Endothelial function in vasovagal syncope

Abstract

Vasovagal syncope (VVS) is a common form of fainting. The pathophysiology of VVS is complex and involves changes in the autonomic and vascular tone, resulting in reflex bradycardia with marked hypotension. Paradoxical peripheral vasodilation caused by endothelial dysfunction may also play a key role in inappropriate hypotension during VVS. Endothelial hyperactivity due to up regulation of nitric oxide synthase leads to profound vasodilation, much stronger than vasodilation caused by adrenergic stimulation in response to orthostatic stress alone. Studies have reported significantly higher flow-mediated dilation and higher plasma nitric oxide concentration in people with vasovagal syndrome. Patients with VVS showed decreased vasoconstrictive agent endothelin-1 levels during orthostatic stress. Coagulation and fibrinolysis activity also play important roles in endothelial function in syncopal patients. The response of the endothelium to orthostatic stress is similar to the reaction to haemorrhagic stress and is likely to be a remnant from the evolutionary adaptation of primates.

Keywords::

• coagulation and fibrinolysis
• endothelium
• endothelium independent dilation
• flow mediated dilation
• nitric oxide
• profound vasoidaltion
• vasovagal syncope

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Erratum

Syncope is a transient loss of consciousness due to transient global cerebral hypo-perfusion characterized by rapid-onset, short-duration and spontaneous complete recovery. Vasovagal syncope (VVS) is the most common form of faint and belongs to the reflex syncope family – disorders that result from a sudden failure of the autonomic nervous system to maintain adequate vascular tone during orthostatic stress [1].

The pathophysiology of VVS is complex and seems to involve changes in the autonomic and vascular tone, resulting in reflex bradycardia with marked hypotension. It is believed that vasodilatation during VVS is passive and occurs through a sudden withdrawal of muscle sympathetic nerve activity. In humans, orthostatic stress increases the activity of the sympathetic nervous system and usually leads to compensatory vasoconstriction of the vessels of skeletal muscle. When this mechanism for maintaining blood pressure in orthostatic stress fails, syncope occurs [1–3].

In spite of numerous studies, the pathology of VVS still has not been fully elucidated. It has been suggested that the processes leading to VVS include changes in hemodynamic parameters caused by alterations in the plasma concentration of vasoactive substances (i.e., catecholamines, nitric oxide (NO), endothelin, vasopressin or prostanoids) as part of the response to orthostatic stress [2,3].

Recent research has focused on the regulation of the peripheral circulation in patients with VVS in an attempt to identify the active or passive mechanism driving peripheral vasodilation [4–6].

Paradoxical, peripheral vasodilation caused by endothelial dysfunction may play a key role in inappropriate, excessive hypotension during orthostatic stress in individuals with VVS [7,8].

There are several possible explanations for this phenomenon. The increase of sympathetic stimulation agents may suppress the release of an unknown vasodilating factor, which rapidly releases and dilates peripheral arteries after the sudden decrease of sympathetic activity. Parasympathetic stimulation in response to sympathetic stimulation during orthostatic stress may also contribute to peripheral vasodilation. Increased vagal activity may lead to augmented synaptic transmission of acetylcholine, which is responsible for vasodilation mediated by NO [7,8].

There are data showing that the endothelium plays the central role in regulation of vascular tone in VVS. Endothelial hyperactivity due to upregulation of nitric oxide synthase leads to profound vasodilation. Vasodilation occurring in response to endothelial function is much stronger than vasodilation caused by adrenergic stimulation in response to orthostatic stress alone, but the mechanism of this vasodilation remains unclear [7,8].

Some authors have suggested that the very rapid decrease in sympathetic drive is not sufficient to cause the vasodilatory response observed during VVS. They suggest that the profound vasodilation observed in humans during VVS is not mediated solely by sympathetic withdrawal. Both β2-adrenergic-receptor-mediated vasodilation and NO are essential in this process. These authors argue that vasodilation during fainting must be caused by another active factor [7].

Vascular endothelium, the largest endocrine organ in humans, is a single layer of cells lining the lumen of blood vessels and forming a barrier between the blood and vessel wall. Its location means that endothelium can respond to various stimuli, both chemical and physical, by excreting a variety of autocrine and paracrine substances, which act on cells on both sides of the vessel wall to help vascular homeostasis. The endothelium produces and releases vasoactive substances regulating the activity of coagulation, fibrinolysis and inflammation, as well as growth factors [9].

One of the main functions of vascular endothelium is to regulate wall tension by releasing various vasoactive substances, vasodilators such as NO, prostacyclin, prostaglandin I2, endothelial hyperpolarizing factor, bradykinin, adrenomedullin, C-type natriuretic peptide and vasoconstrictors such as endothelin-1 (ET-1), angiotensin II, thromboxane A2 (TXA-2), prostaglandin H2, and oxygen radicals [10].

Endothelial secretion may play an important role in the regulation of vascular tone during orthostatic stress (e.g., inappropriately increasing release of vasodilators in response to shear strength stress of blood flow or reduced release of vasoconstrictors). Vasodilation induced by endothelium activity, leading to excessive hypotension, may thus exceed the capacity of compensatory mechanisms to maintain blood pressure and thereby ensure adequate perfusion of the brain [6–9].

Endothelial function can be assessed by measuring flow-mediated dilation (FMD) of the brachial artery. The theory behind this method is that the diameter of the brachial artery after passive hyperemia changes under the influence of mediators released by the action of shear forces of blood flow and that production of these substances depends on the function of the endothelium [11].

Endothelium-independent vasodilation (EID) is a result of direct extension of vascular smooth muscle by nitroglycerin, an exogenous nitric oxide donor, and could be used to determine the upper limit of arterial diastolic reaction.

Reduced FMD is observed in many conditions that are associated with increased risk of atherosclerosis, such as hypertension, smoking, obesity, diabetes as well as in the aging process [10]. It is plausible to suggest that the increase in FMD, as a result of pathological endothelial overactivity in the regulation of vascular wall tension, in response to orthostatic stress, should be a strong predictor of reflex syncope.

Some studies have reported significantly higher FMD and higher plasma NO concentration in young people with vasovagal syndrome than in healthy subjects [12,13]. Augmented endothelial function and abnormal vasodilation of peripheral arteries play an important role in the development of VVS in young subjects. Patients with VVS showed marked and sustained EID, in the presence of a normal FMD. Children with postural orthostatic tachycardia syndrome have also been shown to have augmented FMD and abnormal vascular endothelial function, which may play an important role in syncope induction [4,12–14]. Studies by Wnuk and colleagues in our department indicated that increased FMD or EID, associated with abnormal endothelial function in the regulation of vascular wall tension after tilting of patients with VVS, are strong predictors of reflex syncope (submitted).

It is now recognized that other than NO endothelium-related hormones, such as ET-1, may play a role in the control of vasomotor tone in humans. Although ET-1 levels increase in response to orthostatic stress, the exact role of this hormone in the pathology of VVS is unclear. Some studies have found that patients with syncope induced by the head-up tilt test failed to show an increase in ET-1 levels, whereas other studies have found increased plasma levels of endothelin during tilt-induced syncope, compared to objects with negative response to head-up tilt test [14,15]. Fedorowski and colleagues reported that in patients with VVS, unlike those with orthostatic hypotonia, showed decreased ET-1 levels during orthostatic stress. Measurement of ET-1 may be useful for discriminating between classical reflex syncope and that induced by orthostatic hypotension [5].

Coagulation and fibrinolysis activity are also very important aspects of endothelial function in patients with reflex syncope [16,17]. In 2008, Masoud and colleagues described a novel physiological mechanism, ‘orthostatic procoagulation,’ in which endothelial-dependent procoagulant and anticoagulant systems are activated during prolonged static standing [18].

There have been several studies of endothelium-dependent changes in blood clotting. Significant increases in concentration or activity of blood coagulation factors in response to orthostatic stress have been reported [16–18]. Cvirn and colleagues reported that the procoagulant effect of orthostatic stress persists for up to 20 min after presyncope, which is the endpoint of cardiovascular stress. Orthostatic stress has to be considered as an important risk factor for hypotension susceptibility, particularly in these patients in whom the activation of coagulation during orthostatic challenge persists after the challenge [19].

Our data show that there is a significant increase in d-dimer concentration in parallel with increases in von Willebrand factor and tissue plasminogen activator serum level in the majority of patients with VVS, who developed syncope during the tilt test (submitted).This suggests that orthostatic stress in VVS patients can induce important changes in coagulation activity and subsequent activation of fibrinolysis (submitted). It has been suggested that the clotting process activated by orthostatic stress may have evolved to protect against hemorrhage. The reduced blood volume resulting from bleeding leads to increased coagulation which helps to ‘clog the leak’. Maintaining normal blood pressure during hemorrhage would exacerbate the loss of blood, so increased clotting induced in this way may prevent fatal blood loss [16,20].

In conclusion, vascular endothelium plays an important role in profound hypotonia during VVS. Vasoactive endothelial hormones act alongside the vasovagal reflex. Activation of coagulation and fibrinolysis are important components of the endothelial response to orthostatic stress. The response of endothelium to the orthostatic stress is similar to the hemostatic reaction to hemorrhagic stress and is likely to be a remnant from the evolutionary adaptation of primates.

Financial & competing interests disclosure

AZ Pietrucha is an investigator of a study sponsored by Servier. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.