There are identifiable mechanisms that can be contributing to a patient's orthostatic intolerance. Many of these mechanisms may result in a lack of oxygen to the brain upon standing. Blood pooling in the veins of the lower body is a major factor in the vast majority of patients with orthostatic intolerance (Streeten, 1999).
The following is a partial list of proposed mechanisms that may be occurring in patients with orthostatic intolerance:
Alpha-receptor dysfunction may be occurring in some POTS patients (Gordon, Opfer-Gehrking, Novak & Low, 2000). Alpha-1 receptors cause peripheral vasoconstriction when stimulated. Alpha-1 receptor supersensitivity may be causing dysautonomia in some patients (Stewart & Erickson, 2002). Others with POTS may have an autonomic neuropathy that predominantly affects the lower extremities. This neuropathy may be resulting in alpha-1 adrenergic denervation hypersensitivity. Denervation hypersensitivity may be provoking the pooling of blood in a number of individuals with this disorder (Stewart & Erickson, 2002).
Beta-receptor supersensitivity may occur with hyperadrenergic states in some people with POTS (Low, 2000). The heart is responding to excessive catecholamine output in these patients.
Brain-stem dysregulation may be occurring in some POTS patients (Novak, Novak, Opfer-Gehrking, O'Brien & Low, 1998). Researchers have identified a subset of patients with marked orthostatic hypertension, markedly labile blood pressure and troublesome orthostatic symptoms (Low, Schondorf, Novak, Sandroni, Opfer-Gehrking & Novak, 1997, pp. 686-687). These patients present as though they are suffering from baroreflex failure, although the baroreflexes are working. Excessive sympathetic activity is noted, which suggests the possibility of central (presumably brain-stem) dysregulation. One patient reportedly improved after microvascular decompression at the region of the left medulla (Low et al., 1997, p. 687).
Central autonomic regulation abnormalities leading to a hyperadrenergic state are a proposed cause of POTS. However, physicians have yet to determine whether a central abnormality of the autonomic nervous system is the primary mechanism or if the increase in sympathetic activity is an appropriate response to an underlying defect, such as a decreased blood volume or a circulating vasodilator (Jacob & Biaggioni, 1999). Circulating vasodilators are suspected of provoking dysautonomia in disorders such as hyperbradykininism, mast-cell activation and hyperdopaminergic states.
Delayed forms of orthostatic intolerance have been observed in POTS patients. Some physicians believe POTS symptoms should occur within 10 minutes of standing. However, studies on orthostatic intolerant patients prove that some display a delayed form of orthostatic intolerance in which orthostatic hypotension occurs after ten minutes of standing (Streeten & Anderson, 1992). One study showed that out of 23 chronic fatigue patients, 17 had orthostatic tachycardia alone during the initial period of head-up tilt. However, 22 eventually had obvious orthostatic hypotension after an extended period of time (Bou-Holaigah, Rowe, Kan & Calkins, 1995).
Hyperdopaminergic states maybe the underlying problem for some people with orthostatic intolerance. Some patients have been found to have a significant increase in upright (free + sulfconjugated) dopamine levels (Kuchel, Buu, Hamet, Larochelle, Gutkowska, Schiffrin, Bourque & Genest, 1985). Free plasma norepinephrine also tends to be higher in these patients. The excessive dopamine release might be causing natriuresis and vasodilatation, thus contributing to the pathophysiology of this disorder (Jacob & Biaggioni, 1999).
Orthostatic hypotension occurs in some patients with orthostatic intolerance. However, there are physicians who exclude orthostatic hypotension when defining POTS. Orthostatic hypotension is traditionally defined as a fall in systolic blood pressure of 20 mm Hg or more upon standing. Some physicians believe smaller drops in blood pressure associated with symptoms are also significant (Grubb & Karas, 1999). Orthostatic hypotension may become apparent only after prolonged standing. Baroreceptor-initiated reflex tachycardia is a potent physiological mechanism for correcting hypotension (Streeten, 1999). Hence, the standing tachycardia observed in POTS patients is sometimes occurring because the body is attempting to counteract falling blood pressure.
Some patients become more symptomatic than others when their blood pressure drops. Patients who experience few symptoms while hypotensive have a minimal decline in brain blood flow and good dilating blood vessels. Patients who become symptomatic when their blood pressure drops have a greater decline in blood flow to the brain (Coghlan, 2002).
Reduced cerebral blood flow has been noted in several studies of POTS patients. However, one studydid not report this finding, and concluded that cerebral perfusion and autoregulation in many patients with POTS does not differ from that of normal control subjects (Schondorf, Benoit & Stein, 2005).
A reduction of cardiac output by arrhythmias, bradycardia, or intrinsic cardiac causes of pump failure can cause fainting, or other clinical manifestations of reduced cerebral blood flow (Streeten, 1999). Blood pooling in the lower body may also cause reduced blood flow to the brain. It has been reported that a person with POTS can have a 28% decrease in brain blood flow upon standing (Robertson, 2000). A normal person will have about a 9% decrease in blood flow to the brain upon standing. Transcranial Doppler ultrasonography is useful in detecting a reduction in cerebral blood flow (Fredman, Biermann, Patel, Uppstrom & Auer, 1995). Orthostatic symptoms have been attributed to impaired cerebral perfusion, even in the absence of a significant fall in blood pressure (Jacob & Biaggioni, 1999).
Central nervous system abnormalities may be occurring in patients with reduced cerebral blood flow (Hermosillo, Jauregui-Renaud, Kostine, Marquez, Lara & Cardenas, 2002). One study reported that continuous observation of the Doppler recording in patients with postural tachycardia showed intermittent fluctuation of the cerebral blood flow velocity, with an oscillatory pattern (Hermosillo et al., 2002). This fluctuation in cerebral blood flow velocity occurred in spite of there being no systemic hypotension. This study also showed that when compared with neurocardiogenic syncope patients, those with postural tachycardia had larger variations of the pulsatility index (systolic velocity-diastolic velocity/mean velocity). The results suggest that patients with postural tachycardia, on standing up, could have an inefficient regulation of cerebral blood vessels (Hermosillo, et al., 2002). These findings led the researchers to conclude that central nervous system abnormalities may play a pivotal role in the pathogenesis of postural tachycardia syndrome (Hermosillo, et al., 2002).
Reduced venous return is one of the main mechanisms that results in POTS symptoms. Venous return can be reduced due to conditions such as low plasma volume (see hypovolemia), venous pooling and denervation (Low, 2000). A hyperadrenergic state may result as the body attempts to compensate for these abnormalities. Conditions resulting in reduced venous return often overlap or occur because of one another. The following are some abnormalities that can result in reduced venous return:
Abnormal veins that stretch excessively can result in pooling blood (Stewart, 2000).
Altered capillary permeability can affect capillary leakiness and cause excessive fluid collection in the lower body (Stewart, 2000). This may be contributing to orthostatic intolerance in a number of POTS patients.
Blood vessels that don't seem to constrict appropriately have been noted in POTS patients. Some physicians believe this subnormal orthostatic venous constriction, resulting from impaired sympathetic innervation, is the cause of blood pooling excessively in the legs of POTS patients (Streeten, 1999). This loss in the ability to vasoconstrict leads to excessive heart rate increases and contractions (Grubb, 2000).
Denervation occurs in some POTS patients. A number of patients do not sweat in various parts of their bodies. Some patients report losing their ability to sweat altogether. This lack of sweating shows that the nerve supply to the area is damaged (Low, 2000). As a result, the vessels that the nerve supplies lose their tone and become slack. Blood volume is normal but vessel capacity is excessive (Low, 2000). This causes decreased venous return of blood flow to the heart, decreased cardiac output and (probably) orthostatic reduction in cerebral blood flow (Streeten, 1999). Peripheral neuropathy may be present in these patients. This neuropathy seems to be selective, with slight responses in some regions being compensated for by overactivity in other regions (Bush, Wight, Brown & Hainsworth, 2000).
Hypovolemia (low blood volume) sometimes occurs in POTS patients. The patients may have a reduced blood volume throughout their body, or the hypovolemia may occur due to blood pooling in the abdomen and legs. Reduced plasma renin activity often accompanies the low blood volume. Reduced levels of renin release consequently result in reduced secretion of aldosterone. This would be expected to impair renal sodium conservation thereby contributing to hypovolemia (Streeten, 1999). Findings suggest that the impaired renin release may possibly result from sympathetic denervation (Jacob & Biaggioni, 1999). Abnormalities in the kidney are also suspected of causing the reduced renin and aldosterone levels (Raj, Biaggioni, Yamhure, Black, Paranjape, Byrne & Robertson, 2005). Physicians believe hypovolemia and inappropriately low levels of plasma renin activity may be important pathophysiological components of orthostatic intolerance (Jacob, Robertson, Mosqueda-Garcia, Ertl, Robertson & Biaggioni, 1997). Decreases in body temperature may result from hypovolemia (Heitz & Horne, 2005, 35).
The findings in hypovolemic POTS patients have been dubbed the "renin-aldosterone paradox" and are explained as follows:
Under normal circumstances, low plasma volume is sensed in the kidney (and in the heart and aorta) and stimulates an increase in plasma renin activity (renin), angiotensin II (A-II), and aldosterone (ALDO). The increase in plasma renin activity and aldosterone promotes salt and water retention, which leads to an increase in extracellular fluid volume and plasma volume. In POTS, there is a failure to sense and appropriately respond to low plasma volume. There is no appropriate increase in plasma renin activity, angiotensin II, and aldosterone given the hypovolemia. Because plasma renin activity and aldosterone are not increased, salt and water retention is not increased, and plasma volume is not increased (Raj, et. al., 2005).
Erythropoietin response impairment may be contributing to a patient's hypovolemia. Erythropoietin is a hormone made by the kidneys. It helps stimulate red blood cell production. Impairment of the normal erythropoietin response to low levels of red blood cell mass could contribute to hypovolemia. Physicians postulate that subnormal erythropoietin response may be resulting from a disorder in the normal sympathetic stimulation of erythropoietin release by the kidney (Streeten, 1999). Read more
Paradoxically, POTS can occur because of hypovolemia or hypovolemia can occur because of POTS. This can happen because hypovolemia may lead to a chronic state of adrenergic activation, which may produce POTS symptoms. Chronic adrenergic activation reduces intravascular volume, which may produce hypovolemia (Stewart & Erickson, 2002). Read more
Impaired venous emptying can cause excessive fluid collection in the lower body. This can lead to blood pooling in the lower limbs and consequently, orthostatic intolerance.
Splanchnic pooling is occurring after meals in some POTS patients. Excessive pooling of blood in the abdomen has been shown to occur while the patient is supine and at rest (Tani, Singer, McPhee, Opfer-Gehrking, Haruma, Kajiyama & Low, 2000). The splanchnic vascular bed contains up to 30% of blood volume. Limited autonomic neuropathy causing peripheral denervation may be the cause of increased resting flow and reduced mesenteric resistance in these patients.
Sympathetic Overactivity is observed in many POTS patients. The sympathetic overactivity can be secondary to a number of factors, some of which may be peripheral denervation, venous pooling, or end-organ dysfunction (Low et al, 1998). Hyperadrenergic states with elevated norepinephrine levels are often found in patients with sympathetic overactivity. One study found that 29% of POTS patients had elevated norepinephrine levels upon standing, and the mean level was 531 pg/mL (Thieben, Sandroni, Sletten, Benrud-Larson, Fealey, Vernino, Lennon, Shen & Low, 2007). Norepinephrine is similar to adrenaline and is a natural vasoconstrictor. Genetic or acquired deficits in norepinephrine activation may result in hyperadrenergic states that lead to orthostatic intolerance (Shannon, Flattem, Jordan, Jacob, Black, Biaggioni, Blakely & Robertson, 2000). These deficits can cause patients to experience symptoms suggestive of not enough norepinephrine simultaneously with high norepinephrine levels. Many of the mechanisms listed here can result in states of chronic adrenergic activation that lead to orthostatic intolerance.
Sympathetic underactivty can also occur in some forms of orthostatic intolerance (Robertson, 2000), such as pure autonomic failure.
The above are some of the possible mechanisms that may be resulting in orthostatic intolerance. Physicians should attempt to discover the underlying mechanisms contributing to a patient's symptoms. This will ensure that treatment plans are tailored to target the specific mechanisms resulting in autonomic dysfunction, and that patients will receive the most effective care.
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