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Highlights in clinical autonomic neurosciences: Orthostatic intolerance—insights into pathophysiology and treatment
Autonomic Neuroscience: Basic and Clinical 159 (2011) 4–6
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u
Highlights in clinical autonomic neurosciences: Orthostatic intolerance—insights into pathophysiology and treatment Prepared by: Satish R. Raj Autonomic Dysfunction Center, Departments of Medicine & Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
Section Editor: Roy Freeman Department of Neurology, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA
Cardiac origins of the postural orthostatic tachycardia syndrome. Fu Q, Vangundy TB, Galbreath MM, Shibata S, Jain M, Hastings JL, Bhella PS, Levine BD (Dallas, TX, USA). J Am Coll Cardiol. 2010 Jun 22;55:2858-68. Article Summary Patients with postural tachycardia syndrome (POTS) have marked increases in heart rate during orthostasis. However, the underlying mechanisms are unknown and the effective therapy is uncertain. The authors tested the hypothesis that a small heart combined with reduced blood volume contributes to the POTS and that exercise training improves this syndrome. Twenty-seven POTS patients underwent autonomic function tests, cardiac magnetic resonance imaging, and blood volume measurements. Twenty-five of them participated in a 3-month specially designed exercise training program with 19 completing the program; these patients were re-evaluated after training. Results were compared with those of 16 healthy controls. The authors found that upright heart rate and total peripheral resistance were greater, whereas stroke volume and cardiac output were smaller in patients than in controls. Left ventricular mass (median [25th, 75th percentiles], 1.26 g/kg [1.12, 1.37 g/kg] vs. 1.45 g/kg [1.34, 1.57 g/kg]; p b 0.01) and blood volume (60 ml/kg [54, 64 ml/kg] vs. 71 ml/kg [65, 78 ml/kg]; p b 0.01) were smaller in patients than in controls. Exercise training increased left ventricular mass (12%) and blood volume (7%) and decreased upright heart rate by 9 beats/min [1, 17 beats/min]. Ten of 19 patients no longer met the POTS criterion after training, whereas quality of life assessed by the SF-36 was improved in all patients after training. The authors concluded that the marked tachycardia during orthostasis in POTS was attributable to a small heart coupled with reduced blood volume. Exercise training improved or even cured this syndrome in most patients. The authors suggest a new name for POTS based on its underlying pathophysiology, the “Grinch syndrome,” because in this famous children's book by Dr. Seuss, the main character had a heart that was “two sizes too small.” Commentary This study by Fu et al. is an important study that contributes significantly to our understanding of the pathophysiology of postural tachycardia syndrome (POTS). The investigators conducted an exten1566-0702/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2010.10.005
sive hemodynamic and cardiovascular evaluation in a cohort of patients with POTS that included cardiac magnetic resonance imaging, autonomic function tests, assessment of blood volume, and measurement of intracardiac pressure. Consistent with prior reports, they have found that the upright heart rate was higher, and stroke volume, cardiac output and blood volume were diminished in POTS. A novel finding was that left ventricular mass was decreased. Taken together, these data are consistent with a pattern of deconditioning. A small heart and small stroke volume in these patients with POTS were critical features underlying the orthostatic tachycardia. The authors suggest the use of the term “Grinch syndrome” in an effort to describe the problem of the heart being “too small”. They administered a 3-month structured exercise program for their POTS patients. Of the 27 POTS patients who underwent baseline evaluation, 19 were able to complete the 3-month exercise protocol. They report that following exercise program, 10 of these 19 patients no longer met the orthostatic tachycardia criteria for POTS and all reported improvements in quality of life. This is an important study that both confirms and extends observations about low blood volume and low stroke volume in patients with POTS, and for the first time shows that an exercise intervention improved symptoms and decreased tachycardia. While we have always suggested to our patients that they partake of regular exercise, this is not an easy task in this patient population. Almost by definition, POTS patients report a high incidence of exercise intolerance. With these data, we can tell patients that the apparent improvement with exercise, at least in some patients, may be causal and not merely an association. At the same time, it is worth noting that there are limitations to this approach. A significant percentage of their POTS patients were not able to complete this exercise program. Further, the structured exercise program in the study was labor intensive and a similar program would not be readily available in the typical Autonomic Clinic. It would be interesting to obtain data on long-term follow-up of this cohort with exercise. How many of these clearly motivated POTS patients were able to sustain the exercise and the benefits of exercise following completion of this research protocol? The term “Grinch syndrome” may do our patients a disservice. While it does have the advantage of potentially explaining an important concept in a simple manner, it could also be seen as trivializing the disorder. While the authors likely intended the use of this term to convey very real physiological abnormalities in patients with POTS, I fear that the average physician (who is not well read about POTS) may be more dismissive
S.R. Raj / Autonomic Neuroscience: Basic and Clinical 159 (2011) 4–6
5
about patients with POTS because of this term. Finally, most physicians and clinical researchers that work with POTS patients agree that POTS is not a single disease, but a heterogeneous mixture of underlying pathophysiologies. Deconditioning and a small heart may be the final common pathway of POTS, but it is not necessarily the underlying cause. There are a multitude of symptoms that are seen in POTS patients that are not easily explained by low stroke volume and low cardiac mass alone. Despite these limitations, this study must be viewed as a landmark study that improves our understanding of pathophysiology in some POTS patients, and provides objective data for the potential benefits of a structured exercise program.
tolerate graded orthostatic stress. Thus, in this healthy population, African-American women seem to demonstrate an ability to increase their sympathetic nervous system tone to a greater extent than Caucasian woman. This may be a salutary effect in this younger age group, and offers protection against orthostatic intolerance. This same mechanism, however, may contribute to higher levels of hypertension in African-American that is seen in older age groups.
Greater orthostatic tolerance in young black compared with white women. Hinds K, Stachenfeld NS (New Haven, CT, USA). Hypertension. 2010 Jul;56:75-81.
Article Summary
Article Summary The authors hypothesized that orthostatic tolerance is higher in young, healthy black compared with white women. To determine orthostatic tolerance, 22 women (11 black and 11 white) underwent graded lower body negative pressure to presyncope. They measured blood pressure, heart rate, and R–R interval (ECG) continuously at baseline and through all of the levels of lower body negative pressure. Blood samples were taken at baseline along with presyncope for the measurement of plasma catecholamine concentrations, serum aldosterone concentration, and plasma renin activity. Cumulative stress index, the sum of the product of time and lower body negative pressure, was the indicator of orthostatic tolerance. Orthostatic tolerance in the black women was greater than in the white women [cumulative stress index: −1003 (375) versus −476 (197); p b 0.05]. Although plasma concentrations of norepinephrine increased in both groups at presyncope, the increase was greater in black [Delta plasma norepinephrine: 167 (123)] versus white women [86 (64) pg/mL; pb 0.05], as was the increase in PRA [Delta PRA 2.6 (1.0) versus 0.6 (0.9) ng/mL/h; p b 0.05, for black and white women, respectively). Although heart rate increased and R–R interval decreased to a greater extent during lower body negative pressure in black women compared with white women (ANOVA: pb 0.05), baroreflex function was unaffected by race. These data indicate that orthostatic tolerance is greater in black compared with white women, which appears to be a function of greater sympathetic nervous system responses to orthostatic challenges.
Erythropoietin in the treatment of postural orthostatic tachycardia syndrome. Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Sheikh M, Grubb BP (Toledo, OH, USA). Am J Ther 2010 Sep 10. [Epub ahead of print].
Erythropoietin improves symptoms of orthostatic intolerance in patients suffering from orthostatic hypotension. Previous reports on the use of erythropoietin in patients with POTS have included only a very small number of patients. In the current study, the authors report on the use of erythropoietin in patients with refractory POTS. A retrospective nonrandomized analysis was performed in one autonomic center for POTS from 2003 to 2010. The diagnosis of POTS was based on patient history, physical examination, and response to head-up tilt-table testing with a mean follow-up period of 6 months. The patients were included in the current study if they had a diagnosis of POTS with severe symptoms of orthostatic intolerance and were refractory to the commonly used medications. All these patients were treated with erythropoietin. After screening 200 patients with POTS, 39 patients (age 33±12, 37 females) were found to be eligible for inclusion in the current study. The response to the treatment was assessed subjectively in each patient and was obtained in a retrospective fashion from patient charts and physician communications. Eight (21%) patients demonstrated no improvement in symptoms after administration of erythropoietin. Three (8%) patients showed an improvement in symptoms of orthostatic intolerance of b3 months. Twenty-seven (71%) patients demonstrated sustained improvement in their symptoms of orthostatic intolerance at the mean follow-up of 6 months. Erythropoietin significantly improved sitting diastolic blood pressure but had no effect on other hemodynamic parameters. The authors conclude that in a select group of POTS patients who are refractory to commonly used medications, erythropoietin may help improve symptoms of orthostatic intolerance. Commentary
Commentary Most studies of patients with POTS include a very high proportion of Caucasian females and a relatively low proportion of African-American patients. It is not obvious why we see a lower proportion of AfricanAmerican females with POTS than the proportion of African-Americans in the general population. There are numerous possible explanations. One possibility relates to cultural differences in the perception of clinical research. There have been some historically troubling research studies that have involved African-American populations. Some have argued that there is a resultant generalized mistrust of clinical research in this population. A second possibility is that there are differences in the access to medical care. While there is variability within both the Caucasian and African-American populations in the United States in access to high quality healthcare, this may be worse in the African-American community. This article by Hinds et al. offers a third, and more physiological, explanation for these differences. They assessed orthostatic tolerance using graded lower body negative pressure in a cohort of young healthy African-American women and compare them to the cohort of young healthy Caucasian woman. They found that the orthostatic tolerance was better in the young African-American woman. In response to orthostatic stress, African-American women had higher levels of plasma norepinephrine and plasma renin activity, both markers of elevated sympathetic nervous system tone. These resulted in a doubling of their ability to
The University of Toledo runs a high volume autonomic clinic and has extensive clinical experience with POTS patients. In this article, they addressed a controversial issue in the management the patients with POTS, the use of recombinant erythropoietin. Many studies have documented a low blood volume in POTS patients. Most often, there is a balanced reduction in both plasma volume and red cell volume. It is often easier to attempt to treat the plasma volume deficits, initially with conservative measures (increased dietary salt and water) and possibly with fludrocortisone. The decrease in red cell volume is not as easy to treat. Other medical specialties have successfully used recombinant erythropoietin to stimulate red cell production. However, this therapy is expensive, requires parenteral administration, and is not without risk (there are recent reports of increased cardiovascular events and cancer). In this report, the authors found 39 patients over a 7 year period who were treated with erythropoietin. This was used as the fourth and fifth line therapy for POTS patients who were refractory to conventional approaches to POTS. Of the 39 patients who received erythropoietin, 27 patients (71%) experienced a sustained improvement that lasted at least 6 months. Improvement was defined purely based on the patients' subjective assessment, and not with the use of standardized rating tools. This report does provide some “smoke” to suggest that erythropoietin treatment may be useful in some POTS patients. Erythropoietin can be effective both by expanding blood volume, and also acting as a “pressor
6
S.R. Raj / Autonomic Neuroscience: Basic and Clinical 159 (2011) 4–6
agent”. Nephrologists have long reported their clinical experience that the blood pressure increases out of proportion to the increase in blood volume when dialysis patients are initiated on erythropoietin. This therapy, however, should only be used with caution. First, there has been one randomized controlled trial (Dr. Barry Hurwitz, University of Miami—NIH R01 HL065668) studying erythropoietin in patients with chronic fatigue syndrome (this study included some patients also diagnosed with POTS). In the Miami study, erythropoietin was not found to significantly improve
symptoms in the overall group. At this time, there is no good evidence for use of erythropoietin in POTS patients. Second, multiple studies in hemodialysis populations have documented an increase in cardiovascular morbidity and mortality from the aggressive use of erythropoietin (attempting to normalize the hematocrit). In our POTS patients, the hematocrit is usually not reduced. Therefore, there is the real potential for excessively increasing the hematocrit (despite careful monitoring) and adversely affecting rheology.
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t n e u
Highlights in clinical autonomic neurosciences: Orthostatic intolerance—insights into pathophysiology and treatment Prepared by: Satish R. Raj Autonomic Dysfunction Center, Departments of Medicine & Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
Section Editor: Roy Freeman Department of Neurology, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA
Cardiac origins of the postural orthostatic tachycardia syndrome. Fu Q, Vangundy TB, Galbreath MM, Shibata S, Jain M, Hastings JL, Bhella PS, Levine BD (Dallas, TX, USA). J Am Coll Cardiol. 2010 Jun 22;55:2858-68. Article Summary Patients with postural tachycardia syndrome (POTS) have marked increases in heart rate during orthostasis. However, the underlying mechanisms are unknown and the effective therapy is uncertain. The authors tested the hypothesis that a small heart combined with reduced blood volume contributes to the POTS and that exercise training improves this syndrome. Twenty-seven POTS patients underwent autonomic function tests, cardiac magnetic resonance imaging, and blood volume measurements. Twenty-five of them participated in a 3-month specially designed exercise training program with 19 completing the program; these patients were re-evaluated after training. Results were compared with those of 16 healthy controls. The authors found that upright heart rate and total peripheral resistance were greater, whereas stroke volume and cardiac output were smaller in patients than in controls. Left ventricular mass (median [25th, 75th percentiles], 1.26 g/kg [1.12, 1.37 g/kg] vs. 1.45 g/kg [1.34, 1.57 g/kg]; p b 0.01) and blood volume (60 ml/kg [54, 64 ml/kg] vs. 71 ml/kg [65, 78 ml/kg]; p b 0.01) were smaller in patients than in controls. Exercise training increased left ventricular mass (12%) and blood volume (7%) and decreased upright heart rate by 9 beats/min [1, 17 beats/min]. Ten of 19 patients no longer met the POTS criterion after training, whereas quality of life assessed by the SF-36 was improved in all patients after training. The authors concluded that the marked tachycardia during orthostasis in POTS was attributable to a small heart coupled with reduced blood volume. Exercise training improved or even cured this syndrome in most patients. The authors suggest a new name for POTS based on its underlying pathophysiology, the “Grinch syndrome,” because in this famous children's book by Dr. Seuss, the main character had a heart that was “two sizes too small.” Commentary This study by Fu et al. is an important study that contributes significantly to our understanding of the pathophysiology of postural tachycardia syndrome (POTS). The investigators conducted an exten1566-0702/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autneu.2010.10.005
sive hemodynamic and cardiovascular evaluation in a cohort of patients with POTS that included cardiac magnetic resonance imaging, autonomic function tests, assessment of blood volume, and measurement of intracardiac pressure. Consistent with prior reports, they have found that the upright heart rate was higher, and stroke volume, cardiac output and blood volume were diminished in POTS. A novel finding was that left ventricular mass was decreased. Taken together, these data are consistent with a pattern of deconditioning. A small heart and small stroke volume in these patients with POTS were critical features underlying the orthostatic tachycardia. The authors suggest the use of the term “Grinch syndrome” in an effort to describe the problem of the heart being “too small”. They administered a 3-month structured exercise program for their POTS patients. Of the 27 POTS patients who underwent baseline evaluation, 19 were able to complete the 3-month exercise protocol. They report that following exercise program, 10 of these 19 patients no longer met the orthostatic tachycardia criteria for POTS and all reported improvements in quality of life. This is an important study that both confirms and extends observations about low blood volume and low stroke volume in patients with POTS, and for the first time shows that an exercise intervention improved symptoms and decreased tachycardia. While we have always suggested to our patients that they partake of regular exercise, this is not an easy task in this patient population. Almost by definition, POTS patients report a high incidence of exercise intolerance. With these data, we can tell patients that the apparent improvement with exercise, at least in some patients, may be causal and not merely an association. At the same time, it is worth noting that there are limitations to this approach. A significant percentage of their POTS patients were not able to complete this exercise program. Further, the structured exercise program in the study was labor intensive and a similar program would not be readily available in the typical Autonomic Clinic. It would be interesting to obtain data on long-term follow-up of this cohort with exercise. How many of these clearly motivated POTS patients were able to sustain the exercise and the benefits of exercise following completion of this research protocol? The term “Grinch syndrome” may do our patients a disservice. While it does have the advantage of potentially explaining an important concept in a simple manner, it could also be seen as trivializing the disorder. While the authors likely intended the use of this term to convey very real physiological abnormalities in patients with POTS, I fear that the average physician (who is not well read about POTS) may be more dismissive
S.R. Raj / Autonomic Neuroscience: Basic and Clinical 159 (2011) 4–6
5
about patients with POTS because of this term. Finally, most physicians and clinical researchers that work with POTS patients agree that POTS is not a single disease, but a heterogeneous mixture of underlying pathophysiologies. Deconditioning and a small heart may be the final common pathway of POTS, but it is not necessarily the underlying cause. There are a multitude of symptoms that are seen in POTS patients that are not easily explained by low stroke volume and low cardiac mass alone. Despite these limitations, this study must be viewed as a landmark study that improves our understanding of pathophysiology in some POTS patients, and provides objective data for the potential benefits of a structured exercise program.
tolerate graded orthostatic stress. Thus, in this healthy population, African-American women seem to demonstrate an ability to increase their sympathetic nervous system tone to a greater extent than Caucasian woman. This may be a salutary effect in this younger age group, and offers protection against orthostatic intolerance. This same mechanism, however, may contribute to higher levels of hypertension in African-American that is seen in older age groups.
Greater orthostatic tolerance in young black compared with white women. Hinds K, Stachenfeld NS (New Haven, CT, USA). Hypertension. 2010 Jul;56:75-81.
Article Summary
Article Summary The authors hypothesized that orthostatic tolerance is higher in young, healthy black compared with white women. To determine orthostatic tolerance, 22 women (11 black and 11 white) underwent graded lower body negative pressure to presyncope. They measured blood pressure, heart rate, and R–R interval (ECG) continuously at baseline and through all of the levels of lower body negative pressure. Blood samples were taken at baseline along with presyncope for the measurement of plasma catecholamine concentrations, serum aldosterone concentration, and plasma renin activity. Cumulative stress index, the sum of the product of time and lower body negative pressure, was the indicator of orthostatic tolerance. Orthostatic tolerance in the black women was greater than in the white women [cumulative stress index: −1003 (375) versus −476 (197); p b 0.05]. Although plasma concentrations of norepinephrine increased in both groups at presyncope, the increase was greater in black [Delta plasma norepinephrine: 167 (123)] versus white women [86 (64) pg/mL; pb 0.05], as was the increase in PRA [Delta PRA 2.6 (1.0) versus 0.6 (0.9) ng/mL/h; p b 0.05, for black and white women, respectively). Although heart rate increased and R–R interval decreased to a greater extent during lower body negative pressure in black women compared with white women (ANOVA: pb 0.05), baroreflex function was unaffected by race. These data indicate that orthostatic tolerance is greater in black compared with white women, which appears to be a function of greater sympathetic nervous system responses to orthostatic challenges.
Erythropoietin in the treatment of postural orthostatic tachycardia syndrome. Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Sheikh M, Grubb BP (Toledo, OH, USA). Am J Ther 2010 Sep 10. [Epub ahead of print].
Erythropoietin improves symptoms of orthostatic intolerance in patients suffering from orthostatic hypotension. Previous reports on the use of erythropoietin in patients with POTS have included only a very small number of patients. In the current study, the authors report on the use of erythropoietin in patients with refractory POTS. A retrospective nonrandomized analysis was performed in one autonomic center for POTS from 2003 to 2010. The diagnosis of POTS was based on patient history, physical examination, and response to head-up tilt-table testing with a mean follow-up period of 6 months. The patients were included in the current study if they had a diagnosis of POTS with severe symptoms of orthostatic intolerance and were refractory to the commonly used medications. All these patients were treated with erythropoietin. After screening 200 patients with POTS, 39 patients (age 33±12, 37 females) were found to be eligible for inclusion in the current study. The response to the treatment was assessed subjectively in each patient and was obtained in a retrospective fashion from patient charts and physician communications. Eight (21%) patients demonstrated no improvement in symptoms after administration of erythropoietin. Three (8%) patients showed an improvement in symptoms of orthostatic intolerance of b3 months. Twenty-seven (71%) patients demonstrated sustained improvement in their symptoms of orthostatic intolerance at the mean follow-up of 6 months. Erythropoietin significantly improved sitting diastolic blood pressure but had no effect on other hemodynamic parameters. The authors conclude that in a select group of POTS patients who are refractory to commonly used medications, erythropoietin may help improve symptoms of orthostatic intolerance. Commentary
Commentary Most studies of patients with POTS include a very high proportion of Caucasian females and a relatively low proportion of African-American patients. It is not obvious why we see a lower proportion of AfricanAmerican females with POTS than the proportion of African-Americans in the general population. There are numerous possible explanations. One possibility relates to cultural differences in the perception of clinical research. There have been some historically troubling research studies that have involved African-American populations. Some have argued that there is a resultant generalized mistrust of clinical research in this population. A second possibility is that there are differences in the access to medical care. While there is variability within both the Caucasian and African-American populations in the United States in access to high quality healthcare, this may be worse in the African-American community. This article by Hinds et al. offers a third, and more physiological, explanation for these differences. They assessed orthostatic tolerance using graded lower body negative pressure in a cohort of young healthy African-American women and compare them to the cohort of young healthy Caucasian woman. They found that the orthostatic tolerance was better in the young African-American woman. In response to orthostatic stress, African-American women had higher levels of plasma norepinephrine and plasma renin activity, both markers of elevated sympathetic nervous system tone. These resulted in a doubling of their ability to
The University of Toledo runs a high volume autonomic clinic and has extensive clinical experience with POTS patients. In this article, they addressed a controversial issue in the management the patients with POTS, the use of recombinant erythropoietin. Many studies have documented a low blood volume in POTS patients. Most often, there is a balanced reduction in both plasma volume and red cell volume. It is often easier to attempt to treat the plasma volume deficits, initially with conservative measures (increased dietary salt and water) and possibly with fludrocortisone. The decrease in red cell volume is not as easy to treat. Other medical specialties have successfully used recombinant erythropoietin to stimulate red cell production. However, this therapy is expensive, requires parenteral administration, and is not without risk (there are recent reports of increased cardiovascular events and cancer). In this report, the authors found 39 patients over a 7 year period who were treated with erythropoietin. This was used as the fourth and fifth line therapy for POTS patients who were refractory to conventional approaches to POTS. Of the 39 patients who received erythropoietin, 27 patients (71%) experienced a sustained improvement that lasted at least 6 months. Improvement was defined purely based on the patients' subjective assessment, and not with the use of standardized rating tools. This report does provide some “smoke” to suggest that erythropoietin treatment may be useful in some POTS patients. Erythropoietin can be effective both by expanding blood volume, and also acting as a “pressor
6
S.R. Raj / Autonomic Neuroscience: Basic and Clinical 159 (2011) 4–6
agent”. Nephrologists have long reported their clinical experience that the blood pressure increases out of proportion to the increase in blood volume when dialysis patients are initiated on erythropoietin. This therapy, however, should only be used with caution. First, there has been one randomized controlled trial (Dr. Barry Hurwitz, University of Miami—NIH R01 HL065668) studying erythropoietin in patients with chronic fatigue syndrome (this study included some patients also diagnosed with POTS). In the Miami study, erythropoietin was not found to significantly improve
symptoms in the overall group. At this time, there is no good evidence for use of erythropoietin in POTS patients. Second, multiple studies in hemodialysis populations have documented an increase in cardiovascular morbidity and mortality from the aggressive use of erythropoietin (attempting to normalize the hematocrit). In our POTS patients, the hematocrit is usually not reduced. Therefore, there is the real potential for excessively increasing the hematocrit (despite careful monitoring) and adversely affecting rheology.