학 측정을 통해

병태생리학적 과정을 추론하는 방법에 대한 논의가 선행될 것입니다.

1.2. Normal blood pressure regulation

The baroreflex is constantly active and responds to any alteration of BP, either a decrease or increase. The circulatory response to standing up is a well-known example of baroreflex control: because blood tends to gravitate downwards, the volume of blood flowing back to the heart (the ‘venous return’) diminishes, so volume pumped out by the heart (the ‘cardiac output’) decreases likewise, and arterial BP will start to fall. This is sensed by receptors in the carotid sinus and in the aorta, with the aortic ones sensitive to lower pressure than the carotid ones (Lau et al., 2016). The receptors send afferent impulses to the central nervous system, where a response is orchestrated. The resulting efferent impulses descend through dual sympathetic and parasympathetic pathways to the effector organs.

When the baroreflex is triggered by hypotension, the parasympathetic response consists of a decrease of vagal drive to the heart that increases heart rate (HR) (Fig. 1). This will increase cardiac output (CO), driving more blood into the arteries. The sympathetic response results in an increase in activity to the heart that also increases HR, as well as an increase of impulses to arterioles that result in more vasoconstriction, increasing total peripheral resistance (TPR), thereby impeding blood flowing out of the arteries. The dual effects of driving more blood into the arteries while impeding blood flowing out them increase arterial BP (Fig. 1). An initial disturbance in the form of a BP increase will have opposite effects on HR and TPR, so BP will decrease. A fundamental feature of baroreflex control is the reciprocal relation between changes of BP and HR: BP decreases are normally accompanied by HR increases, and vice versa.

1.2. 정상적인 혈압 조절

baroreflex는

지속적으로 활성화되어 있으며,

혈압의 감소나 증가 등 모든 변화에 반응합니다.

일어서는 것에 대한 순환계의 반응은

바르오레플렉스 조절의 잘 알려진 예입니다:

혈액이 아래쪽으로 내려가는 경향이 있기 때문에,

심장으로 되돌아가는 혈액의 양('정맥 복귀')이 감소하고,

따라서 심장에서 펌핑되는 혈액량('심박출량')도 마찬가지로 감소하여,

동맥 혈압이 떨어지기 시작합니다.

이것은

경동맥동과 대동맥에 있는 수용체에 의해 감지되는데,

대동맥에 있는 수용체는

경동맥보다 낮은 압력에 민감합니다(Lau et al., 2016).

수용체는 구심성 자극을 중추신경계로 보내고,

중추신경계는 이에 반응합니다.

그 결과로 생긴 원심성 자극은

교감신경과 부교감신경의 이중 경로를 통해

효과기 기관으로 내려갑니다.

저혈압으로 인해 바르오레플렉스가 작동하면,

부교감 신경 반응은

심박수(HR)를 증가시키는

심장에 대한 미주신경의 자극을 감소시키는 것으로 구성됩니다(그림 1).

이것은

심장 박출량(CO)을 증가시켜

더 많은 혈액을 동맥으로 몰아넣습니다.

교감 신경 반응은

심장에 대한 활동을 증가시켜 심박수를 증가시키고,

동맥 세동맥으로의 자극을 증가시켜 혈관 수축을 증가시킴으로써

말초 저항(TPR)을 증가시켜

동맥 밖으로의 혈액 유출을 방해합니다.

더 많은 혈액을 동맥으로 몰아넣으면서

동시에 동맥 밖으로의 혈액 유출을 방해하는 이중 효과는

동맥 혈압을 증가시킵니다(그림 1).

혈압이 증가하는 형태의 초기 교란은

심박수와 맥박수 감소에 반대되는 영향을 미치므로,

혈압은 감소합니다.

혈압 반사 조절의 근본적인 특징은

혈압과 심박수의 변화 사이의 상호 관계입니다.

혈압 감소는

일반적으로 심박수 증가를 동반하며,

그 반대도 마찬가지입니다.

Fig. 1. Schematic view of the circulation.

The circulation is drawn with a focus on the arterial part of the circulation. The autonomic control over blood pressure (BP) is exerted through descending parasympathetic influence over heart rate (HR), and sympathetic influences on HR and total peripheral resistance (TPR). These autonomic influences can lower as well as increase HR and TPR.

그림 1. 순환의 개략도.

순환은 순환의 동맥 부분에 초점을 두고 그려졌습니다.

자율 신경계는

심박수(HR)에 대한 부교감 신경의 영향과 심박수 및

총 말초 저항(TPR)에 대한

교감 신경의 영향을 통해 혈압(BP)을 조절합니다.

이러한

자율 신경계의 영향은

심박수와 TPR을 증가시킬 뿐만 아니라 감소시킬 수도 있습니다.

The volume the heart pumps out per beat is the stroke volume (SV). The product of HR and SV is the volume pumped out by the heart into the arteries during 1 min: the cardiac output (CO). TPR impedes the flow of blood out of the arteries, and is enacted by sympathetically controlled vasoconstriction in arterioles. The product of TPR and CO is BP, shown here as the typical oscillation observed with continuous BP measurements. Under normal stable circumstances, the volume of blood returning to the heart, venous return, is per minute the same as CO.

심장이 1회 박동할 때 펌핑하는 혈액의 양을

박출량(stroke volume, SV)이라고 합니다.

심박수와 박출량의 곱은

1분 동안 심장이 동맥으로 펌핑하는 혈액의 양인 심박출량(cardiac output, CO)입니다.

총 말초저항(TPR)은

동맥으로부터의 혈액의 흐름을 방해하며,

세동맥에서 교감 신경에 의해 조절되는 혈관 수축을 통해 발생합니다.

TPR과 CO의 곱은 혈압(BP)이며,

여기에서는 지속적인 혈압 측정으로 관찰되는 전형적인 진동으로 표시됩니다.

정상적인 안정된 상황에서 심장으로 돌아오는 혈액량,

즉 정맥 복귀량은 분당 CO와 동일합니다.

1.3. Disentangling hemodynamic influences

Although Ohm's law was designed to describe the relations between electrical current, voltage and resistance, there is an analogue that describes the flow of fluids through conduits, such as the circulation. Here, the arterial system shall be the conduit (Fig. 1). Current is analogous to blood flow, here CO, in liters per minute. Voltage is analogous to the pressure that drives flow, which is arterial BP (or, more precisely, the pressure difference between the left ventricle and ultimately the right atrium). Finally, electrical resistance is the analogue of the resistance posed by the arterioles where active vasoconstriction takes place, in other words, TPR:CO=BPTPR

This equation can be rearranged to yield: BP = CO·TPR. As CO is the product of HR and SV, the equation becomes:BP=HR·SV·TPR

BP is therefore the product of three hemodynamic parameters. Changes in BP at any given time can be assigned with confidence to a specific mechanism only if all three parameters are known for that time. The principle is that a BP decrease at some point in time must be due to whichever of the parameters HR, SV and TPR decreased at that time. If any of the three in contrast increased at that time, that one cannot have caused low BP. Instead, the increase must be due to one of two other explanations: the increase could be the result of a compensatory effort to limit the BP decrease, or it is a direct mechanical consequence of the decrease of another parameter. Two examples may help understand the reasoning:

If BP decreases slowly, while HR rises, SV decreases, and TPR stays the same, then low SV is the cause of low BP, with a corrective effort by HR and no role for TPR.

If a sudden BP decrease is accompanied by an abrupt lowering of HR, an increase of SV and no change of TPR, then low BP can be attributed to low HR; the rise in SV probably reflects augmented filling of the left ventricle during prolonged diastole.

1.3. 혈류역학적 영향의 분리

옴의 법칙은 전류, 전압, 저항 사이의 관계를 설명하기 위해 고안되었지만, 순환과 같은 관을 통한 유체의 흐름을 설명하는 아날로그가 있습니다. 여기서 동맥계는 관(그림 1)이 됩니다. 전류는 혈류량, 여기서 CO, 분당 리터로 표현됩니다. 전압은 흐름을 유도하는 압력과 유사하며, 동맥 혈압(보다 정확하게는 좌심실과 궁극적으로 우심방 사이의 압력 차이)입니다. 마지막으로, 전기 저항은 활동성 혈관 수축이 일어나는 세동맥에 의해 야기되는 저항과 유사합니다. 즉, TPR:CO=BPTPR

이 방정식은 다음과 같이 재구성할 수 있습니다: BP = CO·TPR. CO는 HR과 SV의 곱이므로, 방정식은 다음과 같이 됩니다:

BP=HR·SV·TPR

혈압 = 심박수*1회 심박출량*말초저항

따라

서 혈압은

세 가지 혈류역학적 매개변수의 산물입니다.

주어진 시간에 혈압의 변화는 그 시간에 대한 세 가지 매개변수가 모두 알려진 경우에만 특정 메커니즘에 확실하게 할당될 수 있습니다. 원칙적으로 특정 시점의 혈압 감소는 그 시점에 HR, SV, TPR 중 어느 한 매개변수가 감소했기 때문이어야 합니다. 만약 그 시점에 세 가지 중 하나가 증가했다면, 그 매개변수는 혈압 저하의 원인이 될 수 없습니다. 그 대신, 증가가 다른 두 가지 설명 중 하나에 기인해야 합니다: 증가가 BP 감소를 제한하려는 보상 노력의 결과이거나, 다른 매개 변수의 감소에 따른 직접적인 기계적 결과일 수 있습니다. 다음 두 가지 예는 그 이유를 이해하는 데 도움이 될 수 있습니다.

BP가 천천히 감소하는 동안 HR이 증가하고, SV가 감소하고, TPR이 동일하게 유지되는 경우, 낮은 SV가 낮은 BP의 원인이고, HR에 의한 보정 노력과 TPR의 역할은 없습니다.

갑작스러운 BP 감소가

HR의 급격한 저하,

SV의 증가,

TPR의 변화 없음과 함께 발생한다면,

낮은 BP는 낮은 HR 때문이라고 할 수 있습니다.

SV의 증가는 아마도 확장기 동안 좌심실의 충진 증가를 반영하는 것입니다.

Three aspects regarding the application of the equation should be kept in mind. Firstly, the equation describes a momentary state and should not be used to predict BP alterations. In other words, it should not be assumed that, if one parameter changes, the other parameters will stay the same. The others may well respond to the primary change over time. For example, doubling HR, by pacing, is not likely to exactly double BP: the higher HR decreases the filling time of the heart, and that will lower SV, partially negating the HR effect. The intricate relation between HR and SV means that changes are not easy to predict. When HR, BP and CO are all in low normal ranges, increases of HR are likely to increase CO; however, above around 125 bpm, increasing HR may well result in a net decrease of CO, in VVS and other conditions (Stewart et al., 2020).

Secondly, there is at present no method to directly measure all the parameters BP, CO, HR, SV and TPR (Izzo et al., 2019). HR and BP can be measured easily and reliably. Some assessment methods measure CO and use that to calculate SV, while others, such as Modelflow, use a measure of SV to calculate CO. All methods rely on calculations to obtain a value for TPR, using the relation between CO, BP and TPR. As TPR lies at the end of a chain of calculations, it is probably most prone to error.

Thirdly, the interpretation needs caution. In some cases, autonomic nervous influences may be deduced safely: when HR changes within one or two heart beats, the cause probably lies in vagal influences. But in many other cases, in particular longer lasting changes, the influence of autonomic as well as hormones and other humoral factors should be considered.

이 방정식의 적용과 관련하여 세 가지 측면을 염두에 두어야 합니다. 첫째, 이 방정식은 순간적인 상태를 나타내므로, 혈압 변화를 예측하는 데 사용해서는 안 됩니다. 다시 말해, 한 변수가 변하면 다른 변수가 그대로 유지될 것이라고 가정해서는 안 된다는 뜻입니다. 다른 변수들은 시간이 지남에 따라 주요 변수에 반응할 수 있습니다. 예를 들어, 페이싱을 통해 심박수를 두 배로 늘리면 혈압이 정확히 두 배로 증가하지는 않습니다. 심박수가 증가하면 심장의 충진 시간이 감소하고, 그 결과 심실 수축량이 감소하여 심박수 증가 효과가 부분적으로 무효화됩니다. HR과 SV 사이의 복잡한 관계는 변화가 예측하기 쉽지 않다는 것을 의미합니다. HR, BP, CO가 모두 정상 범위보다 낮을 때, HR이 증가하면 CO가 증가할 가능성이 높습니다. 그러나 125bpm 이상일 경우, HR이 증가하면 CO, VVS 및 기타 조건이 감소할 수 있습니다(Stewart et al., 2020).

둘째, 현재 모든 변수인 BP, CO, HR, SV, TPR을 직접 측정할 수 있는 방법은 없습니다(Izzo et al., 2019). HR과 BP는 쉽고 안정적으로 측정할 수 있습니다. 일부 평가 방법은 CO를 측정하고 이를 사용하여 SV를 계산하는 반면, Modelflow와 같은 다른 평가 방법은 SV의 측정치로 CO를 계산합니다. 모든 방법은 CO, BP, TPR 간의 관계를 사용하여 TPR 값을 얻기 위해 계산에 의존합니다. TPR은 계산 체인의 끝에 위치하기 때문에 오류가 발생할 가능성이 가장 큽니다.

셋째, 해석에 주의가 필요합니다. 어떤 경우에는 자율 신경의 영향을 안전하게 추론할 수 있습니다: 심박수가 한두 번의 심장 박동 내에서 변하는 경우, 그 원인은 아마도 미주 신경의 영향 때문일 것입니다. 그러나 다른 많은 경우, 특히 더 오래 지속되는 변화의 경우에는 자율 신경뿐만 아니라 호르몬과 기타 체액성 요인의 영향도 고려해야 합니다.

1.4. VVS as a reflex

The reflex pathways of VVS differ in at least two cardinal ways from normal baroreceptor-driven BP control.

Firstly, the VVS process causes arterial hypotension; if hypotension is to be explained as the product of a regulatory reflex, the expected disturbance setting that reflex in motion should be hypertension, or at least some function associated with hypertension. This is obviously not the case in VVS; two possible explanations come to mind to explain the discrepancy. One is that the reflex response is out of control and completely inappropriate to the original disturbance. The second is that the reflex response is in fact adequate, which supposes that there is a problem that is solved by shutting down the circulation and thereby the brain. This possibility supposes that VVS, a uniquely human response, has an evolutionary benefit. Whether this is so has not been settled, due to a lack of evidence. Hypotheses include that VVS protects the body against hemorrhage, against human assailants, or that VVS protects the heart (van Dijk and Sheldon, 2008; Alboni and Alboni, 2017). A recent finding pointed towards the existence of a specific adrenoreceptor subtype that is both tied to human evolution and to VVS; if substantiated, this relation favors an adaptive role for VVS (Komiyama et al., 2015).

The second cardinal difference from normal baroreceptor control is that BP and HR decrease together in most forms of reflex syncope and definitely in the final stages of VVS (see Section 2.2.3). The reversal of the usual reciprocal behavior means that normal baroreceptor control is lost during VVS (Ogoh et al., 2004) or overridden by a stronger command.

1.4. VVS는 반사 작용으로 작용한다.

VVS의 반사 경로는 일반적인 혈압 조절 방식인 바르오레셉터에 의한 BP 조절과 적어도 두 가지 중요한 면에서 다릅니다.

첫째, VVS 과정은 동맥 저혈압을 유발합니다. 저혈압이 조절 반사의 결과로 설명될 수 있다면, 반사가 작용하는 예상되는 장애 설정은 고혈압이거나 적어도 고혈압과 관련된 기능이어야 합니다. 이것은 VVS의 경우와는 분명히 다릅니다; 이 차이를 설명할 수 있는 두 가지 가능한 설명이 떠올랐습니다. 하나는 반사 반응이 통제 불능 상태이고 원래의 방해 요인에 완전히 부적합하다는 것입니다. 두 번째는 반사 반응이 실제로 적절하다는 것입니다. 이는 순환을 차단함으로써 뇌를 해결할 수 있는 문제가 있다는 것을 가정합니다. 이 가능성은 인간 특유의 반응인 VVS가 진화론적 이점을 가지고 있다는 가정을 전제로 합니다. 이것이 사실인지 여부는 증거가 부족하여 아직 밝혀지지 않았습니다. 가설에는 VVS가 출혈이나 인간 공격자로부터 신체를 보호하거나 VVS가 심장을 보호한다는 내용이 포함됩니다(van Dijk and Sheldon, 2008; Alboni and Alboni, 2017). 최근의 연구 결과에 따르면, 인간의 진화와 VVS에 모두 연관되어 있는 특정 아드레날린 수용체 아형이 존재한다는 사실이 밝혀졌습니다. 이 관계가 입증된다면, VVS의 적응적 역할이 강조될 것입니다(Komiyama et al., 2015).

일반적인 압력 수용체 조절과 두 번째로 근본적으로 다른 점은 대부분의 반사성 실신에서, 그리고 VVS의 최종 단계에서 혈압과 심박수가 함께 감소한다는 점입니다(2.2.3절 참조). 일반적인 상호 행동 양식의 역전 현상은 VVS 동안에 정상적인 압력 수용체 조절이 사라지거나(Ogoh et al., 2004) 더 강력한 명령에 의해 무시된다는 것을 의미합니다.

1.5. Afferent pathways: central/emotional versus peripheral/orthostatic

Efferent activity can be measured, using means such as measuring nerve traffic in sympathetic nerve bundles to blood vessels in muscles, or dissecting hemodynamic parameters such as HR, TPR and SV using noninvasive continuous blood pressure monitoring devices. Unfortunately, neither sensor activity nor neural afferent responses can be monitored with ease, so afferent pathways in VVS are much less clear than efferent ones.

Knowledge of afferent paths of necessity relies on inferences made from the triggers. VVS is commonly triggered by pain, fear and prolonged standing (Brignole et al., 2018a), but the chances of VVS occurring are influenced by a host of factors, such as stopping with running, resting after a heavy meal, not drinking enough, fever, a hot environment, crowding, as well as less quantifiable circumstances such as long-term anxiety. Some factors may have a circulatory change in common, such as a lowering of blood pressure, or a reduction or redistribution of the circulating volume. Others may well rely on pain afferents. Emotional triggers stand apart from all other triggers in that they can cause VVS purely by transferring cognitive information, for instance talking about someone else's surgery. Oddly, the human circulation can come to a standstill after the reception of relatively innocent information. We will label such fear-related triggers, including pain, as ‘emotional’. The afferent pathway of emotional VVS is largely unknown. The final phase of the efferent path of emotional VVS obviously comprises low BP with or without low HR, and is therefore known, but the events preceding that final pathway are unknown. We know of no test protocol that evokes pure emotional VVS.

Knowledge of the pathophysiology of VVS almost exclusively rests on tilt table testing (TTT) and similar techniques such as lower body negative pressure, implying or mimicking a gravitational challenge. When patients with emotional VVS develop VVS during TTT, the result does not appear fundamentally different from that in those with orthostatic VVS. Still, this does not mean that the pathways of emotional and orthostatic VVS must be the same. TTT may evoke fear as well as providing an orthostatic challenge, and it is also possible that the VVS pathways that are primarily activated by TTT are only orthostatic ones.

1.5. 구심성 경로: 중심/감성 대 주변/직립성

원심성 활동은

근육의 혈관 내 교감 신경 다발의 신경 전달을 측정하거나,

비침습적 연속 혈압 모니터링 장치를 사용하여

HR, TPR, SV와 같은 혈역학 파라미터를 분석하는 등의 방법을 사용하여

측정할 수 있습니다.

안타깝게도, 센서 활동이나 신경 구심성 반응은 쉽게 모니터링할 수 없기 때문에, VVS의 구심성 경로는 원심성 경로보다 훨씬 덜 명확합니다.

구심성 경로에 대한 지식은

유발 요인으로부터 도출된 추론에 의존합니다.

VVS는

통증, 공포, 장시간 서 있는 것(Brignole et al., 2018a)에 의해 일반적으로 유발되지만,

VVS가 발생할 가능성은

달리기 중 멈춤,

과식 후 휴식,

충분한 음주 부족,

발열, 더운 환경,

혼잡, 장기적인 불안과 같은 정량화하기 어려운 상황 등

다양한 요인에 의해 영향을 받습니다.

어떤 요인들은 혈압의 저하, 순환량의 감소 또는 재분배와 같은 순환계 변화와 공통점이 있을 수 있습니다. 다른 요인들은 통증 구심성에 의존할 수 있습니다. 감정적 유발 요인은 다른 모든 유발 요인들과는 달리, 다른 사람의 수술에 대해 이야기하는 것과 같이 인지적 정보를 전달하는 것만으로 VVS를 유발할 수 있다는 점에서 다릅니다.

이상하게도, 인간의 순환계는 비교적 무해한 정보를 받은 후에 정지될 수 있습니다. 우리는 통증과 같은 두려움과 관련된 유발 요인을 '정서적'이라고 분류할 것입니다.

정서적 VVS의 구심성 경로는 거의 알려져 있지 않습니다.

정서적 VVS의 원심성 경로의 마지막 단계는

분명히 낮은 심박수(HR)를 동반하거나 동반하지 않는 낮은 혈압으로 구성되어 있으므로 알려져 있지만,

그 마지막 경로를 앞둔 사건은 알려져 있지 않습니다.

순수한 정서적 VVS를 유발하는 검사 프로토콜은 알려져 있지 않습니다.

VVS의 병태생리학에 대한 지식은

거의 기울기 테이블 검사(TTT)와 중력 과부하를 유발하거나 모방하는 하체 음압과 같은 유사한 기술에 의존하고 있습니다.

정서적 VVS 환자가 TTT 중에 VVS가 발생하면,

그 결과는 기립성 VVS 환자의 결과와 근본적으로 다르지 않습니다.

그렇다고 해서 감정적 VVS와 기립성 VVS의 경로가 같아야 한다는 의미는 아닙니다.

TTT는 두려움을 불러일으킬 수 있을 뿐만 아니라 기립성 문제를 야기할 수 있으며,

TTT에 의해 주로 활성화되는 VVS 경로가 기립성 경로일 수도 있습니다.

2. Hemodynamics of vasovagal syncope

2.1. Setting the background

2.1.1. Classical views of VVS

The history of pathophysiological understanding of VVS was reviewed in two papers (Wieling et al., 2016; Jardine et al., 2018). Early views on VVS held that vasodilatation was the main cause of low BP; as this was deduced from TPR measurements, arterial vasodilatation was meant. The efferent pathway was seen as a combination of decreased arteriolar vasoconstriction (low TPR) and vagal bradycardia (low HR). However, later studies found cardiac output (CO) to decrease well before syncope and well before any significant arteriolar vasodilatation, if that occurred at all. Low CO was due to a decrease of SV, attributed to reduced venous return, itself attributed to venous blood pooling, in the splanchnic or muscular veins. Note that venous pooling also implies vasodilatation, but of veins; to prevent confusion, we will systematically differentiate between venous and arterial vasodilatation.

2. 혈관미주신경성 실신의 혈역학

2.1. 배경 설정

2.1.1. VVS에 대한 고전적 견해

VVS의 병리 생리학적 이해의 역사는 두 개의 논문에서 검토되었습니다(Wieling et al., 2016; Jardine et al., 2018). VVS에 대한 초기 견해는 혈관 확장이 저혈압의 주요 원인이라고 주장했습니다. 이는 TPR 측정에서 추론된 결과로, 동맥 혈관 확장을 의미합니다. 원심성 경로는 감소된 세동맥 혈관 수축(낮은 TPR)과 미주성 서맥(낮은 HR)의 조합으로 간주되었습니다. 그러나 이후의 연구에 따르면, 실신과 상당한 세동맥 혈관 확장이 발생하기 훨씬 전에 심박출량(CO)이 감소하는 것으로 나타났습니다. 낮은 CO는 정맥혈의 감소로 인한 것이었는데, 이는 내장 또는 근육 정맥의 정맥혈이 고여 있기 때문이었습니다. 정맥혈의 고이는 혈관 확장을 의미하기도 하지만, 정맥의 혈관 확장을 의미하기도 한다는 점에 유의하시기 바랍니다. 혼동을 피하기 위해, 정맥과 동맥의 혈관 확장을 체계적으로 구분하겠습니다.

2.1.2. Vasodepression and cardioinhibition

The concept ‘vasodepression’ (VD) was used in some papers as a release of vasoconstriction in arterioles only (low TPR), while other sources (Brignole et al., 2000) did not stipulate a specific site or mechanism. We will present arguments in Section 2.2.2 to widen the meaning of VD to encompass both venous and arterial vasodilatation.

Cardioinhibition was pragmatically defined in the VASIS context to describe TTT patterns. The ‘VASIS 2A’ pattern concerns bradycardia without asystole, with bradycardia defined as HR being less than 40 bpm during at least 10 s, and asystole as a pause of at least 3 s. When asystole occurred, events were classified as ‘VASIS 2B’ (Brignole et al., 2000). These standardized abnormality thresholds for bradycardia and asystole have proven very useful to promote consistency in VVS research. However, they are not associated with specific pathophysiological consequences for BP or for brain perfusion, so their occurrence does not point to a specific BP or a specific level of brain perfusion.

How quickly asystole can cause loss of consciousness (LOC) can be extracted from arrhythmias, in which asystole starts without the confounding influences of vasodepression. Based on older sources that are difficult to falsify, a review reported loss of consciousness to start as early as 4–8 s after the last beat in standing subjects, and 12–15 s if they were lying down. (Wieling et al., 2009). Note that asystolic periods of 3 s need not even be perceived by patients. Asystole in VVS attracted a great deal of attention because it could in principle be remedied with cardiac pacing, a subject largely outside the subject of this chapter. Asystole is an extreme expression‎ of CI and often follows less severe bradycardia, showing that CI encompasses more than just asystole.

2.1.2. 혈관수축과 심장억제

'혈관수축'이라는

개념은 일부 논문에서 동맥의 혈관 수축(낮은 TPR)의 해제로 사용되었지만,

다른 출처(Brignole et al., 2000)에서는 특정 부위나 메커니즘을 명시하지 않았습니다. 2.2.2절에서 정맥과 동맥의 혈관 확장을 모두 포함하도록 VD의 의미를 확장하는 논증을 제시할 것입니다.

심장억제는 TTT 패턴을 설명하기 위해

VASIS 맥락에서 실용적으로 정의되었습니다.

'VASIS 2A' 패턴은 무수축성 서맥을 동반한 서맥과 관련이 있으며,

서맥은 최소 10초 동안 심박수가 분당 40회 미만인 경우,

무수축성 서맥은 최소 3초 동안의 일시적 정지입니다.

무수축성 서맥이 발생하면 사건은 'VASIS 2B'로 분류됩니다(Brignole et al., 2000).

서맥과 심실성 빈맥에 대한 이러한 표준화된 이상치 임계값은

VVS 연구의 일관성을 유지하는 데 매우 유용하다는 것이 입증되었습니다.

그러나,

이 임계값은 혈압이나 뇌관류에 대한 특정 병리생리학적 결과와 관련이 없기 때문에,

그 발생이 특정 혈압이나 특정 수준의 뇌관류를 가리키는 것은 아닙니다.

무수축이 얼마나 빨리 의식 상실(LOC)을 유발할 수 있는지는 혈관 수축의 혼란스러운 영향 없이 무수축이 시작되는 부정맥에서 추출할 수 있습니다. 위조하기 어려운 오래된 자료를 바탕으로 한 연구에 따르면, 서 있는 피실험자의 경우 마지막 박동 후 4~8초, 누워 있는 피실험자의 경우 12~15초 후에 의식 상실이 시작된다고 합니다(Wieling et al., 2009). 무수축 기간이 3초인 경우, 환자가 이를 인지하지 못할 수도 있다는 점에 유의하십시오. VVS의 무수축은 원칙적으로 심장 박동 조절로 치료할 수 있기 때문에 많은 관심을 끌었습니다. 무수축은 심박출 저하증의 극단적인 표현이며, 종종 덜 심각한 서맥에 이어 나타나기 때문에 심박출 저하증은 무수축 이상의 것을 포함한다는 것을 보여줍니다.

2.2. Novel insights

2.2.1. ‘Low blood pressure phenotype’

The 2018 ESC guidelines coined the concept ‘low BP phenotype’ to indicate a susceptibility to VVS. While the concept was based on clinical experience, in that factors that contribute to low BP, such as dehydration and little water or salt intake, increase the chances of VVS, it was not formally proven. A multicohort cross-sectional study changed this, using resting BP measurements (Brignole et al., 2021). Diastolic BP (DBP) and HR were higher in VVS populations than in the general population in both sexes and systolic BP (SBP) was lower in men, but not in women. The differences were not large (3–5 mmHg for DBP and 5 bpm for HR) but highly significant. The hemodynamic state of VVS patients therefore differed in the resting state from that of healthy controls, and the pattern might be more accurately described as ‘low systolic BP phenotype’. The pattern, with low SBP, high DBP, and therefore a low pulse pressure, was compatible with reduced venous return and low SV. The authors proposed several explanations: an overall low circulating volume or a redistribution of blood, a low BP setpoint, and a different neuroendocrinological state. Finally, VVS patients showed a lower-than-expected increase of BP with age, a finding that may underlie the upper half of the bimodal age distribution of VVS.

The ‘low BP phenotype’ may tie in with another novel concept, that of ‘hypotensive susceptibility’ in the TTT context (Sutton and Brignole, 2014). An abnormal result of a TTT in this view does not provide a certain diagnosis of VVS, but instead signifies a tendency towards hypotension that becomes manifest in the upright position. This susceptibility may explain why the TTT can be positive in some patients with diverse disorders, including emotional VVS and some forms of cardiac syncope that involve hypotension. The theory assumes that any tendency towards hypotension may become activated in the upright position and result in VVS.

Although a recent paper voiced the opinion that TTT is not of value in the diagnosis of VVS (Kulkarni et al., 2020), this contradicted both European and North American evidence-based syncope guidelines (Brignole et al., 2018a, Brignole et al., 2018b; Shen et al., 2017). A response (Sutton et al., 2021) made the point that TTT improved syncope care. A recent European guideline stressed that the diagnostic value of TTT for VVS could be improved by comparing complaints during TTT with those during spontaneous events (Thijs et al., 2021).

2.2. 새로운 통찰력

2.2.1. '저혈압 표현형'

2018년 유럽심장학회(ESC) 가이드라인은 VVS에 대한 감수성을 나타내기 위해 '저혈압 표현형'이라는 개념을 만들었습니다. 이 개념은 임상 경험을 바탕으로 한 것이지만, 탈수나 물이나 소금 섭취 부족과 같은 저혈압에 기여하는 요인들이 VVS의 가능성을 높인다는 점에서 공식적으로 입증된 것은 아닙니다. 휴식 시 혈압 측정(Brignole et al., 2021)을 이용한 다집단 교차 연구로 이 결과가 바뀌었습니다. 이완기 혈압(DBP)과 심박수는 남녀 모두에서 VVS 집단이 일반 인구보다 높았고, 수축기 혈압(SBP)은 남성에서 낮았지만 여성에서는 그렇지 않았습니다. 그 차이는 크지 않았지만(DBP의 경우 3-5mmHg, 심박수의 경우 5bpm), 매우 유의미했습니다. 따라서 VVS 환자의 혈역학 상태는 건강한 대조군과 휴식 상태에서 차이가 있었고, 그 패턴은 '낮은 수축기 혈압 표현형'으로 더 정확하게 설명될 수 있습니다. 낮은 SBP, 높은 DBP, 그리고 낮은 맥박압을 가진 이 패턴은 정맥 복귀 감소 및 낮은 SV와 일치합니다. 저자들은 여러 가지 설명을 제안했습니다: 전반적인 낮은 순환량 또는 혈액의 재분배, 낮은 BP 설정점, 그리고 다른 신경 내분비학적 상태. 마지막으로, VVS 환자들은 예상보다 나이가 들면서 혈압이 낮아지는 경향을 보였는데, 이는 VVS의 양극성 연령 분포의 상반부에 근거가 될 수 있는 결과입니다.

'저혈압 표현형'은 TTT 맥락에서 '저혈압 감수성'이라는 또 다른 새로운 개념과 관련이 있을 수 있습니다(Sutton and Brignole, 2014). 이 관점에서 TTT의 비정상적인 결과는 VVS에 대한 확실한 진단을 제공하지는 않지만, 똑바로 선 상태에서 나타나는 저혈압 경향을 의미합니다. 이러한 경향성은 감정적 VVS와 저혈압과 관련된 일부 형태의 심장 실신 등 다양한 장애를 가진 일부 환자에서 TTT가 양성일 수 있는 이유를 설명할 수 있습니다. 이 이론은 똑바로 선 상태에서 저혈압 경향이 활성화되어 VVS가 발생할 수 있다고 가정합니다.

최근의 한 논문에서 TTT가 VVS 진단에 가치가 없다는 의견이 제기되었지만(Kulkarni et al., 2020), 이는 유럽과 북미의 근거 기반 실신 지침(Brignole et al., 2018a, Brignole et al., 2018b; Shen et al., 2017)과 상충됩니다. 한 응답(Sutton et al., 2021)은 TTT가 실신 치료에 도움이 된다는 점을 지적했습니다. 최근 유럽 지침에서는 TTT 중의 증상과 자발적 실신 중의 증상을 비교함으로써 VVS에 대한 TTT의 진단적 가치를 향상시킬 수 있다는 점을 강조했습니다(Thijs et al., 2021).

2.2.2. Quantifying VD and CI

In the following sections we will show that orthostatic VVS starts with VD, followed by a combination of VD and CI. When VD and CI together lower BP, it was not obvious how much each contributes to the BP decrease (Saal et al., 2017). Under such circumstances, conclusions regarding their relative importance could only be drawn under rare circumstances, such as when there was no HR decrease at all. Another example of such a circumstance was when asystole starts after the onset of LOC (Saal et al., 2017). This ‘late asystole’ is discussed in Section 2.2.3.

A novel way to quantify the relative changes of VD and CI in orthostatic VVS has been described: the ‘log-ratio method’ (Van Dijk et al., 2020b). The method is based on the physiological multiplicative equation BP = HR·SV·TPR. It rests on defining periods of interest and calculating one value per patient per period for mean arterial pressure (MAP), HR, SV and TPR. The following step expressed the value of a patient's parameter for one period, say near syncope, as a ratio of that of the baseline period. The chosen baseline was a period shortly after head-up tilt, and therefore reflected the early upright position, in which the VVS process has not yet gained weight; any later hemodynamic changes therefore reflected orthostatic VVS only, not the upright position itself.

The resulting ratios still follow the physiological relation BPR = HRR · SVR· TPRR. They are dimensionless, allowing parameters expressed in different units (for instance L for SV and mmHg·min ·L−1 for TPR) to be compared directly. The next step was based on the multiplicative nature of the relation and the need to provide groupwise summaries. If three ratios are HRR = 0.5, SVR = 2.0 and TPRR = 1.0, then BP will not have changed. In another person, with HRR = 2.0, SVR = 0.5 and TPRR = 1.0, BP will also not have changed. Simply taking the mean of the ratios would result in 1.25 for both HR and SV, suggesting a nonexistent BP increase. Taking the logarithms of the ratios prevented such errors, and transformed the relation into an additive one: BPLR = HRLR + SVLR + TPRLR.

This log-ratio method allowed the relative influences of changes of HR, SV and TPR on BP to be assessed quantitatively over time, between groups, in VVS and in other conditions. While doing justice to the underlying multiplicative physiological relation. This method showed that, a slow decrease of SV was the first observed change in 163 patients with tilt-evoked VVS. It occurred in some subjects as early as nine minutes before syncope (Van Dijk et al., 2020b, Fig. 2). This slow decrease was initially accompanied by a corrective increase of HR with incomplete success, as BP still decreased slowly. TPR did not change significantly in this time (Fig. 3).

2.2.2. VD와 CI의 양적 측정

다음 섹션에서는 기립성 VVS가 VD로 시작하여 VD와 CI의 조합으로 이어진다는 것을 보여줄 것입니다. VD와 CI가 함께 혈압을 낮추는 경우, 각 요소가 혈압 감소에 얼마나 기여하는지 명확하지 않았습니다(Saal et al., 2017). 이런 상황에서, 상대적 중요성에 대한 결론을 도출할 수 있는 경우는 드물고, 예를 들어 HR 감소가 전혀 없는 경우입니다. 또 다른 예는 LOC 발병 후 무수축이 시작되는 경우입니다(Saal et al., 2017). 이 '후기 무수축'에 대해서는 2.2.3절에서 설명합니다.

정맥성 기립성 저혈압에서 VD와 CI의 상대적 변화를 정량화하는 새로운 방법이 설명되었습니다: '로그 비율 방법'(Van Dijk et al., 2020b). 이 방법은 생리학적 곱셈 방정식 BP = HR·SV·TPR을 기반으로 합니다. 이 방법은 관심 기간을 정의하고 평균 동맥압(MAP), HR, SV 및 TPR에 대해 기간당 환자당 하나의 값을 계산하는 것에 기초합니다. 다음 단계는 한 기간 동안, 예를 들어 실신 직전 상태에 대한 환자의 매개변수 값을 기준 기간에 대한 비율로 나타낸 것입니다. 선택된 기준 기간은 헤드업 틸트 직후의 기간이었기 때문에, VVS 과정이 아직 가중치를 얻지 않은 초기 직립 자세를 반영했습니다. 따라서 이후의 혈역학 변화는 기립성 VVS만을 반영했으며, 직립 자세 자체는 반영하지 않았습니다.

그 결과 비율은 여전히 생리학적 관계 BPR = HRR · SVR· TPRR을 따릅니다. 이 비율은 차원이 없기 때문에 서로 다른 단위로 표현된 매개변수(예를 들어 SV의 경우 L, TPR의 경우 mmHg·min ·L−1)를 직접 비교할 수 있습니다. 다음 단계는 관계의 곱셈적 특성과 그룹별 요약을 제공해야 하는 필요성에 기반을 두고 있습니다. 세 가지 비율이 HRR = 0.5, SVR = 2.0, TPRR = 1.0이면 BP는 변하지 않습니다. 다른 사람의 경우, HRR = 2.0, SVR = 0.5, TPRR = 1.0이면 BP도 변하지 않습니다. 단순히 비율의 평균을 구하면 HR과 SV 모두 1.25가 되어 BP 증가가 존재하지 않는다는 것을 암시합니다. 비율을 로그로 계산하면 이러한 오류를 방지할 수 있으며, 관계를 추가적인 관계로 변환할 수 있습니다: BPLR = HRLR + SVLR + TPRLR.

이 로그-비율 방법을 통해 HR, SV, TPR의 변화가 BP에 미치는 상대적 영향을 시간 경과에 따른 그룹 간, VVS 및 기타 조건에서 정량적으로 평가할 수 있었습니다. 이 방법은 근본적인 생리적 관계에 대한 정의를 내리는 데 도움이 되었습니다. 이 방법을 통해 틸트 유발 VVS 환자 163명에서 SV의 느린 감소가 처음으로 관찰된 변화라는 사실이 밝혀졌습니다. 일부 피험자의 경우 실신 9분 전부터 이런 현상이 발생했습니다(Van Dijk et al., 2020b, 그림 2). 이렇게 서서히 감소하는 현상이 처음에는 혈압이 여전히 서서히 감소하는 가운데 부정맥으로 인한 HR의 교정적 증가를 동반했습니다. 이 기간 동안 TPR은 크게 변하지 않았습니다(그림 3).

Fig. 2. Hemodynamic features of orthostatic VVS.

The figure is adapted from Van Dijk et al., 2020b. See the main text for a description. The hemodynamic parameters BP, HR, SV and TPR are relative to a baseline period shortly after head-up tilt. The lines represent averages of log-ratio values of 163 persons with tilt-induced VVS. The log-ratio values imply that BP is the sum of the vales of HR, SV and TPR at each instant.

The earliest abnormality of orthostatic VVS is a decrease of SV about 9 min before syncope, due to venous pooling: this represents venous vasodepression. This has the effect of decreasing BP, which is tempered by an increase of HR. About 1 min before syncope, cardioinhibition (CI) starts in the form of an HR decrease. The histogram of the start of CI shows that its onset is variable. The median value was 58 s before syncope. CI causes an acceleration of the BP fall, ending in syncope. While CI is active, there is a modest additional decrease of TPR, adding arterial vasodepression to the much stronger effects of venous VD and CI.

그림 2. 기립성 VVS의 혈역학 특징.

이 그림은 Van Dijk et al., 2020b에서 발췌한 것입니다. 자세한 설명은 본문을 참조하십시오. 혈역학 파라미터인 BP, HR, SV, TPR은 기립성 VVS가 발생한 직후의 기준 기간과 비교한 상대적 수치입니다. 선은 기립성 VVS가 발생한 163명의 평균 로그 비율 값을 나타냅니다. 로그 비율 값은 BP가 각 순간에 HR, SV, TPR 값의 합이라는 것을 의미합니다.

기립성 VVS의 가장 초기 이상 징후는 실신 약 9분 전에 나타나는 SV의 감소로, 이는 정맥 풀링으로 인한 것입니다. 이것은 정맥 혈관 수축을 나타냅니다. 이것은 BP를 감소시키는 효과가 있으며, HR의 증가로 완화됩니다. 실신 직전 약 1분 동안 심박수 감소의 형태로 심박수 억제(CI)가 시작됩니다. CI 시작의 히스토그램은 그 시작이 가변적임을 보여줍니다. 중앙값은 실신 전 58초였습니다. CI는 혈압 강하를 가속화하여 실신으로 끝납니다. CI가 활성화되는 동안 TPR이 약간 더 감소하여 정맥 VD 및 CI의 훨씬 더 강력한 효과에 동맥 혈관 수축이 추가됩니다.

Fig. 3. Overview of the presumed pathophysiological cascade in VVS before the onset of CI.

The abnormalities of orthostatic VVS start with venous pooling (1), here shown as venous vasodilatation. The volume of blood returning to the heart decreases (2), directly translated into a decrease of SV (3). This is partially compensated for by an increase of HR (4), but not enough, so CO decreases (5). In this phase TPR does not change, and BP decreases (6). The typical BP pattern is that systolic BP decreases more than diastolic BP.

그림 3. CI 발병 전 VVS에서 추정되는 병리 생리학적 캐스케이드 개요.

기립성 VVS의 이상은 정맥 풀링(1)으로 시작되며, 여기에서는 정맥 혈관 확장으로 표시됩니다. 심장으로 돌아가는 혈액의 양이 감소(2)하여 SV(3)가 감소합니다. 이 감소는 HR(4)의 증가로 부분적으로 보상되지만, 충분하지 않아 CO(5)가 감소합니다. 이 단계에서 TPR은 변하지 않고, BP는 감소합니다(6). 일반적인 BP 패턴은 수축기 BP가 이완기 BP보다 더 많이 감소하는 것입니다.

At a median time of 58 s before LOC, HR started to decrease in 91% of patients, as evidence of the onset of CI. From then on, HR plummeted, and just before syncope the contribution of low HR to low BP was as large as that of the much slower decrease of SV. There also was a moderate decrease of TPR, adding very little of the effects of SV and HR (Fig. 4). The decrease of SV was explained through a gradual increase of venous pooling that slowly eroded venous return. The authors proposed to expand the concept VD to encompass both venous VD, apparent as a decrease of SV in orthostatic VVS, and arterial VD, apparent through a decrease of TPR. In effect, VD was defined as all processes in reflex syncope that lower BP in other ways than through low HR.

1. Download: Download high-res image (105KB)
2. Download: Download full-size image

Fig. 4. Overview of the presumed pathophysiological cascade in VVS after the onset of CI.

Continued venous pooling (1) leads to a stronger decrease of venous return (2) and a stronger decrease of SV (3). Now, however, HR decreases (4), so CO decreases more than before (5). Concurrent with the decrease of HR, TPR also decreases slightly (6), so BP reflects the combined influences of decreasing SV, HR and TPR (7). Bp decrease more than before, again with a larger decrease of systolic than diastolic BP.

The initial decrease of SV was in agreement with events summarized in a review (Jardine et al., 2018). However, that review stated that TPR tended to rise, perhaps less so in VVS patients. The reason for the difference is probably that the baseline period in several reviewed papers was the supine condition before head-up tilt, whereas the baseline in the log ratio paper concerned the early upright condition. If the supine position is used as baseline, hemodynamic changes in the upright condition will consist of responses to head-up tilt itself, typically involving a TPR increase, as well as to the VVS process proper, in which a slight TPR decrease is more likely.

2.2.3. Expanding the role of CI: ‘late asystole’

As said, few conclusions could be drawn about the relative importance of CI and VD when both occurred together. Even so, one combination of events allowed an unequivocal conclusion about the role of cardioinhibition, although this was limited to asystole (Saal et al., 2017): asystole cannot be the primary cause of LOC if it starts when patients are already unconscious. In a TTT study using video-EEG to assess LOC, asystole starting 3 s before the onset of LOC or later was considered to not be the primary cause of LOC. The 3 s threshold was based on the earliest interval of 4 s described in Section 2.1.2. This ‘late asystole’ occurred in one third of the study group, with consequences for cardiac pacing: conventional back-up pacing, in which pacing starts when HR drops below 50 or 60 bpm, might not prevent LOC in one third of cases with asystole.

It may not be assumed that asystole in those with ‘early asystole’, i.e. asystole starting earlier than 3 s before the onset of LOC, must be the prime mechanism of LOC. Firstly, the 3 s threshold was very conservative, so more than one third of cases may well fall in the ‘late asystole’ group. Secondly, and more importantly, LOC in those with early asystole was not due to CI only, but to a mixture of CI and VD, as exemplified by low MAP values at the start of asystole.

These results showed that the time course of VD and CI differed between patients, with as yet mostly unexplored consequences. The existence of late asystole underlines that documenting HR only provides a very uncertain basis on which to base pacing decisions in orthostatic VVS. Adding a posture detection device to implantable loop recorders might at least detect those in whom asystole starts after a fall: in such persons, asystole-based pacing would be futile.

By its nature, late asystole occurs late in the VVS process (Van Dijk et al., 2020b), so it can only come to light during TTT if the head-up condition lasts long enough to produce complete syncope. This was the case in the log-ratio study (Van Dijk et al., 2020b), as the inclusion criterion was LOC, assessed through video-EEG. However, TTT studies using presyncope as an endpoint are unsuitable to assess the preval‎ence of asystole, and of that of ‘late asystole’ in particular.

2.2.4. Expanding the role of CI: not just asystole

CI has been defined as the decrease of HR towards syncope (Van Dijk et al., 2020b), based on a study of 163 patients with complete syncope and a consensus procedure to determine the onset of CI. The examiners were blinded to BP, SV and TPR data. The end of CI was determined as the point of minimum HR around syncope. Measuring both the onset and end of CI allowed its duration, magnitude and speed to be calculated.

In 91% of patients, consensus was reached regarding the point in time at which CI began. This does not mean that HR did not decrease in the remaining 14 patients, just that its onset may have been too slow to allow it to be pinpointed. Magnitude, duration and speed varied considerably between patients.

Aligning the records according to the onset of CI revealed that the already ongoing BP decrease accelerated sharply when CI began, and more so as the speed of CI was higher. CI started when HR was still high, at a mean value of 98 bpm. This high value represented the corrective influence of HR increase. Even the moderate reduction of HR at the start of CI already had a negative impact on BP. HR then continued to decrease to the level needed to maintain the upright condition, and then to its nadir around syncope.

“As said, the onset of CI represents a fundamental change: normal efforts to correct low BP through an increase of HR are abandoned. We suspect that this fundamental change is a consequence of the ongoing vasodepression (Van Dijk et al., 2020a), meaning it is triggered by a circulatory parameter crossing some threshold. In the past, too little filling of the heart was proposed as a trigger, but echocardiography did not reveal the heart to be ‘empty’ at syncope (Novak et al., 1996; Davrath et al., 1999). One way to indentify the culprit may be to study both the start and end of CI: CI ends at syncope when haemodynamic conditions rapidly normalise, suggesting that CI is maintained as long as a specific condition is fulfilled. Potential factors are haemodynamic or humoral in nature and include wall tension in blood vessels or heart chambers, with perhaps a role for adenosine. Such influences may be modified by how the SA-node integrates incoming signals to form HR.”

The demonstrated importance of the corrective effects of the HR increase suggests that preventing CI might keep BP relatively high for longer, hopefully allowing patients the time to sit or lie down and to abort the ongoing VVS evolution. Attempts to prevent the effects of CI may require replacing fall-back pacing, i.e. using preset HR of 50 or 60 bpm, with ‘early CI pacing’, based on sensing the onset of the HR decrease or another parameter changing in the early stages of orthostatic VVS.

2.2.5. Staging VVS

During orthostatic VVS, the parameters BP, HR, SV and TPR can undergo complex changes: for instance, HR first rises, then starts to decrease at the onset of CI, to reach a nadir at syncope, followed by a rise and a temporary maximum (Van Dijk et al., 2020a). Such ‘changes of direction’ can consist of an increase or a decrease starting either from a stable situation or from a turn. ‘Stages’ represented periods between changes of direction; during a stage, the hemodynamic state could be described simply, such as ‘BP fell, SV fell and HR rose’. The staging system was based on groupwise observations, did not rest on preconceived notions, and was not intended for individual use.

The two most important changes of direction were the onset of the SV decrease and the onset of CI. The beginning of CI marked the point in time where BP and HR both decreased, i.e. when normal baroreceptor control was lost and replaced by a fundamentally different type of control. Hence, the onset of CI was regarded as a fundamental as well as a literal turning point in the evolution of VVS.

2.3. Cerebral perfusion in VVS

Syncope ensues when cerebral perfusion drops below a critical value, and under normal circumstances brain blood flow depends, as holds for any organ, on the pressure difference of arteries and veins allowing blood in and out of the organ, and the resistance in between. In the case of the brain, the main drive forcing blood into the brain is systolic blood pressure (SBP). Three other pressures can impede that flow: the first is intracranial pressure, normally so low it can be ignored; the second is the resistance of brain blood vessels, normally much lower than in other organs, so the brain is even perfused during diastole. The third pressure is venous pressure, again very low under normal circumstances (Van Dijk et al., 2020a). Hence, in the absence of changes in intracranial and venous pressure, the most important factor driving brain perfusion is SBP, with an added role for DBP, in view of the brain's low resistance. The other factors only play a role when intracranial pressure is very high, or when BP is extremely low, such as in syncope. Cerebral blood flow during syncope was reviewed before (Van Dijk et al., 2020a). Suffice it to state that cerebral autoregulation does its best to decrease the brain's resistance to flow when BP drops in VVS, but cannot keep up with the decrease, so ultimately brain perfusion fails (Schondorf et al., 2001).

Cerebral perfusion was conventionally measured with transcranial Doppler, which is accurate and offers a high temporal resolution, but can suffer from thick skull bones and be difficult to measure when patients move. The advent of ‘near-infrared spectroscopy’, also called ‘noninvasive brain oximetry’, is less limiting in this respect. A promising finding in VVS was a decrease in cerebral oxygenation, stated to occur when there were no hemodynamic changes yet (Kharraziha et al., 2019; Bachus et al., 2018). As brain perfusion critically depends on arterial BP and CO, this is an unlikely combination of findings. A first possible explanations is that there were in fact subtle systemic hemodynamic changes that for unknown reasons did not come to light. Another one is a specific impairment of cerebral perfusion, perhaps through hyperventilation, although then systemic effects should be apparent too (see Section 3). Finally, a shortcoming of near-infrared spectroscopy may be to blame: the technique also records extracranial tissue oxygenation (Badenes et al., 2021). It is reasonable to assume that subtle decreases of CO and BP will affect the noncerebral circulation well before the well-protected cerebral circulation is allowed to suffer. More direct comparisons of near-infrared spectroscopy with transcranial ultrasound studies in VVS are required.

An alternative technique that overcomes some problems of transcranial Doppler is to use ultrasound Doppler studies of cerebral arteries in the neck (Yamamoto et al., 2021).

2.4. Influence of age

The relative contributions of CI and VD probably change with age. In toddlers and young children, asystole is very common in VVS. The duration of asystole decreased with age in small children using eyeball pressure, a technique to evoke VVS (Stephenson, 1990). At the other end of the age spectrum, TTT studies suggested that the proportion of those with asystole decreased with advancing age (Schroeder et al., 2011; Numan et al., 2015). A problem with various such studies was that patients may have been tilted back at presyncope, which may have abolished late events in VVS, including CI and asystole. A recent TTT report, using the Italian protocol relying on syncope as the endpoint of TTT, confirmed that the proportion of asystolic VVS responses decreased with age, and also stated that the contribution of VD increased with age (Rivasi et al., 2021). If confirmed, the latter finding shows that ageing in VVS is not just a matter of overall weakening of autonomic control, but involves differential ageing of CI and VD.

3. Respiratory influences3.1. Interactions between respiration and the circulation

Respiration influences the circulation in several ways. The first is that intrathoracic respiratory pressure changes not only move air in and out of the thorax, but blood as well. This cyclical effect causes respiratory sinus arrhythmia, an expression‎ of vagal HR control. The respiratory pump enhances venous return, an effect that can in fact increase BP, provided hyperventilation is avoided (Thijs et al., 2007; Thijs et al., 2008).

Hyperventilation, through an increase of respiratory frequency, depth, or both, causes CO2 to be washed out faster than metabolism can replenish it, resulting in hypocapnia. Hypocapnia in principle causes peripheral vasodilatation and cerebral vasoconstriction. The peripheral vasodilatation may cause arterial hypotension, while cerebral vasoconstriction will increase the resistance of the brain to blood flow. Together, these two factors may quicken and worsen an ongoing syncope tendency. Note that there is no evidence that hyperventilation on its own can cause syncope, even though it may feature in textbook lists of causes of syncope.

The actual effects of hyperventilation on the circulation are complex, because the described effects of ventilation on vessel diameter are normally counteracted by the autonomic nervous system. The peripheral vasodilatation caused by hyperventilation is much more apparent when the autonomic nervous system is damaged, such as in neurogenic orthostatic hypotension, because the counteraction is then reduced (Thijs and van Dijk, 2006; Thijs et al., 2007).

The net effect of hyperventilation on a tendency towards syncope will therefore depend on the magnitude of the respiratory pump, on effects on peripheral and cerebral vasoconstriction, and on counter regulation by the autonomic nervous system.

3.2. Respiratory influences in VVS

VVS can be triggered by fear or anxiety, and such emotions independently cause an increase in ventilation. Symptoms of impending VVS may cause anxiety, potentially resulting in a vicious circle. Hence, hyperventilation and VVS will tend to occur together, even without any physiological interaction between the two processes. It is therefore not surprising that there is evidence of increased ventilation during the evolution of orthostatic VVS during TTT (Kurbaan et al., 2000; Norcliffe-Kaufmann et al., 2008).

However, the effects of respiration on the circulation may be stronger in VVS patients than in controls: voluntary hyperventilation resulted in a greater reduction of peripheral resistance and of cerebral perfusion in patients with VVS than in healthy controls. (Norcliffe-Kaufmann et al., 2008) meaning the stronger response of VVS to hyperventilation may increase the tendency to develop VVS.

People who reported being prone to VVS-like dizziness exhibited more hypocapnia when viewing a surgery video than controls, suggesting that VVS patients have a stronger tendency to respond with anxiety-induced hyperventilation (Harrison et al., 2017). In blood donors, those with more anxiety before donation had larger CO2 decreases during donation, and larger CO2 changes were associated with a higher chance of needing treatment for a reaction during donation (Mennitto et al., 2020). A randomized controlled trial comparing ‘anti-hyperventilation’ with muscle tensing and with no intervention in blood donors concluded that the ‘anti-hyperventilation’ therapy, while not lowering end-tidal CO2, did reduce respiratory frequency. Those with little fear of medical situations responded the most (Mennitto et al., 2019).

Hence, all steps in the cascade from anxiety, through hyperventilation and ending with the circulation appear to be enacted stronger in VVS patients than in controls, so this cascade will promote VVS once started. It is possible that the self-reinforcing cascade can start at any point in the emotional, respiratory and circulatory feedback loop.

4. Autonomic control

4.1. Heart rate variability in VVS

Heart rate variability (HRV) is a tool to try to distinguish between sympathetic and parasympathetic influences on HR. As both branches of the autonomic nervous system influence HR, it is inherently difficult to disentangle their effects. HRV efforts to do so largely rely on the two branches responding to different triggers and operating on different time scales. For instance, HR responses to respiration are mostly dependent of parasympathetic control; in a Fourier analysis, these are apparent as the so-called high-frequency peak, whereas sympathetic influences operate at a lower frequency.

Various difficulties have emerged regarding the application of HRV results. A major difficulty is controlling for respiration: HRV is most reliable when BP, HR and in particular respiration are stationary for periods of up to 5 min (Penttilä et al., 2005; Ernst, 2017). All three however change considerably during TTT. As said, many patients hyperventilate, so their respiration changes in depth and frequency. This must alter the high frequency peak, which is then not a reliable indicator of vagal tone. HRV studies during tilt-evoked VVS should therefore attempt to control for rapid respiratory changes.

Many HRV measures depend strongly on mean HR (Monfredi et al., 2014; De Geus et al., 2019; Boyett et al., 2019). Some authors even stated that HRV is just a proxy for HR (Boyett et al., 2019). Unfortunately, how to account for baseline HR is far from settled (Monfredi et al., 2014; De Geus et al., 2019).

HRV analyses can provide pathophysiological insights, in particular when coupled with other approaches such as microneurography. The decrease of baroreceptor control in VVS, described above, differed between the autonomic branches: cardiac baroreflex gain decreased while sympathetic baroreceptor modulation was virtually abolished (Furlan et al., 2019).

There have been attempts to use HRV analyses to predict the outcome of TTT and through this to improve the diagnosis of VVS, with variable degrees of success (Ciliberti et al., 2018; Klemenc and Štrumbelj, 2015; Miranda and Silva, 2016; Zheng et al., 2020).

A variety of novel HRV methods have been developed and applied to VVS. Examples are very low frequency HR variation (Ciliberti et al., 2018), HR asymmetry (Pawłowski et al., 2021), the cardiac deceleration capacity (Zheng et al., 2020) and self-organized criticality using Zipf's law (Fortrat, 2020). Their clinical value in most cases awaits reproduction.

4.2. Parasympathetic receptors

Beutelstetter and colleagues sought for expressions of vagal overactivity in patients with ‘reflex syncope’, which presumably concerned VVS (Beutelstetter et al., 2019). The authors reported overexpression‎ of muscarinic M2 receptors in the blood of both adults and children compared to controls. In these patients, acetylcholinesterase expression‎ was also increased. In adults, M2 expression‎ and acetylcholinesterase expression‎ were more pronounced in those who had a positive response to carotid sinus massage. Blood samples were not taken close to a VVS spell, which might be useful for the suggested use as a biomarker (Beutelstetter et al., 2019).

4.3. Role of the baroreflex in VVS

As stated above, HR and BP decrease together in VVS once CI has started, signifying an absence of normal baroreflex control. However, the baroreflex might also act abnormally in VVS patients at rest, or in an earlier phase before CI starts, when BP decreases slowly due to VD. The activity of the baroreflex is usually assessed by measuring how much the RR-interval, the inverse of HR, changes for a given change of BP. The result, baroreflex gain or sensitivity, is expressed as ms per mmHg. Note that this assessment only assesses the parasympathetic effector part of the reflex acting on HR, not the sympathetic part causing vasoconstriction. The amount of vasoconstrictor nerve impulses can be measured using ‘microneurographic sympathetic nerve activity’. Recent developments allow an assessment of how much vasoconstriction these impulses represent (Hissen and Taylor, 2020).

A brief review of the baroreflex in VVS (Chaddha et al., 2016) showed contradictory results for baroreflex gain in VVS: some studies showed decreases, others increases or no changes (Chaddha et al., 2016). The conflicting results were attributed to differences in methods or patients groups.

5. Humoral factors in VVS

5.1. Hormones

Benditt et al. reviewed the role of neurohormones in VVS recently (Benditt et al., 2020). Hormonal effects were usually tested in the context of TTT, i.e. orthostatic VVS. Unfortunately, high cost and other reasons make it difficult to obtain multiple blood samples at a high temporal resolution. This means that data are yet lacking to study interactions with the quickly changing hemodynamic situation in VVS.

During presyncope of orthostatic VVS, adrenalin concentration increased considerably, while noradrenalin levels stayed unaltered or increased very little. Near syncope, adrenalin levels were 6 to 15 times higher than at baseline. (Benditt et al., 2020) In other words, the ratio of adrenalin to noradrenalin levels increased, and high ratios proved to associated with a shorter latency to syncope (Kohno et al., 2019; Torabi et al., 2019). When the adrenalin concentration is higher than the noradrenalin one, vasodilatation may occur in some muscle vascular beds. This may contribute to venous pooling in orthostatic VVS. For other hormones we refer to the review (Benditt et al., 2020).

An unsolved problem with these hormonal changes is that it is unclear whether they represent a compensatory effort for aberrant autonomic control, whether they are part of the problem, or both at different times.

5.2. Low-adenosine syncope

As the time of writing, it was not entirely clear whether this type of syncope should be classified as a type of reflex syncope. However, it may well overlap with VVS (Brignole et al., 2020). Adenosin causes bradycardia though A1 receptor stimulation and vasodilatation through A2 receptor stimulation, so its actions fit well with known mechanisms of reflex syncope (Brignole et al., 2020). The clinical characteristics of syncope in patients with low adenosine were viewed recently (Brignole et al., 2020). In short, this type of syncope is characterized by a sudden start of syncope, no prodromes or prodromes of less than 5 s' duration and no cardiac abnormalities (Brignole et al., 2020; Guieu et al., 2020; Deharo et al., 2013; Deharo et al., 2021; Brignole et al., 2017). Compared to typical VVS cases, the low-adenosine patients are generally over 40 years of age; a TTT tends to be negative and the history of syncope is short. (Brignole et al., 2020; Deharo et al., 2013). During syncope these patients have a sudden-onset AV-block or sinus arrest, without the progressive preceding bradycardia commonly seen in VVS (Brignole et al., 2017). The AV-block does not evolve into a permanent AV-block (Blanc and Le Dauphin, 2014).

While typical VVS patients have a purinergic biochemical profile with high adenosine levels, low-adenosine patients have the opposite pattern. Adenosine is normally released during hypoxia, ischemia, beta-adrenergic stimulation and inflammation (Guieu et al., 2020). Adenosine causes a slowing of HR, coronary vasodilatation and a lowering of BP (Guieu et al., 2020). When adenosine plasma levels are low, adenosine mainly affects A1 receptors in the sino-atrial and atrioventricular nodes. The low adenosine levels increase the sensitivity of these receptors, so a temporary adenosine increase can cause a profound bradycardia or AV-block (Brignole et al., 2020).

Unfortunately, the pathophysiology of this type of syncope is not yet clear. Whether the sinus arrest or AV-block syncope is triggered or not, and if so, by which triggers, is at present unknown (Brignole personal communication).

Recognition of the low-adenosine type may allow a better differential diagnosis of the various causes of AV-block and may also have therapeutic consequences, as theophylline should reduce syncope frequency in these patients (Brignole et al., 2019). However, putting this into practice requires the widespread ability to measure adenosine, which is not yet the case.

Adenosine may also affect TTT procedures as it acts faster than nitroglycerine (Kirsch et al., 2007; Tajdini et al., 2021). In one study the positivity rate of TTT did not differ from that of nitroglycerine (Tajdini et al., 2021), and in another it was lower (Kirsch et al., 2007).

5.3. Iron deficiency in ‘breath holding spells’

‘Breath-holding spells’ (BHS) may not be commonly regarded as VVS, but the facts that ‘pallid BHS’ is triggered by unpleasant stimuli and is characterized by severe cardioinhibition, without a strong respiratory role, shows that its basic features are identical to those of VVS. Unfortunately, the use of multiple names such as ‘reflex anoxic seizures’ contributes to confusion (Stephenson, 2001). The cyanotic type depends on respiration stopping in expiration (Breningstall, 1996), with circulatory effects occurring secondarily to respiratory ones; as such, cyanotic BHS appear to have no adult counterpart. In spite of these pathophysiological differences, the two types can coexist in a child, and in much of the literature the types are not distinguished. Unfortunately, pathophysiological studies similar to earlier cardinal ones (Stephenson, 1990) seem to have stopped.

Low iron levels, with or without anemia, were repeatedly reported in BHS (Azab et al., 2015). A meta-analysis of iron supplementation to patients with BHS and iron deficiency showed that supplementation reduced the frequency of spells (Hecht et al., 2020). The authors stressed that the treatment effect depended on iron deficiency, not on anemia. There are reports of low iron levels in older children with VVS as well (Guven et al., 2013; Li et al., 2013), but no reports on iron metabolism in adults with VVS were found.

5.4. Low vitamin D

Two studies reported low vitamin D levels in patients with VVS compared to controls. The first observations concerned 75 adults with VVS and 52 controls; reasons to test vitamin D were not mentioned (Usalp et al., 2020). The result was reproduced in 75 children and adolescents with VVS compared to 15 controls (Zhang et al., 2021). Its functional role is, however, yet unclear.

6. Psychological aspects6.1. Emotional triggering of VVS

As explained before, the afferent pathway and the early efferent pathway of emotional VVS are essentially unknown. It is clear that the final efferent pathway, with profound hypotension and CI, is the same as in orthostatic VVS. However, lacking a protocol that elicits emotional VVS without any gravitational challenge, it is unknown what happens in emotional VVS before CI is triggered. Clinical experience shows that asystolic emotional VVS may well occur in susceptible patients who undergo medical procedures in the supine position, proving that gravitational stress is certainly not an absolute requirement for VVS. The open question is whether the early phase of emotional VVS resembles the one of orthostatic VVS, with venous pooling and low SV.

Fear and anxiety as triggers of VVS have been abundantly studied in the context of blood donation. For example, donors who were fearful of having a venipuncture were more likely have a vasovagal reaction than those who did not. Of interest, asking about such fears did not increase the risk of such a reaction (France et al., 2019)

Clinical experience also suggest that anxiety need not only act as a precipitating direct trigger of emotional VVS, but can also act as a predisposing factor over a longer timescale. This is supported by an association of childhood sexual and physical abuse with syncope frequency (O'Hare et al., 2017)

6.2. Psychological and psychiatric comorbidity in VVS

Russo et al. investigated personality traits in VVS, because personality was known to modulate an individual's sensitivity to stress, and VVS was known to respond to emotional arousal and uncertainty (Russo et al., 2017). VVS patients indeed proved to be more sensitive to stressors and adapted less quickly to stress. This study is important in that temperament and personality are considered to be fairly stable over long terms, so they should not reflect temporary stressors only.

Other studies reported more anxiety, anxiety sensitivity and depression in VVS patients (Ng et al., 2019; Atici et al., 2020). Childhood physical or sexual abuse was associated with a higher syncope frequency in childhood, and may contribute to a lifelong VVS tendency (O'Hare et al., 2017). While these psychological factors contributed to low quality of life (Ng et al., 2019), it was impossible to determine whether anxiety was the cause or the consequence of VVS, or whether they reinforced one another, with VVS increasing anxiety, and anxiety increasing the VVS tendency. Whether such a positive feedback loop, operating on a time scale of weeks or months, exists for VVS cannot be determined. However, it does exist on the time scale of minutes: the so-called ‘status vasovagalis’ in which VVS in a medical situation precipitates another VVS spell, is evidence of such positive feedback (Thijs et al., 2009).

7. Short summaries and unanswered questions

7.1. Hemodynamic questions

Recent hemodynamic advances allowed a quantification of the relative impact of CI, arterial and venous VD (Van Dijk et al., 2020b).

Clearly, VVS does not occur every time that patients with orthostatic VVS stand for a long time. What is not clear is whether the primary problem is whether a tendency towards venous pooling can become so strong that it cannot be corrected by normal autonomic and hormonal regulation, or whether these corrected efforts are at times too weak to correct normal fluctuations. It is likely that such questions can only be answered if and when a practical and reliable measurement of ongoing venous pooling becomes available.

In either case, it may be wondered whether the venous pooling that initiates the orthostatic VVS cascade should be considered part of a reflex. One would expect that the degree of venous pooling is under autonomic control; if so, the apparent inability to prevent pooling spiraling out of control resembles autonomic failure, or ‘decompensation’, rather than an overactive reflex. In this scenario, the reflex part of VVS only starts with the onset of CI.

CI was redefined as the decrease of HR towards syncope (Van Dijk et al., 2020b). The start of CI consisted of a moderate reduction of the ongoing corrective high HR, and even this resulted in an immediate acceleration of the ongoing BP decrease. These findings, together with the concept of ‘late asystole’, suggest that attempts to prevent LOC in VVS with conventional back-up pacing are likely to fail in an uncomfortably large proportion of cases. Back-up pacing merely sets HR to a threshold value (e.g. 50 or 60 bpm) when spontaneous HR drops below that threshold. When HR reaches that threshold in VVS, VD may already have caused such a large BP decrease that LOC is difficult to prevent. Back-up pacing may likely work well only in those in whom asystole occurs when BP is still high at the onset of asystole. Such hemodynamic considerations suggest that pacing may work much better in orthostatic VVS if two alterations are made: firstly, pacing might start early, at the onset of CI, and the rate should perhaps be high and near the rate at which CI starts, meaning at 90–100 bpm. Such ‘early high-rate pacing’ might in effect abolish the hemodynamic effects of CI.

The contributions of VD, venous and arterial CI may well be different in other causes of reflex syncope, or indeed differ within VVS. In fact, the large variability of changes of HR, SV and TPR may hide as yet undiscovered different hemodynamic patterns. Types of reflex syncope with a very quick onset, such as carotid sinus syncope, are unlikely to start with slow venous pooling, and may represent the presumed ‘classical’ reflex type, with CI and arterial VD only.

There is definitely room to improve measurements of cerebral perfusion in VVS. As discussed above, measuring brain oximetry holds promise, once the problem of possible contamination extracranial tissue oxygenation is solved and comparisons with transcranial Doppler will have been performed.

7.2. Respiratory questions

Anxiety, hyperventilation and its circulatory effects reinforce one another in VVS patients, so their combined effects appear geared to promote VVS. While increased respiratory movements help increase venous return and increases BP, the resulting hypocapnia causes vasodilatation as well as an increase of sympathetic outflow. Hence, the net impact on BP is uncertain. We suspect that the hemodynamic consequences of hyperventilation on VVS are underestimated, possibly because measurements of respiration, such as end-tidal CO2, are not an integer part of TTT measurements. However, they can be added easily (Thijs et al., 2021), which should provide a basis to determine the net contribution of respiration to VVS.

7.3. Autonomic questions

Some of the efforts to predict the outcome of TTT using HRV measures might be able to shed light on autonomic control during VVS, if reproduced.

7.4. Humoral questions

Clarifying the real role of hormones in VVS, i.e. whether they are they part of the cause or part of the effect, may well require determining hormonal levels at fairly high temporal resolution, together with hemodynamic assessments. The novel low-adenosine type of syncope shows that humoral factors may be very important in VVS and associated types of syncope, giving rise to the concept of ‘neurohumoral’ syncope (Brignole et al., 2020). As adenosine can cause both bradycardia and vasodilatation, it may be involved in cardioinhibition as well as in vasodepression.

Whether other metabolic parameters, such as vitamin D or iron levels, will affect clinical practice remains to be seen. However, the subject of ‘iron in BHS’ provides cause for thought: although there was no strong reason to think that iron would be involved in BHS, characterized as BHS is by a paroxysmal response to external triggers in otherwise healthy infants, there is now a meta-analysis showing that iron supplementation decreases BHS attack frequency (Hecht et al., 2020).

7.5. Psychological questions

The psychology of VVS is obviously of great importance for VVS, but how it affects the hemodynamic state is difficult to assess. This holds in particular for possible long-term influences: does long-term anxiety promote a tendency towards venous pooling, and, if so, through which intermediaries? Both autonomic and hormonal influences may be important here.

However, one psychological pathway can potentially be clarified, and that is how emotional stimuli cause VVS. It should be possible to develop a test for emotional VVS, by eliciting emotional VVS in supine susceptible subjects by showing surgery videos or similar means. A first question would be whether emotional VVS starts with venous pooling as in orthostatic VVS, or whether they proceed directly to pronounced CI and arterial VD. A secondary question might be whether the relatively slow process of anticipation of fearful stimuli promotes venous pooling; if so, sudden unexpected painful or emotional stimuli, such as a fright or stubbing one's toe, might set a different mechanism in motion than anticipating venipuncture.

These questions might have therapeutical consequences: if emotional VVS does not share a slow venous VD phase with orthostatic VVS before CI starts, then the hemodynamic situation with intact venous return should be more amenable to cardiac pacing.

7.6. No more questions?

The most fundamental aspects of VVS are still unknown: how can the sight of blood cause the heart to stop? In orthostatic VVS, why is venous pooling allowed to go unchecked from time to time? Why does HR first increase in an attempt to limit the decrease of BP, and then acts as a ‘turncoat’, causing BP to plummet?

The overview presented above suggests that answers are more likely to be found when research fields are integrated, which will require cooperation and a broadening of interest to encompass hormone functions, respiration effects as well as psychological factors. Apart from designing directed studies to answer specific questions, much can probably be learned from judicious study of TTT results. Simple means such as adding video recording have led to new insights in the past (van Dijk et al., 2014; Tannemaat et al., 2013; Shmuely et al., 2018), and monitoring more physiological systems, such as respiration, brain perfusion and hormones, are likely to provide additional insights at very low additional cost (Thijs et al., 2021).

References

1. Alboni and Alboni, 2017
2. Atici et al., 2020
3. Azab et al., 2015
4. Bachus et al., 2018
5. Badenes et al., 2021