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Postural Orthostatic Tachycardia Syndrome (POTS) in Denmark: Increasingly recognized or new epidemic?
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Postural Orthostatic Tachycardia Syndrome (POTS) in Denmark: Increasingly recognized or new epidemic? ⁎
Louise Brintha,b, , Kirsten Porsb, Jasmina Medic Spahicc, Richard Suttond, Artur Fedorowskic,e, Jesper Mehlsenb a
Department of Clinical Physiology & Nuclear Medicine, Bispebjerg Frederiksberg Hospital, DK-2000 Frederiksberg, Denmark Coordinating Research Center/Syncope Unit, Bispebjerg Frederiksberg Hospital, DK-2000 Frederiksberg, Denmark c Department of Clinical Sciences, Malmö, Faculty of Medicine, Lund University, SE-205 02 Malmö, Sweden d National Heart & Lung Institute, Imperial College, London, UK e Department of Cardiology, Skåne University Hospital, Malmö, Sweden b
A B S T R A C T
Aims: The incidence of Postural Orthostatic Tachycardia Syndrome (POTS) has grown in recent years. Whether this is an emerging epidemic or increasing recognition is unclear. Methods: We retrospectively examined 8790 tilt-table tests (HUT) performed between 1997 and 2014 in patients with orthostatic intolerance and/or suspected syncope. Tests were reclassified according to the current diagnostic criteria for POTS. The number of POTS diagnoses in proportion to the number of tilt tests performed per year was calculated. The number of papers published with the term “Postural Orthostatic Tachycardia Syndrome” 1997–2014 was retrieved from PubMed and related to yearly POTS incidence. Results: Eight-hundred-and-seventy-five tests with suspected POTS were thoroughly evaluated. The reclassification of test results yielded 243 POTS diagnoses (age, 27.0 ± 11.8 years). An increase in total number of POTS diagnoses was observed but the proportion of POTS-positive tests per year was relatively constant (≈2–3%) except for the period 2013–2014 (≈7%). The increase in POTS diagnoses was preceded by an increase in number of POTS-related papers in PubMed. Conclusion: The proportion of POTS diagnoses among patients investigated for suspected syncope and/or orthostatic intolerance was relatively constant 1997–2012. The growing number of POTS-related publications in PubMed preceded the steep increase in diagnostic rate of POTS observed after 2012.
1. Introduction Postural Orthostatic Tachycardia Syndrome (POTS) is one of the most common forms of chronic orthostatic intolerance in young patients (Benarroch, 2012). The condition is believed to be a heterogeneous form of autonomic dysfunction characterized by abnormal increment in heart rate upon assumption of the upright posture accompanied by orthostatic intolerance and symptoms of sympathetic autonomic dominance (Benarroch, 2012). An increase in heart rate equal to or > 30 min−1 or above 120 min−1 and absence of overt orthostatic hypotension during a head-up tilt test is the main diagnostic criterion (Sheldon et al., 2015). A recently published consensus states that an increase of > 40 min−1 should be used for patients aged 12 to 19 years (Sheldon et al., 2015). One-third of POTS patients report recurrent syncope (Grubb, 2008). POTS can be difficult to diagnose, as tilt table testing with beat-to-
⁎
beat hemodynamic monitoring is essential in the diagnostic workup (Sheldon et al., 2015). Moreover, other medical conditions causing tachycardia, such as structural heart disease, tachyarrhythmias, anemia, severe deconditioning, dehydration, thyroid disease, use of adrenergic drugs, and emotional disorders may mimic POTS and should be ruled out. Postural Orthostatic Tachycardia Syndrome is reported to be more common in women with a 5:1 female-to-male ratio (Sheldon et al., 2015). The overall prevalence is difficult to determine due to the abovementioned circumstances but it is estimated that POTS affects about 500.000 patients in the USA alone (Sheldon et al., 2015). In 1999 Robertson described “the epidemic of orthostatic tachycardia and orthostatic intolerance” as an epidemic of disease recognition rather than an increasing prevalence of the disease as such (Robertson, 1999). Thus, it is unclear whether POTS has been an unrecognized disorder or whether it is an emerging epidemic due to increasing incidence.
Corresponding author at: Department of Cardiology, Bispebjerg Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark. E-mail address: [email protected] (L. Brinth).
https://doi.org/10.1016/j.autneu.2018.03.001 Received 16 January 2018; Received in revised form 1 March 2018; Accepted 2 March 2018 1566-0702/ © 2018 Published by Elsevier B.V.
Please cite this article as: Brinth, L., Autonomic Neuroscience: Basic and Clinical (2018), https://doi.org/10.1016/j.autneu.2018.03.001
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
L. Brinth et al.
In order to assess the extent of awareness of POTS which may have affected the proportion of patients referred for assessment, we performed a PubMed search on papers published with “Postural Orthostatic Tachycardia Syndrome” as Medical Subject Headings (MeSH)-term from 1997 to 2014. Due to the retrospective nature of the study, approval by the University Hospital Ethics Committee was not required. The Danish Data Protection Agency approved the current study. Statistical analysis was performed using SPPS 19 (SPSS Inc. Chicago, IL, USA). Results are expressed as mean values ± standard deviation (SD).
We, therefore, sought to explore how the number of POTS diagnosed patients had developed in the last 18 years using data from a tertiary diagnostic center. We also tested the hypothesis that the diagnostic rate of POTS had increased due to changes in the number of referrals, disease recognition, and diagnostic vigilance. 2. Methods We made a retrospective analysis based on data obtained from 8790 tilt-table tests performed routinely at the tertiary syncope unit of the city of Copenhagen, Denmark. The tests were carried out between 1997 and 2014 in patients referred due to orthostatic intolerance and/or suspected syncope. In this period of time our Syncope Unit has served as the largest investigation center in Denmark performing tilt table tests in patients with chronic orthostatic intolerance referred from all over Denmark. All patients referred to our unit with orthostatic intolerance receive a tilt table test. All tests were re-evaluated regarding cause of referral, patient's medical history, hemodynamic data derived from the tilt table test, and symptoms reported during the test. We analyzed the following clinical characteristics registered in the database: age, gender, height, weight; the latter two parameters allowed calculation of body-mass index (BMI). The test results were reclassified according to the current diagnostic criteria (Sheldon et al., 2015). The patients were assigned a POTS diagnosis if they had a heart rate increment of > 30 bpm (> 40 bpm in adolescents aged 12–19) or to levels above 120 bpm within the first 10 min of HUT accompanied by marked and recognizable orthostatic discomfort and absence of orthostatic hypotension. Patients with other recognized medical conditions associated with tachycardia such as thyroid disease or structural heart disease were excluded, as were patients suffering from other acute or chronic diseases that could affect the hemodynamic response to orthostatic stress. The number of POTS patients per year at the initial evaluation and according to the 2015 diagnostic criteria, respectively, was calculated. Then, the number of patients diagnosed according to 2015 criteria per year was divided by the number of tilt tests performed that year and reported as a percentage of all tilt tests that yielded POTS diagnosis. All tests were performed between 8 a.m. and 2 p.m. in the nonfasting state at standard room temperature according to “Italian protocol” (Bartoletti et al., 2000) with a local modification regarding the length of continued orthostatic stress after administration of nitroglycerine. After at least 10 min of supine rest, the patients were tilted to the head-up position within 3–4 s with the inclination of the table set at 60 degrees and stayed in this position for 20 min, at that point sublingual nitroglycerine would be administered in the absence of diagnostic findings and if a positive history of unexplained pre-/syncope was present. The test was then continued for 10 min or until syncope/ pronounced orthostatic intolerance occurred. In patients referred due to symptoms of chronic orthostatic intolerance without syncope, the test was typically shortened and aborted after 10 min of tilt. During the tests, RR-intervals were measured continuously from one precordial ECG-lead and blood pressure was measured continuously by a non-invasive hemodynamic monitor: Finometer (Finapres Medical Systems BV, Amsterdam, The Netherlands) or Task Force Monitor (CNSystems Medizintechnik AG, Graz, Austria). Data were sampled at 1.0 kHz and analyzed using commercial software (Chart 5.59, AD Instruments Inc., Colorado Springs, CO, USA). The ECG was band-pass filtered using a frequency band of 0.5 to 40 Hz and RR-intervals were converted to instantaneous heart rate. If a patient had been re-evaluated, only the first tilt table test was included in our analysis. We did not have access to valid information regarding the patients' baseline treatment. However, as only newly-referred patients were included in our analysis, none or only very few of them had prescribed high salt diet, fludrocortisone, midodrine or heart rate regulating drugs that otherwise may have been prescribed after a positive tilt table test.
3. Results The reclassification of the eligible 8790 tilt-table tests performed at our unit between 1997 and 2014 according to current diagnostic guidelines (Sheldon et al., 2015) identified 264 patients with likely POTS diagnosis. Of these, four patients did not experience any orthostatic intolerance at HUT and 11 patients had a condition that could affect the hemodynamic response to orthostatic stress: one had cerebral palsy, one had just recovered from endocarditis, five had Parkinson's disease and orthostatic hypotension, one was severely deconditioned, one had myxedema and two were tetraplegic. This yielded 249 patients with POTS diagnosis according to 2015 diagnostic criteria with a mean age of 27.0 ± 11.8 years. Anthropomorphic characteristics of these patients are presented in Table 1. Of these, only 129 patients had been diagnosed with POTS at the time of HUT. Of 249 patients, 189 were female resulting in a female: male ratio of approximately 3:1. Between 1997 and 2014, a total of 173 patients were diagnosed with POTS at the time of HUT/first evaluation but after re-evaluation only 129 of these fulfilled the current diagnostic criteria (Sheldon et al., 2015). (Table 2) Typical reasons for reclassification to non-POTS diagnosis during re-evaluation were presence of other recognizable reasons for tachycardia, such as severe deconditioning or the hemodynamic response on HUT not fulfilling current diagnostic criteria for POTS. When the number of POTS patients seen at our unit per year was assessed, a marked increase could be observed over the last 18 years (Fig. 1). In 1997 two patients fulfilled the diagnostic criteria – in 2014 the number was 49. When the number of patients diagnosed with POTS each year was related to the number of HUT performed per year, the proportion was relatively constant throughout the period of study; between 2 and 3% of all HUT per year. The exception was 2013 and 2014 when the proportion rose to 6–7% (Table 2). An increase was seen in the number of scientific publications on POTS throughout the years evaluated with a steeper increase from 2010 and onwards. (Fig. 1). Of 249 patients with POTS diagnosis after reclassification, 154 (62%) reported syncope and the remaining 95 (38%) were referred due to chronic and unexplained orthostatic intolerance. Table 2 shows the number of diagnoses after reclassification and the mean age of patients stratified by year. Age at presentation of POTS diagnosed patients was unchanged during the study (see: Table 2; Pearson Correlation test −0.109, p = 0.086).
Table 1 Anthropomorphic characteristics of 249 patients who met diagnostic POTS-criteria.
Age (years) Weight (kg) Height (cm) BMI (kg/m2) POTS = Postural Orthostatic BMI = Body Mass Index.
2
Mean
SD
Range
26.8 65.6 172.8 21.9
12.2 13.7 8.6 3.8
13–77 37–111 148–200 14.1–38.9
Tachycardia
Syndrome,
SD = standard
deviation,
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enhanced symptom pattern recognition. At the same time, it should be emphasized that when stated as the proportion of tilt tests performed yielding POTS-diagnoses the number was relatively constant over a long period suggesting a relatively constant prevalence of POTS in the population, independent on the number of patients with syncope or orthostatic intolerance referred for investigation. As to the abrupt increase in the proportion of patients fulfilling diagnostic criteria for POTS in 2013–2014, we believe that this may be due to increasing awareness of POTS in the population plus an influence of social media on patients, doctors, and the whole health care system. For the individual doctor, once they have POTS in their diagnostic repertoire the number of subsequent publications on the matter will probably not change their referral pattern much. However, increasing number of publications and perhaps more so the underlying interest in the diagnosis in the medical establishment that the increasing publication rate reflects will probably tend to make more doctors become aware of the diagnosis and thereby change referral patterns. POTS was probably recognized for decades under different names, and lack of consistent diagnostic criteria may have made the syndrome relatively uncommon until 1990s. The term “Postural Orthostatic Tachycardia Syndrome” was first proposed in 1993 by Low's group from Mayo Clinic (Schondorf & Low, 1993). However, a very similar clinical picture was described as long ago as in 1871 by Da Costa under the name of “irritable heart syndrome” (Da Costa, 1871), and has been later independently reported by other authors who used different terms to describe the combination of inappropriate orthostatic tachycardia, symptoms of orthostatic intolerance and general deconditioning (Bjure & Laurell, 1927). Previous studies have demonstrated that POTS is a common comorbidity in multiple sclerosis (Kanjwal et al., 2010), myalgic encephalomyelitis (Benarroch, 2012; Reynolds et al., 2014), and EhlersDanlos syndrome (Wallman et al., 2014). Our study reports a relatively constant prevalence of POTS among patients referred for HUT over the last 18 years – but does not take into account to what degree the POTSdiagnosis is influenced by its possible etiology. The proportion of POTS-patients experiencing syncope being 67% in this specific patient series is higher than previously reported (Grubb, 2008), which may be explained by referral bias as patients with orthostatic intolerance and syncope are often referred for tilt testing. We have observed a growing awareness, among patients and referring doctors, of the relevance of tilt testing not only in the diagnostic workup of patients with unexplained syncope and acute forms of orthostatic intolerance but also in more chronic forms of orthostatic disorders, typically orthostatic hypotension in the elderly and POTS in the young (Fedorowski & Melander, 2013). The understanding of the pathophysiology of POTS and related disorders such as myalgic encephalomyelitis and chronic fatigue syndrome has been a challenge for the scientific community for decades. However, an increasing number of studies reporting the presence of autoantibodies directed against receptors of the autonomic nervous system supports the hypothesis that POTS may be an autoimmune condition elicited in genetically susceptible individuals by an immunogenic trigger (Li et al., 2014; Fedorowski et al., 2017). New techniques in immunology have provided a possible clue to the autoimmune background for POTS. Recent publications in this area have shown that IgG from POTS patients activates beta-1 and -2 receptors, and simultaneously partially blocks the vasoconstrictive alpha1-adrenoceptor (Li et al., 2014; Fedorowski et al., 2017). Consequently, the autoimmune hypothesis of POTS etiology could provide a potential link between immune triggers, such as viral and bacterial infections, as well as possible iatrogenic factors such as large-scale vaccination programs. The changing environment, behavioral patterns, dietary preferences, and new and previously unknown immunological stimuli might provide a tempting explanation to the observed epidemic of POTS in developed countries (Okada et al., 2010). This hypothesis,
Table 2 Number of scientific publications and diagnoses related to Postural Orthostatic Tachycardia Syndrome per year. Year
Publications with POTS as keyword
Patients diagnosed with POTS according to 2015 criteria
Number of HUT performed
% of HUT yielding POTSdiagnosis
Mean age of patients fulfilling POTScriteria at HUT
2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997
82 63 52 51 43 25 25 20 18 26 11 16 18 14 21 9 5 1
49 54 18 13 11 16 15 8 15 8 15 6 7 5 7 0 0 2
808 779 764 597 544 585 618 650 599 573 586 405 410 319 247 162 83 61
6,1 6,9 2,4 2,2 2,0 2,7 2,4 1,2 2,5 1,4 2,6 1,5 1,7 1,6 2,8 NA NA 3,3
26 25 28 27 23 25 27 27 29 28 25 26 34 40 30 NA NA 25
HUT = head-up tilt testing.
Fig. 1. Number of tilt tests (HUT) performed, number of patients fulfilling criteria for POTS on HUT and number of publications with POTS as keyword.
4. Discussion In this study, we have observed that the proportion of patients with syncope and orthostatic intolerance that presented with Postural Orthostatic Tachycardia Syndrome between 1997 and 2012 has been relatively constant at 2–3%. However, following the increase in number of published studies on POTS observed since 2010, the proportion of patients with POTS diagnosis tripled to 6–7% in years 2013–2014. The increase in patients fulfilling the diagnostic criteria for POTS became steeper after 2012. Whether this is due to an increasing awareness of the condition in both patients and referring doctors, as suggested by the number of publications dealing with POTS, or an absolute increase in the POTS incidence is difficult to determine. A possible explanation could be an increase in awareness of POTS due to media attention directed towards suspected side effects of vaccination against human papilloma virus (HPV) in Denmark from 2013 and onwards. Consequently, both the total number of examined patients, predominantly young women, and the number of POTS diagnoses may have risen due to increase in referral rate and the referral bias. Moreover, some mildly to moderately symptomatic POTS patients may have approached their doctors prompted by media coverage and 3
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
L. Brinth et al.
Member of Speakers' Bureau SJM Abbott Laboratories Inc. None of the other authors have anything to declare in relation to this article.
however, warrants further confirmatory studies performed according to strict rules for environmentally-mediated autoimmune diseases (Miller et al., 2012). Other conditions share similarities with POTS including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia and Chronic Regional Pain syndrome (CRPS). In these clinical conditions, there is a core of symptoms with fatigue, autonomic dysfunction and pain as prominent symptoms, as well as unclear pathophysiology and a lack of efficient treatment options. The overlap between these clinical conditions is substantial (Aaron & Buchwald, 2001). The overlap between POTS and ME/CFS is demonstrated by the inclusion of orthostatic intolerance as one of the two minor criteria for ME/CFS suggested recently by the Institute of Medicine in 2015 (Clayton, 2015). To what degree the patients diagnosed with POTS at our clinic and patients diagnosed with other related diagnoses represent roughly the same population is difficult to ascertain. A recent study from UK suggests a gradual decline in the incidence in ME/CFS and a simultaneous rise in the incidence of Fibromyalgia in the years 2001 to 2013 (Collin et al., 2017a). Worth noting is also that the time from symptom onset to diagnosis may be long – and a substantial proportion of the patients may never get a diagnosis (Collin et al., 2017b). There are clear dangers in attempting to estimate the incidence of any disease from a single center where referral pattern plays such a large part in presentation of patients. A true increase in numbers can, by definition, only be established if all cases in the population are noted. As this is difficult to ascertain we believe that using results from a dedicated syncope unit with referral from a large area of the country is a relevant estimate. However, regarding the generalizability of our findings it is possible that we only see more severe cases, as is typical for a tertiary care unit. Therefore, multi-center and multi-national surveys would probably resolve this issue better and are, thus, called upon by us. In conclusion, the proportion of POTS diagnoses among patients investigated for suspected syncope and/or orthostatic intolerance was relatively constant between 1997 and 2012. Then, a steep increase in diagnoses of POTS was observed, preceded by the growing number of POTS-related publications in PubMed suggesting a relationship. We believe that increasing awareness of POTS in the population and an influence of social media on patients, doctors, and the whole health care system may partially explain the current POTS epidemic.
References Aaron, L.A., Buchwald, D., 2001. A review of the evidence for overlap among unexplained clinical conditions. Ann. Intern. Med. 134, 868–881. Bartoletti, A., Alboni, P., Ammirati, F., et al., 2000. ‘The Italian Protocol’: a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope. Europace 2, 339–342. Benarroch, E.E., 2012. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin. Proc. 87, 1214–1225. Bjure, A., Laurell, H., 1927. Abnormal static circulatory phenomena and their symptoms: arterial orthostatic anemia as neglected clinical picture. Upsala Lakareforen. Forh. 33, 1–23. Clayton, E.W., 2015. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. JAMA 313, 1101–1102. Collin, S.M., Bakken, I.J., Nazareth, I., Crawley, E., White, P.D., 2017a. Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001–2013: a Clinical Practice Research Datalink study. J. R. Soc. Med. 110, 231–244. Collin, S.M., Bakken, I.J., Nazareth, I., Crawley, E., White, P.D., 2017b. Health care resource use by patients before and after a diagnosis of chronic fatigue syndrome (CFS/ ME): a clinical practice research datalink study. BMC Fam. Pract. 18, 60. Da Costa, J., 1871. On irritable heart: a clinical study of a form of a functional cardiac disorder and its consequences. Am J Med Sci 61, 17–52. Fedorowski, A., Melander, O., 2013. Syndromes of orthostatic intolerance: a hidden danger. J. Intern. Med. 273, 322–335. Fedorowski, A., Li, H., Yu, X., et al., 2017. Antiadrenergic autoimmunity in postural tachycardia syndrome. Europace 19, 1211–1219. Grubb, B.P., 2008. Postural tachycardia syndrome. Circulation 117, 2814–2817. Kanjwal, K., Karabin, B., Kanjwal, Y., Grubb, B.P., 2010. Autonomic dysfunction presenting as postural orthostatic tachycardia syndrome in patients with multiple sclerosis. Int. J. Med. Sci. 7, 62–67. Li, H., Yu, X., Liles, C., et al., 2014. Autoimmune basis for postural tachycardia syndrome. J. Am. Heart Assoc. 3, e000755. Miller, F.W., Pollard, K.M., Parks, C.G., et al., 2012. Criteria for environmentally associated autoimmune diseases. J. Autoimmun. 39, 253–258. Okada, H., Kuhn, C., Feillet, H., Bach, J.F., 2010. The hygiene hypothesis' for autoimmune and allergic diseases: an update. Clin. Exp. Immunol. 160, 1–9. Reynolds, G.K., Lewis, D.P., Richardson, A.M., Lidbury, B.A., 2014. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. J. Intern. Med. 275, 409–417. Robertson, D., 1999. The epidemic of orthostatic tachycardia and orthostatic intolerance. Am J Med Sci 317, 75–77. Schondorf, R., Low, P.A., 1993. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 43, 132–137. Sheldon, R.S., Grubb, B.P., Olshansky, B., et al., 2015. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 12, e41-e63. Wallman, D., Weinberg, J., Hohler, A.D., 2014. Ehlers-Danlos syndrome and postural tachycardia syndrome: a relationship study. J. Neurol. Sci. 340, 99–102.
Declaration of interest Dr. Sutton reports that he is Consultant to Medtronic Inc. and
4
Contents lists available at ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
Postural Orthostatic Tachycardia Syndrome (POTS) in Denmark: Increasingly recognized or new epidemic? ⁎
Louise Brintha,b, , Kirsten Porsb, Jasmina Medic Spahicc, Richard Suttond, Artur Fedorowskic,e, Jesper Mehlsenb a
Department of Clinical Physiology & Nuclear Medicine, Bispebjerg Frederiksberg Hospital, DK-2000 Frederiksberg, Denmark Coordinating Research Center/Syncope Unit, Bispebjerg Frederiksberg Hospital, DK-2000 Frederiksberg, Denmark c Department of Clinical Sciences, Malmö, Faculty of Medicine, Lund University, SE-205 02 Malmö, Sweden d National Heart & Lung Institute, Imperial College, London, UK e Department of Cardiology, Skåne University Hospital, Malmö, Sweden b
A B S T R A C T
Aims: The incidence of Postural Orthostatic Tachycardia Syndrome (POTS) has grown in recent years. Whether this is an emerging epidemic or increasing recognition is unclear. Methods: We retrospectively examined 8790 tilt-table tests (HUT) performed between 1997 and 2014 in patients with orthostatic intolerance and/or suspected syncope. Tests were reclassified according to the current diagnostic criteria for POTS. The number of POTS diagnoses in proportion to the number of tilt tests performed per year was calculated. The number of papers published with the term “Postural Orthostatic Tachycardia Syndrome” 1997–2014 was retrieved from PubMed and related to yearly POTS incidence. Results: Eight-hundred-and-seventy-five tests with suspected POTS were thoroughly evaluated. The reclassification of test results yielded 243 POTS diagnoses (age, 27.0 ± 11.8 years). An increase in total number of POTS diagnoses was observed but the proportion of POTS-positive tests per year was relatively constant (≈2–3%) except for the period 2013–2014 (≈7%). The increase in POTS diagnoses was preceded by an increase in number of POTS-related papers in PubMed. Conclusion: The proportion of POTS diagnoses among patients investigated for suspected syncope and/or orthostatic intolerance was relatively constant 1997–2012. The growing number of POTS-related publications in PubMed preceded the steep increase in diagnostic rate of POTS observed after 2012.
1. Introduction Postural Orthostatic Tachycardia Syndrome (POTS) is one of the most common forms of chronic orthostatic intolerance in young patients (Benarroch, 2012). The condition is believed to be a heterogeneous form of autonomic dysfunction characterized by abnormal increment in heart rate upon assumption of the upright posture accompanied by orthostatic intolerance and symptoms of sympathetic autonomic dominance (Benarroch, 2012). An increase in heart rate equal to or > 30 min−1 or above 120 min−1 and absence of overt orthostatic hypotension during a head-up tilt test is the main diagnostic criterion (Sheldon et al., 2015). A recently published consensus states that an increase of > 40 min−1 should be used for patients aged 12 to 19 years (Sheldon et al., 2015). One-third of POTS patients report recurrent syncope (Grubb, 2008). POTS can be difficult to diagnose, as tilt table testing with beat-to-
⁎
beat hemodynamic monitoring is essential in the diagnostic workup (Sheldon et al., 2015). Moreover, other medical conditions causing tachycardia, such as structural heart disease, tachyarrhythmias, anemia, severe deconditioning, dehydration, thyroid disease, use of adrenergic drugs, and emotional disorders may mimic POTS and should be ruled out. Postural Orthostatic Tachycardia Syndrome is reported to be more common in women with a 5:1 female-to-male ratio (Sheldon et al., 2015). The overall prevalence is difficult to determine due to the abovementioned circumstances but it is estimated that POTS affects about 500.000 patients in the USA alone (Sheldon et al., 2015). In 1999 Robertson described “the epidemic of orthostatic tachycardia and orthostatic intolerance” as an epidemic of disease recognition rather than an increasing prevalence of the disease as such (Robertson, 1999). Thus, it is unclear whether POTS has been an unrecognized disorder or whether it is an emerging epidemic due to increasing incidence.
Corresponding author at: Department of Cardiology, Bispebjerg Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark. E-mail address: [email protected] (L. Brinth).
https://doi.org/10.1016/j.autneu.2018.03.001 Received 16 January 2018; Received in revised form 1 March 2018; Accepted 2 March 2018 1566-0702/ © 2018 Published by Elsevier B.V.
Please cite this article as: Brinth, L., Autonomic Neuroscience: Basic and Clinical (2018), https://doi.org/10.1016/j.autneu.2018.03.001
Autonomic Neuroscience: Basic and Clinical xxx (xxxx) xxx–xxx
L. Brinth et al.
In order to assess the extent of awareness of POTS which may have affected the proportion of patients referred for assessment, we performed a PubMed search on papers published with “Postural Orthostatic Tachycardia Syndrome” as Medical Subject Headings (MeSH)-term from 1997 to 2014. Due to the retrospective nature of the study, approval by the University Hospital Ethics Committee was not required. The Danish Data Protection Agency approved the current study. Statistical analysis was performed using SPPS 19 (SPSS Inc. Chicago, IL, USA). Results are expressed as mean values ± standard deviation (SD).
We, therefore, sought to explore how the number of POTS diagnosed patients had developed in the last 18 years using data from a tertiary diagnostic center. We also tested the hypothesis that the diagnostic rate of POTS had increased due to changes in the number of referrals, disease recognition, and diagnostic vigilance. 2. Methods We made a retrospective analysis based on data obtained from 8790 tilt-table tests performed routinely at the tertiary syncope unit of the city of Copenhagen, Denmark. The tests were carried out between 1997 and 2014 in patients referred due to orthostatic intolerance and/or suspected syncope. In this period of time our Syncope Unit has served as the largest investigation center in Denmark performing tilt table tests in patients with chronic orthostatic intolerance referred from all over Denmark. All patients referred to our unit with orthostatic intolerance receive a tilt table test. All tests were re-evaluated regarding cause of referral, patient's medical history, hemodynamic data derived from the tilt table test, and symptoms reported during the test. We analyzed the following clinical characteristics registered in the database: age, gender, height, weight; the latter two parameters allowed calculation of body-mass index (BMI). The test results were reclassified according to the current diagnostic criteria (Sheldon et al., 2015). The patients were assigned a POTS diagnosis if they had a heart rate increment of > 30 bpm (> 40 bpm in adolescents aged 12–19) or to levels above 120 bpm within the first 10 min of HUT accompanied by marked and recognizable orthostatic discomfort and absence of orthostatic hypotension. Patients with other recognized medical conditions associated with tachycardia such as thyroid disease or structural heart disease were excluded, as were patients suffering from other acute or chronic diseases that could affect the hemodynamic response to orthostatic stress. The number of POTS patients per year at the initial evaluation and according to the 2015 diagnostic criteria, respectively, was calculated. Then, the number of patients diagnosed according to 2015 criteria per year was divided by the number of tilt tests performed that year and reported as a percentage of all tilt tests that yielded POTS diagnosis. All tests were performed between 8 a.m. and 2 p.m. in the nonfasting state at standard room temperature according to “Italian protocol” (Bartoletti et al., 2000) with a local modification regarding the length of continued orthostatic stress after administration of nitroglycerine. After at least 10 min of supine rest, the patients were tilted to the head-up position within 3–4 s with the inclination of the table set at 60 degrees and stayed in this position for 20 min, at that point sublingual nitroglycerine would be administered in the absence of diagnostic findings and if a positive history of unexplained pre-/syncope was present. The test was then continued for 10 min or until syncope/ pronounced orthostatic intolerance occurred. In patients referred due to symptoms of chronic orthostatic intolerance without syncope, the test was typically shortened and aborted after 10 min of tilt. During the tests, RR-intervals were measured continuously from one precordial ECG-lead and blood pressure was measured continuously by a non-invasive hemodynamic monitor: Finometer (Finapres Medical Systems BV, Amsterdam, The Netherlands) or Task Force Monitor (CNSystems Medizintechnik AG, Graz, Austria). Data were sampled at 1.0 kHz and analyzed using commercial software (Chart 5.59, AD Instruments Inc., Colorado Springs, CO, USA). The ECG was band-pass filtered using a frequency band of 0.5 to 40 Hz and RR-intervals were converted to instantaneous heart rate. If a patient had been re-evaluated, only the first tilt table test was included in our analysis. We did not have access to valid information regarding the patients' baseline treatment. However, as only newly-referred patients were included in our analysis, none or only very few of them had prescribed high salt diet, fludrocortisone, midodrine or heart rate regulating drugs that otherwise may have been prescribed after a positive tilt table test.
3. Results The reclassification of the eligible 8790 tilt-table tests performed at our unit between 1997 and 2014 according to current diagnostic guidelines (Sheldon et al., 2015) identified 264 patients with likely POTS diagnosis. Of these, four patients did not experience any orthostatic intolerance at HUT and 11 patients had a condition that could affect the hemodynamic response to orthostatic stress: one had cerebral palsy, one had just recovered from endocarditis, five had Parkinson's disease and orthostatic hypotension, one was severely deconditioned, one had myxedema and two were tetraplegic. This yielded 249 patients with POTS diagnosis according to 2015 diagnostic criteria with a mean age of 27.0 ± 11.8 years. Anthropomorphic characteristics of these patients are presented in Table 1. Of these, only 129 patients had been diagnosed with POTS at the time of HUT. Of 249 patients, 189 were female resulting in a female: male ratio of approximately 3:1. Between 1997 and 2014, a total of 173 patients were diagnosed with POTS at the time of HUT/first evaluation but after re-evaluation only 129 of these fulfilled the current diagnostic criteria (Sheldon et al., 2015). (Table 2) Typical reasons for reclassification to non-POTS diagnosis during re-evaluation were presence of other recognizable reasons for tachycardia, such as severe deconditioning or the hemodynamic response on HUT not fulfilling current diagnostic criteria for POTS. When the number of POTS patients seen at our unit per year was assessed, a marked increase could be observed over the last 18 years (Fig. 1). In 1997 two patients fulfilled the diagnostic criteria – in 2014 the number was 49. When the number of patients diagnosed with POTS each year was related to the number of HUT performed per year, the proportion was relatively constant throughout the period of study; between 2 and 3% of all HUT per year. The exception was 2013 and 2014 when the proportion rose to 6–7% (Table 2). An increase was seen in the number of scientific publications on POTS throughout the years evaluated with a steeper increase from 2010 and onwards. (Fig. 1). Of 249 patients with POTS diagnosis after reclassification, 154 (62%) reported syncope and the remaining 95 (38%) were referred due to chronic and unexplained orthostatic intolerance. Table 2 shows the number of diagnoses after reclassification and the mean age of patients stratified by year. Age at presentation of POTS diagnosed patients was unchanged during the study (see: Table 2; Pearson Correlation test −0.109, p = 0.086).
Table 1 Anthropomorphic characteristics of 249 patients who met diagnostic POTS-criteria.
Age (years) Weight (kg) Height (cm) BMI (kg/m2) POTS = Postural Orthostatic BMI = Body Mass Index.
2
Mean
SD
Range
26.8 65.6 172.8 21.9
12.2 13.7 8.6 3.8
13–77 37–111 148–200 14.1–38.9
Tachycardia
Syndrome,
SD = standard
deviation,
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enhanced symptom pattern recognition. At the same time, it should be emphasized that when stated as the proportion of tilt tests performed yielding POTS-diagnoses the number was relatively constant over a long period suggesting a relatively constant prevalence of POTS in the population, independent on the number of patients with syncope or orthostatic intolerance referred for investigation. As to the abrupt increase in the proportion of patients fulfilling diagnostic criteria for POTS in 2013–2014, we believe that this may be due to increasing awareness of POTS in the population plus an influence of social media on patients, doctors, and the whole health care system. For the individual doctor, once they have POTS in their diagnostic repertoire the number of subsequent publications on the matter will probably not change their referral pattern much. However, increasing number of publications and perhaps more so the underlying interest in the diagnosis in the medical establishment that the increasing publication rate reflects will probably tend to make more doctors become aware of the diagnosis and thereby change referral patterns. POTS was probably recognized for decades under different names, and lack of consistent diagnostic criteria may have made the syndrome relatively uncommon until 1990s. The term “Postural Orthostatic Tachycardia Syndrome” was first proposed in 1993 by Low's group from Mayo Clinic (Schondorf & Low, 1993). However, a very similar clinical picture was described as long ago as in 1871 by Da Costa under the name of “irritable heart syndrome” (Da Costa, 1871), and has been later independently reported by other authors who used different terms to describe the combination of inappropriate orthostatic tachycardia, symptoms of orthostatic intolerance and general deconditioning (Bjure & Laurell, 1927). Previous studies have demonstrated that POTS is a common comorbidity in multiple sclerosis (Kanjwal et al., 2010), myalgic encephalomyelitis (Benarroch, 2012; Reynolds et al., 2014), and EhlersDanlos syndrome (Wallman et al., 2014). Our study reports a relatively constant prevalence of POTS among patients referred for HUT over the last 18 years – but does not take into account to what degree the POTSdiagnosis is influenced by its possible etiology. The proportion of POTS-patients experiencing syncope being 67% in this specific patient series is higher than previously reported (Grubb, 2008), which may be explained by referral bias as patients with orthostatic intolerance and syncope are often referred for tilt testing. We have observed a growing awareness, among patients and referring doctors, of the relevance of tilt testing not only in the diagnostic workup of patients with unexplained syncope and acute forms of orthostatic intolerance but also in more chronic forms of orthostatic disorders, typically orthostatic hypotension in the elderly and POTS in the young (Fedorowski & Melander, 2013). The understanding of the pathophysiology of POTS and related disorders such as myalgic encephalomyelitis and chronic fatigue syndrome has been a challenge for the scientific community for decades. However, an increasing number of studies reporting the presence of autoantibodies directed against receptors of the autonomic nervous system supports the hypothesis that POTS may be an autoimmune condition elicited in genetically susceptible individuals by an immunogenic trigger (Li et al., 2014; Fedorowski et al., 2017). New techniques in immunology have provided a possible clue to the autoimmune background for POTS. Recent publications in this area have shown that IgG from POTS patients activates beta-1 and -2 receptors, and simultaneously partially blocks the vasoconstrictive alpha1-adrenoceptor (Li et al., 2014; Fedorowski et al., 2017). Consequently, the autoimmune hypothesis of POTS etiology could provide a potential link between immune triggers, such as viral and bacterial infections, as well as possible iatrogenic factors such as large-scale vaccination programs. The changing environment, behavioral patterns, dietary preferences, and new and previously unknown immunological stimuli might provide a tempting explanation to the observed epidemic of POTS in developed countries (Okada et al., 2010). This hypothesis,
Table 2 Number of scientific publications and diagnoses related to Postural Orthostatic Tachycardia Syndrome per year. Year
Publications with POTS as keyword
Patients diagnosed with POTS according to 2015 criteria
Number of HUT performed
% of HUT yielding POTSdiagnosis
Mean age of patients fulfilling POTScriteria at HUT
2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997
82 63 52 51 43 25 25 20 18 26 11 16 18 14 21 9 5 1
49 54 18 13 11 16 15 8 15 8 15 6 7 5 7 0 0 2
808 779 764 597 544 585 618 650 599 573 586 405 410 319 247 162 83 61
6,1 6,9 2,4 2,2 2,0 2,7 2,4 1,2 2,5 1,4 2,6 1,5 1,7 1,6 2,8 NA NA 3,3
26 25 28 27 23 25 27 27 29 28 25 26 34 40 30 NA NA 25
HUT = head-up tilt testing.
Fig. 1. Number of tilt tests (HUT) performed, number of patients fulfilling criteria for POTS on HUT and number of publications with POTS as keyword.
4. Discussion In this study, we have observed that the proportion of patients with syncope and orthostatic intolerance that presented with Postural Orthostatic Tachycardia Syndrome between 1997 and 2012 has been relatively constant at 2–3%. However, following the increase in number of published studies on POTS observed since 2010, the proportion of patients with POTS diagnosis tripled to 6–7% in years 2013–2014. The increase in patients fulfilling the diagnostic criteria for POTS became steeper after 2012. Whether this is due to an increasing awareness of the condition in both patients and referring doctors, as suggested by the number of publications dealing with POTS, or an absolute increase in the POTS incidence is difficult to determine. A possible explanation could be an increase in awareness of POTS due to media attention directed towards suspected side effects of vaccination against human papilloma virus (HPV) in Denmark from 2013 and onwards. Consequently, both the total number of examined patients, predominantly young women, and the number of POTS diagnoses may have risen due to increase in referral rate and the referral bias. Moreover, some mildly to moderately symptomatic POTS patients may have approached their doctors prompted by media coverage and 3
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Member of Speakers' Bureau SJM Abbott Laboratories Inc. None of the other authors have anything to declare in relation to this article.
however, warrants further confirmatory studies performed according to strict rules for environmentally-mediated autoimmune diseases (Miller et al., 2012). Other conditions share similarities with POTS including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia and Chronic Regional Pain syndrome (CRPS). In these clinical conditions, there is a core of symptoms with fatigue, autonomic dysfunction and pain as prominent symptoms, as well as unclear pathophysiology and a lack of efficient treatment options. The overlap between these clinical conditions is substantial (Aaron & Buchwald, 2001). The overlap between POTS and ME/CFS is demonstrated by the inclusion of orthostatic intolerance as one of the two minor criteria for ME/CFS suggested recently by the Institute of Medicine in 2015 (Clayton, 2015). To what degree the patients diagnosed with POTS at our clinic and patients diagnosed with other related diagnoses represent roughly the same population is difficult to ascertain. A recent study from UK suggests a gradual decline in the incidence in ME/CFS and a simultaneous rise in the incidence of Fibromyalgia in the years 2001 to 2013 (Collin et al., 2017a). Worth noting is also that the time from symptom onset to diagnosis may be long – and a substantial proportion of the patients may never get a diagnosis (Collin et al., 2017b). There are clear dangers in attempting to estimate the incidence of any disease from a single center where referral pattern plays such a large part in presentation of patients. A true increase in numbers can, by definition, only be established if all cases in the population are noted. As this is difficult to ascertain we believe that using results from a dedicated syncope unit with referral from a large area of the country is a relevant estimate. However, regarding the generalizability of our findings it is possible that we only see more severe cases, as is typical for a tertiary care unit. Therefore, multi-center and multi-national surveys would probably resolve this issue better and are, thus, called upon by us. In conclusion, the proportion of POTS diagnoses among patients investigated for suspected syncope and/or orthostatic intolerance was relatively constant between 1997 and 2012. Then, a steep increase in diagnoses of POTS was observed, preceded by the growing number of POTS-related publications in PubMed suggesting a relationship. We believe that increasing awareness of POTS in the population and an influence of social media on patients, doctors, and the whole health care system may partially explain the current POTS epidemic.
References Aaron, L.A., Buchwald, D., 2001. A review of the evidence for overlap among unexplained clinical conditions. Ann. Intern. Med. 134, 868–881. Bartoletti, A., Alboni, P., Ammirati, F., et al., 2000. ‘The Italian Protocol’: a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope. Europace 2, 339–342. Benarroch, E.E., 2012. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin. Proc. 87, 1214–1225. Bjure, A., Laurell, H., 1927. Abnormal static circulatory phenomena and their symptoms: arterial orthostatic anemia as neglected clinical picture. Upsala Lakareforen. Forh. 33, 1–23. Clayton, E.W., 2015. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: an IOM report on redefining an illness. JAMA 313, 1101–1102. Collin, S.M., Bakken, I.J., Nazareth, I., Crawley, E., White, P.D., 2017a. Trends in the incidence of chronic fatigue syndrome and fibromyalgia in the UK, 2001–2013: a Clinical Practice Research Datalink study. J. R. Soc. Med. 110, 231–244. Collin, S.M., Bakken, I.J., Nazareth, I., Crawley, E., White, P.D., 2017b. Health care resource use by patients before and after a diagnosis of chronic fatigue syndrome (CFS/ ME): a clinical practice research datalink study. BMC Fam. Pract. 18, 60. Da Costa, J., 1871. On irritable heart: a clinical study of a form of a functional cardiac disorder and its consequences. Am J Med Sci 61, 17–52. Fedorowski, A., Melander, O., 2013. Syndromes of orthostatic intolerance: a hidden danger. J. Intern. Med. 273, 322–335. Fedorowski, A., Li, H., Yu, X., et al., 2017. Antiadrenergic autoimmunity in postural tachycardia syndrome. Europace 19, 1211–1219. Grubb, B.P., 2008. Postural tachycardia syndrome. Circulation 117, 2814–2817. Kanjwal, K., Karabin, B., Kanjwal, Y., Grubb, B.P., 2010. Autonomic dysfunction presenting as postural orthostatic tachycardia syndrome in patients with multiple sclerosis. Int. J. Med. Sci. 7, 62–67. Li, H., Yu, X., Liles, C., et al., 2014. Autoimmune basis for postural tachycardia syndrome. J. Am. Heart Assoc. 3, e000755. Miller, F.W., Pollard, K.M., Parks, C.G., et al., 2012. Criteria for environmentally associated autoimmune diseases. J. Autoimmun. 39, 253–258. Okada, H., Kuhn, C., Feillet, H., Bach, J.F., 2010. The hygiene hypothesis' for autoimmune and allergic diseases: an update. Clin. Exp. Immunol. 160, 1–9. Reynolds, G.K., Lewis, D.P., Richardson, A.M., Lidbury, B.A., 2014. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. J. Intern. Med. 275, 409–417. Robertson, D., 1999. The epidemic of orthostatic tachycardia and orthostatic intolerance. Am J Med Sci 317, 75–77. Schondorf, R., Low, P.A., 1993. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 43, 132–137. Sheldon, R.S., Grubb, B.P., Olshansky, B., et al., 2015. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 12, e41-e63. Wallman, D., Weinberg, J., Hohler, A.D., 2014. Ehlers-Danlos syndrome and postural tachycardia syndrome: a relationship study. J. Neurol. Sci. 340, 99–102.
Declaration of interest Dr. Sutton reports that he is Consultant to Medtronic Inc. and
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