PATHOPHYSIOLOGIC BASIS FOR VASODEPRESSOR SYNCOPE

The routine use of head-up tilt testing for the evaluation of recurrent unexplained syncope has indicated that the vasodepressor (vasovagal, neurocardiogenic) response may be responsible in up to 50% of cases of recurrent unexplained syncope.6, 14, 55, 70, 73, 144 The vasodepressor response may be triggered by a myriad of stimuli, including orthostatic stress (head-up tilt, lower body negative pressure), emotional stress, relative or absolute blood loss, and severe pain. Similarly, data suggest that other clinical syndromes, such as carotid sinus hypersensitivity or micturition syncope, share a common reflex pathway with the classic vasodepressor response (Fig. 1).73, 78, 106, 177, 180 Interest in elucidating the mechanisms responsible for the control of arterial blood pressure have intrigued physiologists and physicians for more than a century. Hunter (1728–1729) may have inadvertently reported the first description of a vasodepressor response when he wrote: “I bled a lady but she fainted and while she continued in the fit the color of the blood that came from the vein was a fine scarlet. The circulation was very languid.”¹²³ It has been speculated that Hunter noticed the effects of vasodilatation during syncope.²⁰⁷ By the late nineteenth century, Hill⁶⁴ suggested that emotional syncope results from withdrawal of vasomotor neural traffic. This view was further supported in 1932 by Lewis,⁸⁴ who introduced the term vasovagal suggesting that both vasodilatation and bradycardia were involved in the vasodepressor response. Lewis demonstrated that bradycardia was vagally mediated; however, despite prevention of bradycardia with atropine, hypotension persisted.⁸⁴ Further interest in the pathophysiology of this syndrome was triggered by the frequent observation of vasodepressor responses in injured soldiers during World War II.41, 51, 52, 99, 165 This interest was renewed in the 1960s by the advent of aerospace medicine in an attempt to understand the physiology of G force–induced vasodepressor syncope.42, 43, 195 The introduction of head-up tilt as a clinical diagnostic tool in 1986 by Kenny and associates⁷⁷ revived the interest in elucidating the mechanism of vasodepressor syncope.78, 131, 133, 176

Activation of left ventricular vagal–C mechanoreceptors owing to a sympathetically mediated increase in contractility in an empty or preload reduced left ventricular cavity leading to a reflex increase in vagal efferent traffic and sympathetic withdrawal to skeletal muscle arterioles and splanchnic venules has been usually regarded as the potential mechanism of vasodepressor syncope (Fig. 2).12, 69, 95, 199 This view, largely supported by experimental evidence obtained from cats by Öberg118, 119, 120, 121 and Thore´n186, 187 and rats in the mid 1970s prevailed until the observation of vasodepressor syncope in heart transplant recipients reported by several groups.38, 86, 142, 204 Species differences in the genesis of the vasodepressor response may be responsible for this discrepancy.¹⁶⁴ Morita and Vatner¹⁰⁹ observed in conscious dogs sympathoexcitation and tachycardia as the initial response to hemorrhage. Progressive hemorrhage led to sympathetic withdrawal and bradycardia. Interruption of cardiac afferents or arterial baroreceptors, however, was unable to prevent the onset of the vasodepressor response.¹⁰⁹ These findings suggest that cardiac afferents may not be required to trigger the vasodepressor response and have been met with the proposal of alternative hypotheses. This article focuses on the current knowledge regarding the neuroendocrine, hemodynamic, and neurophysiologic components of the vasodepressor response and proposes a unifying hypothesis for vasodepressor syncope.