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Heart Rhythm. Author manuscript; available in PMC 2009 December 1.
Published in final edited form as: Heart Rhythm. 2008 December ; 5(12): 17021703. doi:10.1016/j.hrthm.2008.09.022.

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Is cardiac output the key to vasovagal syncope? A re-evaluation of putative pathophysiology

Satish R Raj, MD MSCI Autonomic Dysfunction Center, Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA Undoubtedly the main cause of the fall in blood pressure in these attacks, and the enfeeblement loss of pulse, is independent of the vagus, and lies in the blood vessels. Attacks in which the blood pressure sinks without a lowering of the pulse rate, and the patient verges on unconsciousness whenever the pressure reaches certain low levels, have been encountered. Thus, the cause of the syncope is mainly vasomotor and not vagal; but the vagus adds impressively to the clinical picture by inducing conspicuous slowing of the heart and gastric manifestations. Sir Thomas Lewis (1932). (1) Vasovagal syncope (reflex fainting) affects about 40% of the population up to age 70 years (2). Despite the wide impact of this type of fainting, our fundamental understanding about the pathophysiology of vasovagal syncope has not changed greatly since Lewiss report. SharpeyShafer (3) is credited with describing the most commonly accepted physiological model for postural vasovagal syncope over 50 years ago. In this model, the initiating event is the shift of blood from the thorax to the abdomen and lower extremities. This decreased venous return leads to an increase in heart rate and cardiac contractility in order to maintain blood pressure. In some instances, this increased contractility is thought to be sensed by ventricular afferent nerves as abnormally vigorous, triggering a reflex decrease in sympathetic tone (which can decrease heart rate and promote vasodilation), an increase in cardiovagal tone (which can decrease heart rate, even conspicuous slowing with asystole), or both. Each of these actions can promote systemic hypotension and ultimately cerebral hypoperfusion with resultant loss of consciousness. There are many limitations to this model (thoughtfully described by Mosqueda-Garcia et al. (4)), but a better model has not yet been developed. Based on current conventional wisdom (and Sir Thomas Lewiss description),the cause of syncope is mainly vasomotor and not vagal (1), with a loss of sympathetic nervous system vasoconstrictor tone being the predominant finding in vasovagal syncope. Studies using direct sympathetic microneurography seem to confirm a marked decrease in sympathetic activity at the time of faint (4). It is in this context that Verheyden at al. (5) report their hemodynamic study of tilt table-induced syncope. They hypothesized that different head up tilt test protocols (with or without nitroglycerin provocation) would result in fainting with different underlying hemodynamic patterns. Using relatively new beat-to-beat non-invasive blood pressure

Correspondence: Satish R Raj MD MSCI, Assistant Professor of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, AA3228 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2195, Office: (615) 343-6499, Fax: (615) 343-8649, Email: Satish.raj@vanderbilt.edu. Conflicts of Interest: None Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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technology and pulse contour based estimates of stroke volume, they assessed hemodynamic parameters in patients that fainted in response to the 2 protocols at baseline, early during tilt, late during tilt (last 4 minutes prior to presyncope/hypotension), and at the time of presyncope. Contrary to their hypothesis, patients with presyncope during their tilt test had similar hemodynamic patterns regardless of protocol. As expected, the authors found that standing (or head-up tilt) resulted in an immediate decrease in stroke volume (SV) and cardiac output (CO), and an increase in heart rate (HR). The blood pressure was preserved due to an increase in systemic vascular resistance (SVR), which is consistent with an increase in sympathetic tone. Over the duration of tilt (early to late tilt), conditions were fairly stable, with small decreases in SV & CO, with small reciprocal increases in HR & SVR. This is consistent with ongoing transcapillary filtration of plasma out of the vascular space (6;7). Starting ~1 minute prior to presyncope/hypotension, the authors found a decline in HR by 10-15 bpm (but not to levels of clinical bradycardia), a small decrease in SV and consequently a ~30% decrease in CO. However, the SVR did not fall.

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Interpretation of Current Findings

These data suggest that the fall in blood pressure that occurs at the time of tilt-induced presyncope is driven by a steep fall in CO and not because of a drop in SVR. There is, however, an inability for the SVR to increase in a compensatory manner. The stable SVR values at the time of presyncope/hypotension are surprising. Our traditional model of the faint posits that the SVR should have decreased coincident with the hypotension. This last finding by Verheyden et al. (5) is at odds with prior studies that have found a reduction in sympathoneural tone (4) and vasodilation at the time of syncope (8). While provocative, these findings require replication (ideally with sympathetic nerve recordings) to put them in proper physiological context. Why does the CO fall precipitously just before presyncope/hypotension? This could relate to decreases in both HR and SV. Clearly, the HR decreases around the time of presyncope/ hypotension, although only modestly to an average of ~90 bpm in this study (5). A modest decrease in HR might be all that is needed to significantly impact blood pressure, if there is an inability to increase vascular resistance. This decrease in HR could be due to a decrease in sympathetic stimulation to, and an increase in vagal restraint on, the sinus node. Both of these actions are consistent with the traditional Sharpey-Shafer model of vasovagal syncope. Verheyden at al. (5) also report a decrease in SV in the last minute prior to presyncope. The authors suggest that the decreased SV might result from either the transcapillary filtration of plasma out of the vascular space or from increased splanchnic blood pooling. There is little doubt that both mechanisms are at work here, but it is less clear why these might exaggerate precipitously during this last minute. Jacob et al. (7) have reported that transcapillary filtration of plasma continues slowly over time with upright tilt. Perhaps there is another trigger. In a very elegant study, Benditt et al. (9) showed that epinephrine is released prior to the onset of hypotension in patients with vasovagal syncope. It is possible that epinephrine or another vasoactive mediator promotes acutely leaky vessels and lowers venous return. Taneja et al. (10) have recently reported that splanchnic blood flow increases around the time of a faint, with a reciprocal decrease in splanchnic resistance. Such a decrease in splanchnic resistance could be due to a decrease in sympathetic tone. These data suggest that strategies to boost HR or augment SV may be effective in preventing vasovagal syncope. HR support can be easily achieved with a pacemaker, but this strategy was not successful in preventing fainting in a cohort with recurrent vasovagal syncope (11). SV could be boosted by increasing blood volume, a strategy that is currently being tested using fludrocortisone in the Second Prevention of Syncope Trial (12).

Heart Rhythm. Author manuscript; available in PMC 2009 December 1.

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These data raise many more questions. Is the marked decrease in CO merely associated with tilt-induced presyncope, or its a low CO the trigger for fainting? Will people faint when the CO drops to a critical level? Or does this only occur in some people and not in others? To answer these questions, follow-up studies will need to compare fainters and non-fainters (not included in the current analysis) to determine if their hemodynamic signatures during tilt are different. The current study by Verheyden et al. (5) forces us to reconsider our thinking about the hemodynamic events presaging vasovagal syncope. A critical drop in CO, and not a precipitous drop in SVR, is the prime hemodynamic event in patients with neurally mediated hypotension and presyncope. Further work is required to understand the physiological events leading to the penultimate decline in CO and whether this decline is unique to patients with vasovagal syncope. This knowledge is vital to help us target effective treatments.

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Acknowledgments
Funding: SRR is supported by grant K23 RR020783 from the National Institutes of Health (Bethesda, MD, USA).

Reference List
1. Lewis T. A lecture on vasovagal syncope and the carotid sinus mechanism with comments on Gowerss and Nothangels syndrome. Br Med J 1932;1:873876. 2. Serletis A, Rose S, Sheldon AG, et al. Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J 2006;27:19651970. [PubMed: 16837484] 3. Sharpey-Schafer EP. Syncope. Br Med J 1956:506509. [PubMed: 13293372] 4. Mosqueda-Garcia R, Furlan R, Tank J, et al. The elusive pathophysiology of neurally mediated syncope. Circulation 2000;102:28982906. [PubMed: 11104751] 5. Verheyden B, Liu J, van Dijk N, et al. A steep fall in cardiac output is the main determinant of hypotension during drug free and nitroglycerine induced orthostatic vasovagal syncope. Heart Rhythm 2008;5:xxyy. 6. Jacob G, Raj SR, Ketch T, et al. Postural pseudoanemia: posture-dependent change in hematocrit. Mayo Clin Proc 2005;80:611614. [PubMed: 15887428] 7. Jacob G, Ertl AC, Shannon JR, et al. Effect of standing on neurohumoral responses and plasma volume in healthy subjects. J Appl Physiol 1998;84:914921. [PubMed: 9480952] 8. Dietz NM, Halliwill JR, Spielmann JM, et al. Sympathetic withdrawal and forearm vasodilation during vasovagal syncope in humans. J Appl Physiol 1997;82:17851793. [PubMed: 9173942] 9. Benditt DG, Ermis C, Padanilam B, et al. Catecholamine response during haemodynamically stable upright posture in individuals with and without tilt-table induced vasovagal syncope. Europace 2003;5:6570. [PubMed: 12504643] 10. Taneja I, Medow MS, Glover JL, et al. Increased vasoconstriction predisposes to hyperpnea and postural faint. Am J Physiol Heart Circ Physiol 2008;295:H372H381. [PubMed: 18502909] 11. Connolly SJ, Sheldon R, Thorpe KE, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA 2003;289:22242229. [PubMed: 12734133] 12. Raj SR, Rose S, Ritchie D, et al. The Second Prevention of Syncope Trial (POST II)--a randomized clinical trial of fludrocortisone for the prevention of neurally mediated syncope: rationale and study design. Am Heart J 2006;151:11861187. [PubMed: 16781217]

Heart Rhythm. Author manuscript; available in PMC 2009 December 1.