Pathophysiology of Reflex Syncope: A Review

Wayne O. Adkisson MD; David G. Benditt MD


J Cardiovasc Electrophysiol. 2017;28(9):1088-1097. 

In This Article

Pathophysiology of Syncope in General

As noted above, syncope results from transient self-limiting global cerebral hypoperfusion due to, except in rare circumstances, a fall in systemic BP. Before examining the reflex syncope syndromes in some detail, a general understanding of cerebral perfusion is required.

Regulation of Cerebral Perfusion

The human brain is an amazing organ, capable of composing symphonies and probing the mysteries of its own function. The 1,400 g brain, roughly 2% of an average adult mass, requires 15–20% of cardiac output (CO), even at rest. Making matters worse, it has little metabolic reserve. Six to seven seconds of cessation of CBF may result in the onset of syncope.[3] Thus, ensuring adequate CBF is essential and the systems for doing so are complex and still inadequately understood.

Baroreflex System

The baroreflex system is central to the regulation of BP, and is therefore a critical component to the maintenance of mean arterial pressure (MAP) and CBF. Baroreflex sensors are found at multiple sites within the systemic vascular system, the pulmonary arteries, and the cardiac chambers. Among the most well-known baroreceptors are those within the carotid sinuses and those within the aortic arch.

The principal vascular-triggered baroreflex arc comprises: (1) afferent fibers from the carotid sinus baroreceptors, running in the glossopharyngeal nerve and (2) afferent fibers from the aortic baroreceptors running through the vagus nerve. The afferent fibers converge in the nucleus tractus solitarii in the medulla oblongata. It is within the nucleus tractus solitarii that baroreceptor afferent inputs are integrated with other sensory inputs. The most crucial efferent signals with regard to reflex syncope are carried to peripheral blood vessels and heart via sympathetic nerves, while parasympathetic fibers in the vagal nerve carry efferent signals to the heart and other organs such as the gastrointestinal tract (small intestine and large intestine up to the splenic flexure) (Figure 1). Of necessity, the description of the reflex arcs provided here is simplistic, and ignores the contributions played by circulating volume, chemical inputs (e.g., carbon dioxide levels), and neuroendocrine effects (e.g., vasopressin, nitric oxide [NO], catecholamines, and neuropeptides), as well as the complex central integration of the reflex inputs in the midbrain.[4]

Figure 1.

A simplified diagram of the principal components of the baroreceptor reflex is displayed. Afferent impulses arise from sensors stimulated by pressure, volume, and chemical changes. Of these, the baroreceptors (pressure receptors) located in the aortic arch and carotid sinus bodies are of primary importance. Central integration within the nucleus tractus solitaries (NTS) includes additional inputs from chemical and volume sensors that are not illustrated in this diagram. The efferent output is carried by sympathetic nerves to the vasculature and the vagus nerve to the sinus node and AV node as well as to the gastrointestinal and genitourinary tract smooth muscle. (See text for details) [Color figure can be viewed at]

The parasympathetic efferent fibers acting in concert with sympathetic tone regulate heart rate and contractility, whereas sympathetic output also regulates peripheral vascular and splanchnic bed resistance. Consequently, in health, an increase in MAP, detected in the aortic arch and carotid sinus baroreceptors, results in an increase in parasympathetic output to the heart; the outcome is slowing of the heart rate and a reduction in contractility. At the same time, sympathetic output to the vasculature is reduced, resulting in a fall in peripheral resistance.[5] Vagal effects on heart rate and contractility occur almost immediately. The sympathetic effects take 2–3 seconds to begin. Likewise, withdrawal of sympathetic tone takes longer to manifest as compared to the withdrawal of parasympathetic tone. Additional contributors to the reflexes include mechanoreceptors in the atria (low pressure receptors) and ventricles of the heart. These may act to modify the overall reflex response.

The MAP reflects the balance between CO and peripheral vascular resistance (PVR). As already noted, in most cases of syncope, the cause of inadequate cerebral perfusion is a fall in MAP. In the above example, a reduction in contractility and heart rate leads to a drop in CO, which in the absence of a change in the PVR would result in a fall in MAP. In a normal physiologic setting, a fall in MAP and/or venous return to the heart results in a decrease in the afferent signals from the baroreceptor system. The subsequent alteration in efferent traffic then serves to raise MAP.

Cerebral Blood Flow

CBF is more complicated than other organ blood flow dynamics because the brain is encased in a rigid structure, the skull.[6] As with most tissues, CBF is dependent on the difference between arterial and venous pressures. Blood flow is also affected by the balance of the pressure within the lumen versus the closing pressure imposed by both wall tension and tissue pressure. In most organs, tissue pressure is rarely an issue; this is not the case for CBF. Given the constraints of the skull, tissue pressure in the brain can increase dramatically, and impact CBF.[7] This latter effect is seen most dramatically after a period of cerebral ischemia, when cerebral tissue edema can diminish CBF dramatically and cause life-threatening cerebral damage.

Venous outflow from the brain is also more complicated than in other organs and has been proposed as a possible contributing factor in some of the situational syncopes but will not be discussed in detail in this communication.

Cerebral Autoregulation

Cerebral autoregulation (CA) refers to the processes that allow CBF to remain relatively constant over a wide range of MAP.[6,8] In addition, the CA "settings" may be altered by chronic disease. Hypertension and diabetes have both been shown to shift the CA curve to higher pressures (Figure 2).[8]

Figure 2.

Cerebral autoregulation (CA): Cerebral blood flow remains constant (C) over a wide range of mean arterial pressure, (MAP). Below an MAP of 60 mmHg CA fails and syncope may result. In disease states, such as hypertension, the range of MAP at which CA functions is shifted to the right (in red). (See text for details) [Color figure can be viewed at]

The operative mechanisms associated with CA are complex and involve an interplay among neurogenic, metabolic, myogenic, and endothelial pathways. Neurogenic effects are primarily mediated by sympathetic nerves that result in vasoconstriction. Of the metabolic pathways, carbon dioxide is a powerful regulator of CA. Hypocapnia is a potent vasoconstrictor leading to a decrease in CBF, while hypercapnia leads to increased CBF, probably via neurogenic and vascular NO release.[9]

CA functions over a defined but nonetheless limited MAP range. At MAP values below the lower limit, CBP falls off rapidly. Cerebral function then deteriorates and TLOC is likely to occur. Techniques that enhance MAP at the level of the brain, such as by lowering the head, or enhancing venous return to the heart to improve CO (e.g., lower body counter-pressure maneuvers and raising the legs above the thorax), are simple nonpharmacological approaches to reversing the diminution of a low MAP impact on CBF.