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Neurocardiogenic Syncope, what’s the physiological explanation A Conceptual paper for the general public Melina Webb Spring 2005 Syncope is defined as a sudden and transient loss of consciousness and postural tone1 with spontaneous recovery. It is thought that about 20% of the population will faint at least once while 10% will faint more than once during their life time (Sheldon et al. 2003). It is estimated that about 3% of all emergency room visits are due to unexplained syncope2 and 1% of general hospital admissions. Syncope is a condition that can affect any age group and the onset can occur at any time during an individual’s life. All though majority of forms of syncope are not life threatening, a synoptic episode can cause physical injury and can also decrease the individual’s quality of life, if episodes are reoccurring. It seems there is an understanding what physiologically happens during a syncope episode but it is unclear why this happens and how different events and chemical levels are related. Neurocardiogenic syncope is one of many possible ways to give a better understanding of why some people experience unexplained syncope even though this condition is somewhat unexplained itself. Neurocardiogenic syncope is the most common name for this condition but it can also be referred to as vasovagal syncope or neurally-mediated syncope. Neurocardiogenic syncope is put in the category of a reflex syncope3, which is related to orthostatic4 intolerance. Figure 1 shows a flow chart of autonomic control disorders and how Neurocardiogenic syncope is categorized within. Neurocardiogenic syncope can be defined as a sudden, transient loss of consciousness 1 due to neurally-mediated5 hypotension6 and bradycardia7 (Kinay et al. 2004). It is thought that a wide variety of activities can cause an episode8 to take place, making this disease relatively difficult to diagnose. Some circumstances that seem to provoke an episode are exercise, heat, excessive standing, fear and many more. With there being such a wide range of activities that can cause an episode there is also a wide degree of severity that an episode can have. Neurocardiogenic syncope is most commonly diagnosed with a tilt table test. A tilt table test involves an individual to be strapped to a table and the place at an angle. The degree of the angle is not standard and seems to range anywhere from 50 to 80 degrees for an amount of time varying for 20 to 45 minutes (Szufladowicz et al, 2004). This test is used because it seems that placing the body at an angle can provoke enough similar stress to have an episode occur. With different people having a greater tolerance to the stress, it is possible for a drug to be given, most commonly nitroglycerin or isoproterenol, to induce a reaction. The administration of these drugs to an individual unaffected by this condition will not induce a synoptic episode. A tilt table test is what is used in almost all of the studies looking at Neurocardiogenic syncope to induce a presyncope or syncope. Multiple studies have been done to measure different physiological events that occur in the body during and previous to a synoptic event. Preceding and during an episode the major functions of the body that seem to be affected are heart rate and blood pressure. The reason why the synoptic event occurs is most likely due a disturbance in the autonomic nerves system9 which then leads to hypotension6, orthostatic intolerance4 and resulting in syncope (Blair Grubb 1999). In a normal person it is thought that about 2 25% of the body’s total circulating blood is in the thorax region10. As soon as an individual stands up about 500mL of blood is pulled downwards, to the lower extremities and the lower abdomen, due to gravity. Within a few seconds after standing almost 50% of the blood is redistributed through out the body. During this process venous return11 to the heart, cardiac filling pressure12, and stroke volume13 all decrease. The stabilization of the body back to its normal functioning after standing, orthostatic stabilization, in a normal person is achieved within a minute of standing. This process is thought to be disturbed some how in a person with Neurocardiogenic syncope but it is still in question how and why this disturbance happens. A major factor that causes confusion with this disease is how variable the symptoms and reactions of the body can be between each affected person. In one study which had the goal of measuring the difference in oxygen levels within the brain, defined the degree of the body’s reaction into four different types (Szufladowicz et al 2004). The first classification was given the label of Type 1 or mixed. In this category heart rate falls only at the time of syncope but the ventricular rate14 does not fall less than 40 beats per minute for more than ten seconds. During this time the heart will become asystolic15 for zero to three seconds. The next category is Type 2A, where cardioinhibition16 occurs without asystole for more than three seconds. Unlike the first type, ventricular rate falls less than 40 beats per minute for more than 10 seconds. In both Type 1 and 2A, blood pressure falls before heart rate falls. Type 2B, is cardioinhibitory and has a ventricular rate less than 40 beats per minute for more then 10 seconds, asystole occurs for more than three seconds, and blood pressure falls with heart rate. The last category is Type 3 which is vasodepressor17, in which the patient’s heart rate does not fall more than 10 percent 3 from its peak when the syncope episode occurs. This study is important in that it labeled many of the different stages that an individual’s body could go through during an episode, but there is never a given reason why these steps are caused. A study by Szufladowiz et al, states that the most widely accepted physiological explanation that occurs during Neurocardiogenic syncope is a disturbance in the regulation of blood pressure and heart rate with a secondary effect being hypoperfusion18 of the brain. It is thought that a low total blood volume, which causes a negative pressure on the lower part of the body is what results in a synoptic episode. A term used to explain the proposed process that causes Neurocardiogenic syncope is the Bezold-Jarish reflex (Szufladowicz et al. 2004). It is thought that this reflex is an extreme version of the reflex that is used to respond to hypotension. This reflex causes bradycardia, dilation in peripheral blood vessels, which results in a lowering of blood pressure. In Figure 2 done by Fang et al it can be seen how blood pressure and heart rate are effected through out the episode. The overall idea presented is that as the heart slows and blood pressure decreases there is a lack of oxygen getting to the brain, which in the end results in syncope. There are a variety of causes and different mechanisms that occur before and during a syncope episode. The major organ monitored in most of Neurocardiogenic syncope testing in the heart (see Figure 3 and 4 for a detailed picture of the heart). In one theory, it is thought that the heart will go through four major phases before a synoptic event (Julu et al 2003). It has been measure that as a tilt table test begins the body goes in the first phase which was labeled as “full compensation.” During this stage, there is a brief decrease in blood pressure. There was an increase in forearm vascular resistance19 4 which stayed high for the remainder of the stage. During this first stage both cardiac vagal tone (CVT) 20 and cardiac sensitivity to baroreflex (CSB) 21 decreased. Since cardiac vagal tone is associated with the parasympathetic nervous system, a decrease in CVT will cause an increase in heart rate. The second phase that Julu et al identified was labeled as tachycardia22. At the start of tachycardia, heart rate and blood pressure increase until they become unstable or hit a peak and level off for the rest of the phase. The reported systolic blood pressure23 decreased but there was not a significant change in diastolic blood pressure24. CVT and CBS seem to stay fairly constant to the values in the first phase, which are considerably lower than the baseline readings. The third stage is identified as instability. The defining characteristic of this stage is the oscillations of arterial blood pressure25 and heart rate. Heart rate seemed to decrease compared to the other two previous stages. Again, both CVT and CBS were much lower then baseline but their values were not different from the two preceding phases. The final stage is labeled as pre-syncope and recovery. During this stage there was a quick decrease in arterial blood pressure and heart rate. In majority of the patients being tested in this experiment, lower blood pressure occurred before bradycardia while in some others, both occurred at this same time or opposite. This phase was ended in the experiment by putting the subject back into a supine position and not allowing a synoptic episode to occur. CVT and CBS were very low through out all of the phases but then increase dramatically once placed in the supine position before dropping back to a resting lever. If CVT had a quick and extremely large increase, asystole was associated with it. This study clearly shows what changes are occurring in the body but never addresses why this could be happening. 5 Another idea involving the cause of Neurocardiogenic syncope is related to exercise. In dynamic or isotonic exercise the muscle length changes to compensate for the added tension put on the muscle. Due to the need for more oxygen to the muscle, cardiac output26, stroke volume, heart rate, and mean arterial pressure27 are increased, and pulmonary vascular resistance28 is decreased. In a study done by Kosinski et al, it is thought that the beginning event in Neurocardiogenic syncope is vigorous ventricular contraction29 which causes the baroreceptors30 to respond improperly. In exercise an individual wants an increased cardiac output but it seems that this could result in a decreased filling pressure which would cause a rapid change in stroke volume. This would then be related to orthostatic stress which then would lead to a synoptic episode (Kosinski et al). Even though the above idea seems to be an explanation, Kosinski et al, also reviewed a couple studies finding no relationship between VO2 max32 and orthostatic tolerance. This still leaves the exact relationship between exercise and an episode unclear but still can lead to an overall understanding of what occurs within the body due to the fact that exercise is a purposed cause. During exercise it is thought that a vigorous myocardial contraction31 can cause a synoptic response (Kosinski et al). One other important factor in determining the exact cause of Neurocardiogenic syncope could be related the plasma levels of β endorphin32, norepinephrine33, and epinephrine34. It is known that endogenous opioids35 and catecholamines36 are connected to autonomic activity. It was seen that β endorphin and epinephrine levels were increased greatly in a tilt-table induced synoptic episode and in an episode induced with nitroglycerin, but they also observed no significant increase in these levels in the episode was induced with isoproterenol or if the patient had a negative response, this data is 6 shown in Table 1 and Figure 5. The conclusions that Takase et al found could be a direct or secondary cause of neurally-mediated syncope. The major problem with this study is that it is thought that nitroglycerin and isopropterenol induce Neurocardiogenic syncope but if there are differences in the chemical levels in the body between the two, then this testing method can be found unreliable. Many of the other studies would use isoproterenol to induce syncope in many subjects who did not have a synoptic episode within 20 to 30 of being placed at an angle. The changes in endogenous opioids35 and catecholamines36 could be an underlying cause of Neurocardiogenic syncope but further research is needed to confirm this. There seems to be multiple factors that cause Neurocardiogenic syncope. There are multiple studies that monitor basic functions of the body but never question why these reactions occur. The next step that needs to be taken to get a better understanding of what causes the body to physiological respond the why it does is to perform a study that measures multiple factors and then purpose there connections. Through the above knowledge it seems that all of the different factors are related but it does not seem that anyone has put everything together and found a clear conclusion to this condition. This is an important topic since Neurocardiogenic syncope affects a large number of people. After looking at what is known about Neurocardiogenic syncope, it can be concluded that it is still unknown what causes the body to react in the way it does and further research needs to be done. Although there are many possible physiological explanations that seem to give a reason for Neurocardiogenic syncope, there are still many unexplained aspects of this condition. It seems that since a few different treatments have been discovered to help 7 people with this condition, doctors are content with using them without having a clear understanding about what is occurring with in the body. Through looking at the multiple studies that give a physiological reason to Neurocardiogenic syncope it seems that this condition is related to a change blood pressure, heart rate, and vagal tone. The next step that needs to be taken before a definite treatment can be decided is more research to understand what causes this reaction in the body. If an understanding of cause and mechanism are obtained then different treatments to correct the problem can take place, resulting in the best way to manage a condition that affects a large number of people. 8 1. postural tone: the tone that is in the muscles and the body that allows the body to have posture, the positioning of the limbs and body 2. unexplained syncope: syncope that occurs for an unexplained reason, the person that experiences this has no structural heart disease, arrhythmia, or neurological disease 3. reflex syncope: syncope that is cause from an involuntary reaction within the body 4. orthostatic: related to or caused by standing up a. orthostatic intolerance: inability to compensate for pressure change when one stands up 5. neurally-mediated hypotension: low blood pressure due to Neurocardiogenic syncope 6. hypotension: low blood pressure 7. bradycardia: decreased heart rate (>60beats/min) 8. synoptic episode: an episode beings when an individual gets pre-synoptic symptoms and ends after the person has fainted 9. autonomic nervous system: is divided into two subdivisions, the sympathetic and parasympathetic nervous system a. sympathetic nervous system: the part of the nervous system used in the “flight or fight” response, this response can increase heart rate, constrict blood vessels and raise blood pressure b. parasympathetic nervous system: the part of the nervous system used in more relaxing situations, this response decreases heart rate, increases intestinal and gland activity and relaxes sphincter muscles 10. thorax region: the area of the body that is above the diaphragm but below the neck 11. venous return: the amount of blood that is returning to the heart from the veins 12. cardiac filling pressure: the pressure within the heart as the blood flows into the heart before the it contracts 13. stroke volume: the amount of blood pumped out of the ventricles of the heart with each beat 14. ventricular rate: 15. asystolic or asystole: absence of heart rate and electrical activity with in the heart 16. cardioinhibition: the heart is being blocked or prevented from performing correctly 17. vasodepressor: a reduction of tone in a blood vessel due to vasodilatation causing blood pressure to lower a. vasodilatation is when a blood vessels passage in the middle is widened due to the smooth muscle relaxing 18. hypoperfusion: a decrease blood flow through an organ, in this context the brain, this then results in a lowered oxygen level 19. forearm vascular resistance: the amount of resistance to blood flow in the blood vessels of the forearm 20. cardiac vagal tone (CVT): the parasympathetic nervous system controls vagal tone which has the role of decreasing heart rate 9 21. cardiac sensitivity to baroreflex (CSB): the baroreceptors are used to detect any pressure changes with in the blood vessels, so this measures the amount of change that occurs in the heart when there is a pressure change 22. tachycardia: an increase in heart rate 23. systolic blood pressure: tells you the amount of pressure that is being put on the walls of the arteries while the heart is contracting. This is the top number when given a blood pressure and is normally considered high if above 150 mmHg 24. diastolic blood pressure: tells you the amount of pressure that is being put on the walls of the arteries while the heart is at rest (not contracted or between heart beats). This is the bottom number when blood pressure is talked and is normally considered high if it is above 90 mmHg 25. arterial blood pressure: 26. cardiac output: is the measurement of the amount of blood flowing through the heart to the rest of the body 27. mean arterial pressure: mean arterial pressure is the average pressure being exerted in the arteries walls, to calculate this the systolic and diastolic pressures are added together and then divided by 2 28. pulmonary vascular resistance 29. ventricular contraction 30. baroreceptors: These are pressure sensitive receptors that can be found on the wall of the atrium of the heart, in the vena cava, the aortic arch and in the carotid sinus. These receptors can detect when the walls of the above structures begin to stretch due to an increase in pressure 31. myocardial contraction: contractile action of the heart 32. VO2 max: The maximal rate of oxygen an individual can consume 33. β endorphin: a chemical within the body that is involved in autonomic activity 34. norepinephrine: chemicals within the body that is involved in autonomic activity 35. endogenous opioids: chemicals within the body that is involved in autonomic activity 36. catecholamines: chemicals within the body that is involved in autonomic activity 10 Figure 1: This is a flow chart from an article done by Blair P. Grubb, 1999. It shows how Neurocardiogenic syncope is related to other disorders of the autonomic control associated with orthostatic intolerance 11 Figure 2: These two graphs show the result from the Fang et al study. The top graph shows the average systolic blood pressure (SBP) at baseline (the patient was in the supine position for 5 minutes and then SBP was taken), at endpoint (when the patient experienced syncope or pre-synoptic symptoms), at supine position for 1 minute, at supine position for 2 minutes, and at supine position for 4 minutes (this was after the endpoint and the patients were returned to there baseline position). The second graph shows heart rate at the same five points that SBP was measured. The top graph, showing SBP, shows that there is a dramatic decrease in SBP at the point of syncope or presyncope and then once the patient is placed back in to a supine position SBP begins to rise to the normal resting or base line level. The second graph shows heart increase during syncope or pre-syncope and then still rising after the episode but then returning to baseline. 12 Figure 3. This is a picture of the heart with all of the major structure labeled. Figure 4. This is a second picture of the heart with only the main blood vessels being labeled. 13 Table 1. This table is from Takase et al., 2003. This table lays out each group that was test; it shows the average and the standard deviation (SD) of the test groups. Figure 5. This shows the results of the Takase et al study of the beta-endorphin levels. They are shown in the four different test groups that are described in the above table (1). 14 Fang, B., Kuo, L. (2000). Usefulness of Head-Up Tilt Test in the Evaluation and Management of Unexplained Syncope or Pre-syncope. Jpn Heart J, 41; 623-631 Kinay, O., Yazici, M., Nazli, C., Acar, G., Gedikli, O., Altinbas, A., Kahraman, H., Dogan, A., Ozaydin, M., Tuzun, N., Ergene, O. (2004). Tilt Training for Recurrent Neurocardiogenic Syncope. Jpm Heart J, 45; 833-843 Grubb, Blair P. (1999). Pathophysiology and Differential Diagnosis of Neurocardiogenic Syncope. The American Journal of Cardiology, 84; 3Q-9Q Eltrafi, A., King, D., Silas, J., Currie, P., Lye, L. (1999). Role of carotid sinus syndrome and neurocardiogenic syncope in recurrent syncope and falls in patients referred to an outpatient clinic in a district general hospital. Postgrad Med Journal, 76; 405-408 Szufladowicz, E., Maniewski, R., Kozluk, E., Zbiec, A., Nosek, A., Walczak, F. (20040. Near-infrared spectroscopy in evaluation of cerebral oxygenation during vasovagel syncope. Institution of Physics Publishing. 823-836 Calkins, H., Shyr, Y., Frumin, M., Schork, A., Morady, F. (April 1995). The value of the clinical history in the differentiation of syncope due to ventricular tatycardia, atrioventricular block, and neurocardiogenic syncope. The Journal of Medicine, 96; 365-373 Julu, P., Cooper, S., Hansen, S., Hainsworth, R. (2003). Cardiovascular regulation in the period preceding vasovagal syncope in conscious humans. The physiological society. 549.1; 299-311 Sheldon, R., Rose, S., Connolly, S. (2003). Prevention of syncope trial (POST): a randomized clinical trial of beta blockers in the prevention of vasovagal syncope. Europace, 5; 71-75 Bloomfield, Daniel (2002). Strategy for the management of vasovagal syncope. Drugs Aging, 19; 179-202 Takase, B., Matsushima, Y., Umeda, E., Satomura, K., Katsushika, S., Ohsuzu, F., Sato, T., Kurita, A. (2003). Endogenous Opioids and Epinephrine in Nitroglycerin Provocation Tilt Test in Patients with Neurally Mediated Syncope. Jpm Heart J, 44; 493-503 Kosinski, D., Grubb, B., Kip, K., Hahn, H. (1996). Exercise induced neurocardiogenic syncope. American Heart Journal, 132; 451-452 15