Evidence for Impaired Renin Activity in Postural Orthostatic Tachycardia Syndrome.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous condition predominantly affecting autonomic control of the cardiovascular system. Its extensive symptom diversity implies multi-organ involvement that interacts in ways still requiring full exploration. Current understanding of POTS pathophysiology suggests alterations in the renin-angiotensin-aldosterone system as a possible contributing factor. Therefore, we investigated the relationship between the activity of the renin-angiotensin-aldosterone system and hemodynamic parameters in a cohort of POTS patients and controls recruited at a tertiary referral center. METHODS: The case-control study included 46 patients with POTS (27 ± 9 years), and 48 healthy controls (30 ± 9 years) without orthostatic intolerance. Plasma renin activity, expressed as angiotensin I generation, and plasma aldosterone were measured by enzyme-linked immunosorbent assay and were correlated with hemodynamic parameters obtained during active standing tests. RESULTS: Renin activity was significantly downregulated in POTS patients compared to healthy individuals (median, 3406 ng/mL vs. 9949 ng/mL, p < 0.001), whereas aldosterone concentration did not differ between POTS and healthy controls (median, 218 pmol/L vs. 218 pmol/L, p = 0.26). A significant inverse correlation between renin activity and supine and orthostatic blood pressure levels was observed in healthy individuals (p < 0.05 for all), but not in POTS patients. CONCLUSIONS: Renin activity, but not aldosterone concentration, is downregulated in patients with POTS. Moreover, renin activity in POTS is dissociated from supine and standing blood pressure levels in contrast to healthy individuals. These findings suggest impaired renin function in POTS, which may direct future therapeutic approaches.

Malmö POTS symptom score: Assessing symptom burden in postural orthostatic tachycardia syndrome.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a common cardiovascular autonomic disorder characterized by excessive heart rate (HR) increase on standing and symptoms of orthostatic intolerance, posing significant limitations on functional capacity. No objective tool exists to classify symptom burden in POTS. METHODS: We conducted a case-control study in 62 POTS patients and 50 healthy controls to compare symptom burden between groups using the newly developed, self-rating, 12-item, Malmö POTS Score (MAPS; 0-10 per item, total range 0-120) based on patients own perception of symptoms through visual analogue scale assessment. We have also explored correlations between symptom severity assessed by MAPS, basic clinical parameters and postural haemodynamic changes. RESULTS: POTS patients showed significantly higher total MAPS score (78 ± 20 vs. 14 ± 12, p < 0.001), higher baseline systolic blood pressure (BP), diastolic BP and HR (p < 0.001) compared with healthy controls. The most prominent symptoms in POTS were palpitations, fatigue and concentration difficulties. Haemodynamic parameters on standing were significantly correlated with palpitations in POTS after adjustment for age and sex (lower systolic and diastolic BP, and higher HR) (p < 0.001 for all). Orthostatic HR was significantly associated with concentration difficulties and total MAPS score. The optimal cut-point value of MAPS to differentiate POTS and healthy controls was ≥42 (sensitivity, 97%; specificity, 98%). CONCLUSIONS: Symptom severity, as assessed by MAPS score, is fivefold higher in POTS compared with healthy individuals. The new MAPS score can be useful as a semiquantitative system to assess symptom burden, monitor disease progression and evaluate pre-test likelihood of disease.

Proconvertase Furin Is Downregulated in Postural Orthostatic Tachycardia Syndrome.

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a cardiovascular autonomic disorder characterized by orthostatic intolerance and high prevalence among young women. The etiology of POTS is uncertain, though autoimmunity and inflammation may play an important role. We aimed to identify novel inflammatory biomarkers associated with POTS. Methods and Results: In the Syncope Study of Unselected Population in Malmö (SYSTEMA) cohort, we identified 396 patients (age range, 15-50 years) with either POTS (n = 113) or normal haemodynamic response during passive head-up-tilt test (n = 283). Blood samples were analyzed using antibody-based Proximity Extension Assay technique simultaneously measuring 57 inflammatory protein biomarkers. The discovery algorithm was a sequential two-step process of biomarker signature identification by supervised, multivariate, principal component analysis and verification by univariate ANOVA with Bonferroni correction. POTS patients were younger (26 vs. 31 years; p < 0.001) and there was no significant difference in sex distribution (74% vs. 67% females, p = 0.24). PCA and Bonferroni-adjusted ANOVA identified proconvertase furin as the most robust biomarker signature for POTS. Plasma level of proconvertase furin was lower (6.38 vs. 6.58 of normalized protein expression units (NPX); p < 0.001 in POTS, compared with the reference group. Proconvertase furin met Bonferroni-adjusted significance criteria in both uni- and multivariable regression analyses. Conclusion: Patients with POTS have lower plasma level of proconvertase furin compared with individuals with normal postural hemodynamic response. This finding suggests the presence of a specific autoimmune trait with disruption of immune peripheral tolerance in this hitherto unexplained condition. Further studies are needed for external validation of our results.

Postural Orthostatic Tachycardia Syndrome (POTS) in Denmark: Increasingly recognized or new epidemic?

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 ±â€¯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.

Syndromes of orthostatic intolerance and syncope in young adults.

OBJECTIVE: To explore the clinical and neuroendocrine characteristics of syndromes of orthostatic intolerance and syncope in young adults. METHODS: Two hundred and thirty-six patients aged 18-40 years with orthostatic intolerance and/or syncope were examined by head-up tilt test (HUT). Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal-endothelin-1 and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were analysed. Patients' history, haemodynamic parameters and plasma biomarkers were related to main diagnoses such as vasovagal syncope (VVS), postural tachycardia syndrome (POTS), orthostatic hypotension (OH) and negative HUT. RESULTS: No self-reported symptom of orthostatic intolerance was highly specific for any diagnosis. Patients with VVS (n=103) were more likely to be men (p=0.011) and had lower resting heart rate (HR; 66±11) compared with POTS (73±11; n=72; p=0.001) and negative HUT (74±11; n=39; p=0.001). Patients with POTS demonstrated greater rise in norepinephrine (p=0.008) and CT-proAVP (p=0.033) on standing compared with negative HUT, and lower resting MR-proANP compared with VVS (p=0.04) and OH (p=0.03). Patients with OH had lower resting renin (p=0.03). Subjects with a resting HR <70 and MR-proANP >45 pm/L had an OR of 3.99 (95 % CI 1.68 to 9.52; p=0.002) for VVS compared with subjects without any of these criteria; if male sex was added the OR was 21.8 (95% CI 3.99 to 119; p<0.001). CONCLUSIONS: Syndromes of orthostatic intolerance and syncope share many characteristics in younger persons. However, patients with VVS are more likely to be men, have lower HR and higher MR-proANP at rest compared with POTS, which might be taken into account at an early stage of evaluation.