Hyperadrenergic Postural Tachycardia Syndrome: Clinical Biomarkers and Response to Guanfacine
Open accessAbstract
BACKGROUND: A subset of patients with postural tachycardia syndrome (POTS) are thought to have a primary hyperadrenergic cause. We assessed clinical biomarkers to identify those that would benefit from sympatholytic therapy. METHODS: We measured sympathetic function (supine muscle sympathetic nerve activity, upright plasma norepinephrine, and blood pressure responses to the Valsalva maneuver) in 28 patients with POTS (phenotyping cohort) to identify clinical biomarkers that are associated with responsiveness to the central sympatholytic guanfacine in a separate uncontrolled treatment cohort of 38 patients that had received guanfacine clinically for suspected hyperadrenergic POTS (HyperPOTS). RESULTS: In the phenotyping cohort, an increase in diastolic blood pressure (DBP) >17 mm Hg during late phase 2 of the Valsalva maneuver identified patients with the highest quartile of resting muscle sympathetic nerve activity (HyperPOTS) with 71% sensitivity and 85% specificity. In the treatment cohort, patients with HyperPOTS, identified by this clinical biomarker, more often reported clinical improvement (85% versus 44% in nonhyperadrenergic; P =0.016), had better orthostatic tolerance (∆Orthostatic Hypotension Daily Activities Scale: −1.9±0.9 versus 0.1±0.5; P =0.032), and reported less chronic fatigue (∆PROMIS Fatigue Short Form 7a: −12.9±2.7 versus −2.2±2.2; P =0.005) in response to guanfacine. CONCLUSIONS: These results are consistent with the concept that POTS is caused by a central sympathetic activation in a subset of patients, which can be identified clinically by an exaggerated DBP increase during phase 2 of the Valsalva maneuver and improved by central sympatholytic therapy. These results support further clinical trials to determine the safety and efficacy of guanfacine in patients with POTS enriched for the presence of this clinical biomarker.
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TL;DR
In POTS, an exaggerated diastolic blood pressure rise during late phase 2 of the Valsalva maneuver (ΔDBP<sub>VM2</sub> >17 mmHg) identified a hyperadrenergic phenotype and predicted greater clinical improvement with guanfacine. The findings support central sympathetic activation in a subset of POTS patients and justify randomized trials of guanfacine enriched for this biomarker.
Key findings
- In the phenotyping cohort (n=28), ΔDBP<sub>VM2</sub> >17 mmHg identified patients in the highest quartile of resting MSNA with 71% sensitivity and 85% specificity (AUC 0.807 [0.603–1.000]; p=0.017).
- In the treatment cohort (n=38), the same ΔDBP<sub>VM2</sub> >17 mmHg cutoff identified guanfacine response with 72% sensitivity and 77% specificity (AUC 0.774 [0.627–0.920]; p=0.006); ΔDBP<sub>VM2</sub> correlated with PGIC improvement (r=−0.352, p=0.030).
- HyperPOTS patients more often reported clinical improvement on guanfacine (85% vs 44%; p=0.016), better orthostatic tolerance (ΔOHDAS −1.9±0.9 vs 0.1±0.5; p=0.032), and less chronic fatigue (ΔPROMIS F-SF −12.9±2.7 vs −2.2±2.2; p=0.005).
- High-MSNA patients had greater late phase 2 BP and ΔDBP<sub>VM2</sub> (21±4 vs 5±2 mmHg; p=0.002) and higher upright BP (122±8/76±5 vs 99±5/62±3 mmHg; p<0.05), but similar orthostatic tachycardia (34±8 vs 34±5 bpm; p=0.988).
Methods
- Protocol 1 phenotyped 28 POTS patients from the Vanderbilt Autonomic Dysfunction Center with supine MSNA, Valsalva maneuver, upright posture, and supine/upright plasma norepinephrine off autonomic medications; ROC analysis identified the ΔDBP<sub>VM2</sub> cutoff for high resting MSNA.
- Protocol 2 studied 38 adult POTS outpatients prescribed guanfacine for suspected hyperadrenergic POTS; an online REDCap survey and medical records assessed PGIC, hyperadrenergic episodes, OHDAS, COMPASS 31, and PROMIS F-SF, with patients categorized by ΔDBP<sub>VM2</sub> >17 mmHg.
- Analyses used t-tests or Mann–Whitney U tests, χ² or Fisher exact tests, ROC curves with Youden index, and two-tailed p<0.05.
Limitations
- Stated: Protocol 2 had selection bias because all patients were prescribed guanfacine for a presumed hyperadrenergic phenotype; the study was open-label, and a placebo-controlled randomized trial is needed to establish efficacy/safety and validate ΔDBP<sub>VM2</sub>.
- Stated: the >17 mmHg threshold prioritizes specificity (85%) over sensitivity (71%), may explain overlap in guanfacine responses, may miss patients who could still improve, and it is unknown whether it is superior to upright plasma norepinephrine; larger studies could refine criteria.
- Evident from the text: sample sizes were small (n=28 phenotyping; n=38 treatment; quartile groups n=7 each), the treatment cohort was uncontrolled and survey-based, and MCAD was not systematically investigated or excluded.
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Claims the paper makes
11 of 33 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Patients with POTS do not have an increased prevalence of anxiety disorders, including panic disorder, compared with the general population.
“Furthermore, formal assessment for psychiatric disorders has shown that patients with POTS do not have an increased prevalence of anxiety disorders, including panic disorder, compared with the general population.38”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Raj V, Haman KL, Raj SR, Byrne D, Blakely RD, Biaggioni I, Robertson D, Shelton RC. Psychiatric profile and attention deficits in postural tachycardia syndrome. J Neurol Neurosurg Psychiatry. 2009; 80: 339– 344. PMC2758320 18977825 source
- Findingown data
There were no differences in duration of guanfacine treatment between Hyper- and non-HyperPOTS patients.
“the duration of guanfacine treatment (Figure S3)”
Quote in the paperNot a substantial claim - Findingown data
Before guanfacine, Hyper- and non-HyperPOTS patients did not differ in chronic fatigue (PROMIS F-SF 71.6±1.6 vs 68.9±2.0; p=0.318).
“chronic fatigue (PROMIS F-SF [T-score] 71.6±1.6 vs. 68.9±2.0; p= 0.318. Figure 4D)”
Quote in the paperNot a substantial claim - Findingown data
Before guanfacine, Hyper- and non-HyperPOTS patients did not differ in burden of autonomic symptoms (COMPASS 31 56.7±4.7 vs 45.6±3.7; p=0.142).
“or the burden of autonomic symptoms (COMPASS 31 total score 56.7±4.7 vs. 45.6±3.7; p=0.142. Figure S2 and Table S3) before guanfacine treatment.”
Quote in the paperNot a substantial claim - Findingown data
In the treatment cohort, Hyper- and non-HyperPOTS patients had similar pre-treatment severity of hyperadrenergic episodes (3.5±0.2 vs 3.2±0.2; p=0.252).
“Hyper- and non-HyperPOTS patients had a similar pre-treatment severity (3.5±0.2 vs. 3.2±0.2 a.u.; p=0.252. Figure 4A)”
Quote in the paperNot a substantial claim
- Findingown data
In the phenotyping cohort, supine blood pressure was similar between low_MSNA and high_MSNA groups.
“Supine BP was also similar in both groups (Figure 2B and 2C. Table S1).”
Quote in the paperNot a substantial claim - Findingown data
In the phenotyping cohort, heart rate responses to the Valsalva maneuver were similar between low_MSNA and high_MSNA groups.
“HR responses to the VM were similar in both groups (Figure 2D and Table S1).”
Quote in the paperNot a substantial claim - Findingown data
In the phenotyping cohort, the high_MSNA group had significantly higher upright blood pressure than the low_MSNA group (122±8/76±5 vs 99±5/62±3 mmHg; p<0.05).
“However, the high_MSNA group had significantly higher upright BP (122±8/76±5 vs. 99±5/62±3 mmHg in the low_MSNA group; p<0.05 for comparisons of SBP and DBP. Figure 2B and 2C).”
Quote in the paperSubstantial claim - Findingown data
During guanfacine treatment, HyperPOTS patients had greater reduction in chronic fatigue (ΔPROMIS F-SF −12.9±2.7 vs −2.2±2.2; p=0.005).
“and reported less chronic fatigue (ΔPROMIS F-SF: −12.9±2.7 vs. −2.2±2.2; p=0.005) in response to guanfacine.”
- Also stated in: § Response to Guanfacine in POTS Patients with and without Hyperadrenergic Phenotype (Protocol 2, Treatment Cohort). · plain
“chronic fatigue (PROMIS F-SF [T-score] −12.9±2.7 vs. −2.2±2.2; p= 0.005. Figure 4D)”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical improvement reported by HyperPOTS patients during guanfacine treatment is attributable to guanfacine rather than to other factors such as placebo, concomitant treatments, or regression to the mean.
- Also stated in: § Response to Guanfacine in POTS Patients with and without Hyperadrenergic Phenotype (Protocol 2, Treatment Cohort). · plain
- Findingown data
During guanfacine treatment, HyperPOTS patients had greater improvement in burden of autonomic symptoms (COMPASS 31 −26.1±4.5 vs −4.4±7.1; p=0.029).
“and burden of autonomic symptoms (COMPASS 31 total score −26.1±4.5 vs. −4.4±7.1; p=0.029. Figure S2 and Table S3).”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical improvement reported by HyperPOTS patients during guanfacine treatment is attributable to guanfacine rather than to other factors such as placebo, concomitant treatments, or regression to the mean.
- Findingown data
There were no differences in dose of guanfacine between Hyper- and non-HyperPOTS patients (median 1 mg/d, range 0.5-2 mg in both groups).
“There were no differences in the dose of guanfacine between Hyper- and non-HyperPOTS patients (median 1 mg/d, range 0.5–2 mg in both groups)”
Quote in the paperNot a substantial claim - Findingown data
In the treatment cohort, supine and upright heart rates were similar between HyperPOTS and non-HyperPOTS groups.
“Supine and upright HRs were similar in both groups (Table S2).”
Quote in the paperNot a substantial claim - Findingown data
In the treatment cohort, Hyper- and non-HyperPOTS patients had similar pre-treatment frequency of hyperadrenergic episodes (3.4±0.1 vs 3.1±0.2; p=0.313).
“and frequency (3.4±0.1 vs. 3.1±0.2 a.u.; p=0.313. Figure 4B) of hyperadrenergic episodes.”
Quote in the paperNot a substantial claim - Findingown data
In the phenotyping cohort, the increase in blood pressure during late phase 2 in the high_MSNA group was preceded by higher MSNA spike rates during early phase 2 (81±9 vs 44±6 spikes/second; p<0.01).
“The increase in BP during late phase 2 in the high_MSNA group was preceded by higher MSNA spike rates during early phase 2 (81±9 vs. 44±6 spikes/second in the low_MSNA groups; p<0.01. Figure 3).”
Quote in the paperSubstantial claim - Findingown data
In the phenotyping cohort, the high_MSNA group had a significantly greater ΔDBPVM2 than the low_MSNA group (21±4 vs 5±2; p=0.002).
“Furthermore, the high_MSNA group had a significantly greater ΔDBPVM2 (21±4 vs. 5±2 in the low_MSNA group; p=0.002).”
Quote in the paperSubstantial claim - Findingown data
In the treatment cohort, Valsalva maneuver showed similar heart rate responses and VM ratios between HyperPOTS and non-HyperPOTS groups.
“The VM showed similar HR responses and VM ratios between patients with and without HyperPOTS.”
Quote in the paperNot a substantial claim - Findingown data
There were no differences in number of concomitant POTS medications added or stopped during guanfacine treatment (median 0, range −2 to 1 in both groups).
“or the number of concomitant POTS medications added or stopped during guanfacine treatment (median 0, range −2 to 1 in both groups).”
Quote in the paperNot a substantial claim - Findingown data
In the phenotyping cohort, supine MSNA showed a positive correlation with upright plasma norepinephrine (r2=0.38, p<0.001).
“Supine MSNA showed a positive correlation with upright NE (r2=0.38, p<0.001, Figure 1B)”
Quote in the paperSubstantial claim - Findingown data
During guanfacine treatment, only the HyperPOTS group had significant improvement in hyperadrenergic symptom severity (−1.3±0.2 vs −0.7±0.3; p=0.047).
“Only the HyperPOTS group had significant improvements in hyperadrenergic symptoms severity (−1.3± 0.2 vs. −0.7±0.3 in non-HyperPOTS; p= 0.047. Figure 4A)”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical improvement reported by HyperPOTS patients during guanfacine treatment is attributable to guanfacine rather than to other factors such as placebo, concomitant treatments, or regression to the mean.
- Findingown data
In the phenotyping cohort, a ΔDBPVM2 >17 mmHg identified high_MSNA patients with 71% sensitivity and 85% specificity (AUC 0.807 [0.603-1.000]; p=0.017).
“In the phenotyping cohort, an increase in diastolic blood pressure (DBP) >17 mmHg during late phase 2 of the VM identified patients with the highest quartile of resting MSNA (“HyperPOTS”) with 71% sensitivity and 85% specificity.”
- Also stated in: § Determination of the Pressor Response to Phase 2 of the VM as a Biomarker of HyperPOTS (Phenotyping and Treatment Cohorts) · plain
“We found that a ΔDBPVM2 >17 mmHg was a conservative cutoff value that identified high_MSNA patients with the highest specificity (85%) and 71% sensitivity (AUC 0.807 [0.603–1.000]; p=0.017.).”
Quote in the paperSubstantial claim - Also stated in: § Determination of the Pressor Response to Phase 2 of the VM as a Biomarker of HyperPOTS (Phenotyping and Treatment Cohorts) · plain
- Findingown data
In the treatment cohort, the HyperPOTS group had a greater blood pressure response to late phase 2 of the Valsalva maneuver than the non-HyperPOTS group (47±6/31±3 vs 18±3/9±1 mmHg; p<0.001).
“As expected, the HyperPOTS group had a greater BP response to late phase 2 of the VM compared to the non-HyperPOTS group (47±6/31±3 vs. 18±3/9±1 mmHg; p<0.001 for both comparisons of SBP and DBP, Table S2).”
Quote in the paperSubstantial claim - Findingown data
In the treatment cohort, a ΔDBPVM2 >17 mmHg identified response to guanfacine with 77% specificity and 72% sensitivity (AUC 0.774 [0.627-0.920]; p=0.006).
“The ROC analysis using PGIC also showed that a conservative cutoff of ΔDBPVM2 >17 mmHg identified a response to guanfacine with 77% specificity and 72% sensitivity (AUC 0.774 [0.627–0.920]; p=0.006).”
Quote in the paperSubstantial claim - Findingown data
In the phenotyping cohort, supine MSNA showed a borderline significant correlation with supine plasma norepinephrine (r2=0.14, p=0.054).
“and a borderline significant correlation with supine norepinephrine levels (r2=0.14, p=0.054).”
Quote in the paperNot a substantial claim - Findingown data
Before guanfacine, Hyper- and non-HyperPOTS patients did not differ in impact of POTS symptoms on daily upright activities (OHDAS 7.0±0.6 vs 6.0±0.5; p=0.127).
“Similarly, Hyper- and non-HyperPOTS patients did not differ in the impact of their POTS symptoms on daily upright activities (OHDAS mean score 7.0±0.6 vs. 6.0±0.5; p= 0.127. Figure 4C)”
Quote in the paperNot a substantial claim - Findingown data
In the phenotyping cohort, ΔDBPVM2 had a stronger correlation with supine MSNA (r2=0.28, p=0.005) than with upright plasma norepinephrine (r2=0.14, p=0.057).
“we found that ΔDBPVM2 (13±2 mm Hg, range 0 to 37, 95% CI 9 to 17) had a stronger correlation with supine MSNA (r2=0.28, p=0.005, Figure 1C) than with upright NE (r2=0.14, p=0.057, Figure 1D).”
Quote in the paperSubstantial claim - Findingown data
There were no differences in reasons for stopping treatment between Hyper- and non-HyperPOTS patients.
“or in the reasons for stopping treatment (Table 2).”
Quote in the paperNot a substantial claim - Findingown data
In the present study, there was no difference in the number of Hyper- and non-HyperPOTS patients with a possible diagnosis of MCAD (5 vs 8; p=0.506).
“In the present study, however, there was no difference in the number of Hyper- and non-HyperPOTS patients with a possible diagnosis of MCAD (5 vs. 8 patients, respectively; p=0.506), but this diagnosis was not systematically investigated or excluded.”
Quote in the paperNot a substantial claim - Findingown data
During guanfacine treatment, a greater percentage of HyperPOTS patients reported improvement in overall health (PGIC ≤3) than non-HyperPOTS (85% vs 44%; p=0.016).
“In the treatment cohort, HyperPOTS patients, identified by this clinical biomarker, more often reported clinical improvement (85% vs 44% in non-hyperadrenergic; p=0.016)”
- Also stated in: § Response to Guanfacine in POTS Patients with and without Hyperadrenergic Phenotype (Protocol 2, Treatment Cohort). · plain
“During guanfacine treatment, a greater percentage of HyperPOTS patients reported an improvement in their overall health (PGIC score ≤ 3) (17 [85%]) than non-HyperPOTS (8 [44%]; p=0.016, Figure S1B).”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical improvement reported by HyperPOTS patients during guanfacine treatment is attributable to guanfacine rather than to other factors such as placebo, concomitant treatments, or regression to the mean.
- Also stated in: § Response to Guanfacine in POTS Patients with and without Hyperadrenergic Phenotype (Protocol 2, Treatment Cohort). · plain
- Findingown data
There were no differences in number of concomitant POTS medications between Hyper- and non-HyperPOTS patients (median 1, range 0-3 in both groups).
“However, there were no differences in the number of concomitant POTS medications between Hyper- and non-HyperPOTS patients (median 1, range 0–3 in both groups; Figure S4)”
Quote in the paperNot a substantial claim - Findingown data
In the phenotyping cohort, the high_MSNA group had greater systolic and diastolic blood pressure during late phase 2 of the Valsalva maneuver than the low_MSNA group (126±11/84±6 vs 81±8/62±6 mmHg; p<0.05).
“The high_MSNA group, however, had greater SBP and DBP during late phase 2 compared to the low_MSNA group (126±11/84±6 vs. 81±8/62±6 mmHg, respectively; p<0.05 for comparisons of SBP and DBP; Figure 2E and 2F, Table S1).”
Quote in the paperSubstantial claim - Findingown data
At the time of survey, a similar proportion of Hyper- and non-HyperPOTS patients were still taking guanfacine (13 [65%] vs 12 [67%]; p=0.914).
“At the time of the survey, a similar proportion of Hyper- and non-HyperPOTS patients were still taking guanfacine (13 [65%] vs. 12 [67%]; p=0.914. Table 2).”
Quote in the paperNot a substantial claim - Findingown data
During guanfacine treatment, only the HyperPOTS group had significant improvement in hyperadrenergic symptom frequency (−1.4±0.2 vs −0.7±0.2; p=0.015).
“and frequency (−1.4± 0.2 vs. −0.7±0.2 in non-HyperPOTS; p= 0.015. Figure 4B)”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical improvement reported by HyperPOTS patients during guanfacine treatment is attributable to guanfacine rather than to other factors such as placebo, concomitant treatments, or regression to the mean.
- Findingown data
In the treatment cohort, ΔDBPVM2 was positively correlated with improvement of the PGIC score (r= −0.352, p=0.030).
“We found that ΔDBPVM2 was positively correlated with improvement of the PGIC score (i.e., a larger ΔDBPVM2 was associated with a greater perception of improvement in overall health; r= −0.352, p=0.030. Figure S1A).”
Quote in the paperSubstantial claim - Findingown data
During guanfacine treatment, HyperPOTS patients had greater improvement in impact of POTS symptoms on daily upright activities (ΔOHDAS −1.9±0.9 vs 0.1±0.5; p=0.032).
“had better orthostatic tolerance (ΔOHDAS: −1.9±0.9 vs. 0.1±0.5; p=0.032)”
- Also stated in: § Response to Guanfacine in POTS Patients with and without Hyperadrenergic Phenotype (Protocol 2, Treatment Cohort). · plain
“in the impact of POTS symptoms on daily upright activities (ΔOHDAS mean score −1.9± 0.9 vs. 0.1±0.5 in non-HyperPOTS; p=0.032. Figure 4C)”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical improvement reported by HyperPOTS patients during guanfacine treatment is attributable to guanfacine rather than to other factors such as placebo, concomitant treatments, or regression to the mean.
- Also stated in: § Response to Guanfacine in POTS Patients with and without Hyperadrenergic Phenotype (Protocol 2, Treatment Cohort). · plain
- Findingown data
In the treatment cohort, orthostatic changes in heart rate and blood pressure were similar between HyperPOTS and non-HyperPOTS groups.
“The orthostatic changes in HR and BP were similar in both groups.”
Quote in the paperNot a substantial claim - Findingown data
We observed a wide range of resting supine MSNA in POTS.
“Similarly to other studies, we observed a wide range of resting supine MSNA in POTS, but our results suggest that high resting MSNA identifies POTS patients with a hyperadrenergic phenotype.”
Quote in the paperSubstantial claim - Findingnone given
The clinical biomarker ΔDBPVM2 uses a conservative threshold of >17 mmHg to ensure high specificity (85%) over sensitivity (71%).
“The clinical biomarker we developed to identify HyperPOTS patients, ΔDBPVM2, uses a conservative threshold of >17 mmHg to ensure high specificity (85%) over sensitivity (71%).”
Quote in the paperSubstantial claim - Findingown data
The clinical biomarker (DBP increase >17 mmHg during VM phase 2) correlated with a beneficial response to treatment with the central sympatholytic guanfacine.
“More importantly, this clinical biomarker correlated with a beneficial response to treatment with the central sympatholytic guanfacine.”
Quote in the paperSubstantial claim - Findingown data
The identical DBP threshold (>17 mmHg) resulted from ROC analysis using MSNA characteristics and, independently, using patients' reported responsiveness to guanfacine (PGIC).
“It is reassuring that the identical DBP threshold (>17 mmHg) resulted from ROC analysis using MSNA characteristics and, independently, using patients’ reported responsiveness to guanfacine (PGIC).”
Quote in the paperSubstantial claim - Findingown data
The HyperPOTS phenotype can be documented by direct measurements of resting sympathetic activity.
“This can be documented by direct measurements of resting sympathetic activity, and this HyperPOTS phenotype can be identified clinically by an exaggerated increase in DBP during phase 2 of the VM.”
Quote in the paperSubstantial claim - Findingown data
The DBP increase during phase 2 of the Valsalva maneuver correlated with a greater improvement in symptoms of orthostatic intolerance and fatigue in response to guanfacine.
“Importantly, this parameter correlated with a greater improvement in symptoms of orthostatic intolerance and fatigue in response to the central sympatholytic guanfacine.”
Quote in the paperSubstantial claim - Findingown data
POTS patients with high resting MSNA have significantly higher upright BPs compared to those with the lowest MSNA despite having similar severity of orthostatic tachycardia.
“These patients have significantly higher upright BPs compared to those with the lowest MSNA despite having similar severity of orthostatic tachycardia.”
Quote in the paperSubstantial claim - Findingown data
There was a lack of association between the magnitude of the upright heart rate and the HyperPOTS phenotype.
“Notably, there was a lack of association between the magnitude of the upright heart rate and the HyperPOTS phenotype.”
Quote in the paperSubstantial claim - Findingown data
POTS patients with high resting MSNA have an exaggerated sympathetic activation in response to the Valsalva maneuver.
“Furthermore, these patients have an exaggerated sympathetic activation in response to the VM, and this is translated as a greater increase in DBP, reflecting sympathetic-mediated vasoconstriction.”
Quote in the paperSubstantial claim - Findingown data
The HyperPOTS phenotype can be identified clinically by an exaggerated increase in DBP during phase 2 of the Valsalva maneuver.
“and this HyperPOTS phenotype can be identified clinically by an exaggerated increase in DBP during phase 2 of the VM.”
Quote in the paperSubstantial claim - Findingown data
An increase in DBP >17 mmHg during phase 2 of the Valsalva maneuver (late-early) is a useful clinical biomarker of HyperPOTS.
“We found that an increase in DBP>17 mmHg during phase 2 of the VM (late-early) to be a useful clinical biomarker of HyperPOTS.”
Quote in the paperSubstantial claim- Rests on an assumption: The DBP response to the Valsalva maneuver is more readily available than direct measurement of MSNA.
- Findingreasoning
The exaggerated sympathetic activation in response to the Valsalva maneuver in these patients is translated as a greater increase in DBP.
“Furthermore, these patients have an exaggerated sympathetic activation in response to the VM, and this is translated as a greater increase in DBP, reflecting sympathetic-mediated vasoconstriction.”
Quote in the paperSubstantial claim - Findingown data
High resting MSNA identifies POTS patients with a hyperadrenergic phenotype.
“our results suggest that high resting MSNA identifies POTS patients with a hyperadrenergic phenotype.”
Quote in the paperSubstantial claim - Premisereasoning
Management approaches for primary hyperadrenergic POTS (e.g., central sympatholytics) would be contraindicated in neuropathic POTS patients who depend on compensatory sympathetic activation to maintain upright blood pressure.
“The ability to identify which patients have a hyperadrenergic phenotype has therapeutic implications because management approaches that could be applied to primary hyperadrenergic patients (e.g., central sympatholytics) would be contraindicated in “neuropathic” patients who depend on compensatory sympathetic activation to maintain upright BP.”
- Also stated in: § Discussion · hedged
“In particular, therapies aimed at targeting sympathetic activation, e.g., central sympatholytics, would be expected to worsen patients in whom the orthostatic tachycardia is an adequate compensatory mechanism to maintain upright BP, e.g., due to volume depletion.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Premisecitation
Patients with hyperadrenergic POTS tend to have exaggerated pressor responses to the Valsalva maneuver.
“We and others have observed that these patients tend to have exaggerated pressor responses to the Valsalva maneuver (VM),12”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Shibao C, Arzubiaga C, Roberts LJ, Raj S, Black B, Harris P, Biaggioni I. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005; 45: 385– 390. 15710782 source
- Interpretationcitation
The improvement in symptoms in HyperPOTS patients was clinically meaningful because these changes were larger than the minimal important differences previously reported.
“This improvement in symptoms in HyperPOTS patients was not only statistically significant but also clinically meaningful given that these changes were larger than the minimal important differences previously reported (see Supplemental methods).”
Quote in the paperSubstantial claim - Interpretationreasoning
A subset of patients with POTS has a central sympathetic activation as their underlying pathophysiology.
“Our results are consistent with the concept that a subset of patients with POTS has a central sympathetic activation as their underlying pathophysiology.”
Quote in the paperSubstantial claim - Interpretationreasoning
Patients who do not meet the strict DBP criteria may still improve on guanfacine.
“Therefore, patients who do not meet our strict DBP criteria may still improve on guanfacine.”
Quote in the paperSubstantial claim - Interpretationreasoning
The greater increase in DBP reflects sympathetic-mediated vasoconstriction.
“and this is translated as a greater increase in DBP, reflecting sympathetic-mediated vasoconstriction.”
Quote in the paperSubstantial claim - Interpretationreasoning
An exaggerated increase in MSNA triggered by standing will likely have the same limitations as upright norepinephrine in differentiating between a primary hyperadrenergic state or a compensatory response.
“It is likely that an exaggerated increase in MSNA triggered by standing will have the same limitations as upright norepinephrine in differentiating between a primary hyperadrenergic state or a compensatory response to e,g., volume depletion.”
Quote in the paperSubstantial claim - Interpretationreasoning
The DBP response to the Valsalva maneuver is the clinical reflection of sympathetic vasoconstriction.
“The DBP response to the VM is more readily available than direct measurement of MSNA, and it’s the clinical reflection of sympathetic vasoconstriction.”
Quote in the paperSubstantial claim - Premisecitation
Patients with documented panic disorders have normal resting MSNA levels.
“Importantly, patients with documented panic disorders have normal resting MSNA levels,39 an observation that argues against a panic disorder underlying the hyperadrenergic state in our HyperPOTS patients.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [39] Wilkinson DJ, Thompson JM, Lambert GW, Jennings GL, Schwarz RG, Jefferys D, Turner AG, Esler MD. Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks. Arch Gen Psychiatry. 1998; 55: 511– 520. 9633669 source
- Interpretationreasoning
The correlation between the clinical biomarker and guanfacine response is prima facie evidence that these patients have central sympathetic activation driving their POTS.
“We believe this is prima facie evidence that these patients have central sympathetic activation driving their POTS because patients in whom sympathetic activation is a compensatory mechanism needed to maintain upright BP would be expected to get worse if treated with a central sympatholytic.”
Quote in the paperSubstantial claim- Rests on an assumption: In patients whose sympathetic activation is a compensatory mechanism needed to maintain upright BP, treatment with a central sympatholytic would be expected to worsen their condition.
- Interpretationown data
Although orthostatic tachycardia reflects sympathetic activation in POTS, it does not inform whether this activation is due to central sympathetic overactivity or an adequate compensatory reflex response.
“Thus, although orthostatic tachycardia reflects sympathetic activation in POTS, it does not inform us whether this activation is due to a central sympathetic overactivity (as in HyperPOTS) or an adequate compensatory reflex response (e.g., to volume depletion).”
Quote in the paperSubstantial claim- Rests on an assumption: Orthostatic tachycardia in POTS reflects sympathetic activation.
- Interpretationcitation
The normal resting MSNA levels in panic disorder argue against a panic disorder underlying the hyperadrenergic state in HyperPOTS patients.
“Importantly, patients with documented panic disorders have normal resting MSNA levels,39 an observation that argues against a panic disorder underlying the hyperadrenergic state in our HyperPOTS patients.”
Quote in the paperSubstantial claim - Interpretationreasoning
The conservative threshold may explain why some overlap in individual responses to guanfacine was observed between groups, with patients who did not meet the strict diagnostic criteria still reporting clinical benefit in the global impression of change score after guanfacine treatment.
“This may explain why we observed some overlap in the individual responses to guanfacine between groups, with patients who did not meet our strict diagnostic criteria still reporting clinical benefit in the global impression of change score after guanfacine treatment.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 13
- May combine two claims. 20
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMore commonly proposed causes of POTS include partial peripheral neuropathy, a deficit in blood volume, abnormalities in the renin-angiotensin-aldosterone system, physical deconditioning, autoantibodies targeting peripheral adrenergic receptors, and a hyperadrenergic state resulting from central activation of the sympathetic nervous system.
“More commonly proposed causes include partial peripheral neuropathy (“neuropathic POTS”),19 a deficit in blood volume, abnormalities in the renin-angiotensin-aldosterone system (RAAS)20, physical deconditioning,10 autoantibodies targeting peripheral adrenergic receptors21 and a hyperadrenergic state resulting from central activation of the sympathetic nervous system (“HyperPOTS”).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [19] Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, Biaggioni I, Ertl A, Black B, Robertson D. The neuropathic postural tachycardia syndrome. N Engl J Med. 2000; 343: 1008– 1014. 11018167 source
- cites [20] Raj SR, Biaggioni I, Yamhure PC, Black BK, Paranjape SY, Byrne DW, Robertson D. Renin-Aldosterone Paradox and Perturbed Blood Volume Regulation Underlying Postural Tachycardia Syndrome. Circulation. 2005; 111: 1574– 1582. 15781744 source
- cites [10] Fu Q, VanGundy TB, Galbreath MM, Shibata S, Jain M, Hastings JL, Bhella PS, Levine BD. Cardiac Origins of the Postural Orthostatic Tachycardia Syndrome. Journal of the American College of Cardiology. 2010; 55: 2858– 2868. PMC2914315 20579544 source
May combine two claims.
PremisecitationPlasma NE >600 pg/ml has been documented in healthy subjects with volume depletion, in patients with diabetic neuropathy, and in patients with neuropathic orthostatic hypotension.
“Indeed, plasma NE >600 pg/ml has been documented in healthy subjects with volume depletion,13 in patients with diabetic neuropathy,25 and even in patients with neuropathic orthostatic hypotension.26”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [13] Garland EM, Gamboa A, Nwazue VC, Celedonio JE, Paranjape SY, Black BK, Okamoto LE, Shibao CA, Biaggioni I, Robertson D, Diedrich A, Dupont WD, Raj SR. Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome. Journal of the American College of Cardiology. 2021; 77: 2174– 2184. PMC8103825 33926653 source
The Results (Comparison of Low Salt Diet Response between POTS and Healthy Controls; page unavailable) report standing plasma norepinephrine of 520 (391–693) pg/mL in healthy controls on a low-salt diet, documenting values above 600 pg/mL. But the Results (Comparison between HS and LS diets response in healthy controls; page unavailable) say their blood volumes on that diet were not significantly different from expected volumes, so the paper does not establish that those controls were volume-depleted. The other patient groups have separate citations in the citing sentence and are not attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [25] Jacob G, Costa F, Robertson D, Biaggioni I. Diabetic autonomic neuropathy. Spectrum of disease and treatment. Clin Auton Res. 1996; 296.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [26] Mar PL, Shibao CA, Garland EM, Black BK, Biaggioni I, Diedrich A, Paranjape SY, Robertson D, Raj SR. Neurogenic hyperadrenergic orthostatic hypotension: a newly recognized variant of orthostatic hypotension in older adults with elevated norepinephrine (noradrenaline). Clin Sci (Lond). 2015; 129: 107– 116. PMC4417057 25706983 source
Citation 26 attaches to the final clause, not the separately cited claims about volume depletion or diabetic neuropathy. The Results (Stand Test with Catecholamines; page not provided) document upright plasma NE above 600 pg/mL in patients with neurogenic orthostatic hypotension. The paper does not identify those patients specifically as having neuropathic orthostatic hypotension, so the narrower patient description is not established by our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
PremisecitationAn upright plasma NE ≥600 pg/mL is the criterion most often used to define hyperadrenergic POTS, and this threshold has been adapted in recent expert consensus statements.
“An upright plasma NE ≥600 pg/mL is the criterion most often used to define hyperadrenergic POTS,4–6 and this threshold has been adapted in recent expert consensus statements.7,8”
Quote in the paperSubstantial claim2 of 5 sources checked- cites [4] Jordan J, Shannon JR, Diedrich A, Black BK, Robertson D. Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity. Hypertension. 2002; 39: 173– 178. 11799098 source
- cites [5] Zhang Q, Chen X, Li J, Du J. Clinical features of hyperadrenergic postural tachycardia syndrome in children. Pediatr Int. 2014; 56: 813– 816. 24862636 source
- cites [6] Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP. Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience. Cardiol J. 2011; 19: 527– 531. 21947988 source
- cites [7] Raj SR, Guzman JC, Harvey P, Richer L, Schondorf R, Seifer C, Thibodeau-Jarry N, Sheldon RS. Canadian Cardiovascular Society Position Statement on Postural Orthostatic Tachycardia Syndrome (POTS) and Related Disorders of Chronic Orthostatic Intolerance. Can J Cardiol. 2020; 36: 357– 372. 32145864 source
- cites [8] Sheldon RS, Grubb BP, Olshansky B, Shen W-K, Calkins H, Brignole M, Raj SR, Krahn AD, Morillo CA, Stewart JM, Sutton R, Sandroni P, Friday KJ, Hachul DT, Cohen MI, Lau DH, Mayuga KA, Moak JP, Sandhu RK, Kanjwal K. 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope. Heart Rhythm. 2015; 12: e41– e63. PMC5267948 25980576 source
May combine two claims.
PremisecitationOrthostatic tachycardia in POTS is due to sympathetic activation, as it is associated with elevated plasma norepinephrine and is blunted by low doses of beta-blockers.
“This orthostatic tachycardia is due to sympathetic activation, given that it is associated with a significant elevation in plasma norepinephrine and is blunted by even low doses of beta-blockers.2”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [2] Raj SR, Black BK, Biaggioni I, Paranjape SY, Ramirez M, Dupont WD, Robertson D. Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less Is More. Circulation. 2009; 120: 725– 734. PMC2758650 19687359 source
The Results (Patient Characteristics) report a significant rise in plasma norepinephrine on standing, and the Discussion (Clinical Summary) reports that low-dose propranolol reduced orthostatic tachycardia. The Introduction says many patients have increased sympathetic tone, but the paper does not establish that sympathetic activation is the cause of orthostatic tachycardia in POTS generally; that causal wording is stronger than its evidence. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA non-specific anxiolytic effect of guanfacine cannot be excluded.
“A similar clinical picture can be seen in panic attacks, and we cannot exclude a non-specific anxiolytic effect of guanfacine, which has been observed in children and adolescents36 and adults with anxiety complicating cardiac surgery.37”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [36] Strawn JR, Compton SN, Robertson B, Albano AM, Hamdani M, Rynn MA. Extended Release Guanfacine in Pediatric Anxiety Disorders: A Pilot, Randomized, Placebo-Controlled Trial. J Child Adolesc Psychopharmacol. 2017; 27: 29– 37. PMC5695796 28165762 source
- cites [37] Srour H, Pandya K, Flannery A, Hatton K. Enteral Guanfacine to Treat Severe Anxiety and Agitation Complicating Critical Care After Cardiac Surgery. Semin Cardiothorac Vasc Anesth. 2018; 22: 403– 406. 29619866 source
May combine two claims.
PremisecitationGuanfacine has fewer CNS adverse effects than clonidine, such as sedation, headache, orthostatic hypotension and impotence, and a lower incidence of withdrawal symptoms such as high BP, headache, tremor, restlessness, and nausea (3% vs. 50-80% with clonidine).
“Also, guanfacine has fewer CNS adverse effects than clonidine, such as sedation, headache, orthostatic hypotension and impotence,42,43 and a lower incidence of withdrawal symptoms such as high BP, headache, tremor, restlessness, and nausea (3% vs. 50–80% with clonidine).42,44–47”
Quote in the paperSubstantial claim1 of 6 sources checked- cites [42] Sorkin EM, Heel RC. Guanfacine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension. Drugs. 1986; 31: 301– 336. 3519177 source
- cites [43] Newcorn JH, Schulz K, Harrison M, DeBellis MD, Udarbe JK, Halperin JM. Alpha 2 adrenergic agonists. Neurochemistry, efficacy, and clinical guidelines for use in children. Pediatr Clin North Am. 1998; 45: 1099– 1022, viii. 9884677 source
- cites [44] Cornish LA. Guanfacine hydrochloride: a centrally acting antihypertensive agent. Clin Pharm. 1988; 7: 187– 197. 3281788
- cites [45] Wilson MF, Haring O, Lewin A, Bedsole G, Stepansky W, Fillingim J, Hall D, Roginsky M, McMahon FG, Jagger P. Comparison of guanfacine versus clonidine for efficacy, safety and occurrence of withdrawal syndrome in step-2 treatment of mild to moderate essential hypertension. Am J Cardiol. 1986; 57: 43E– 49E. 3513530 source
- cites [46] Van Zwieten PA, Thoolen MJ, Timmermans PB. The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine. Hypertension [Internet]. 1984 [ cited 2023 Sep 18]; 6. Available from: https://www.ahajournals.org/doi/10.1161/01.HYP.6.5_Pt_2.II28 6094346 source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [47]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Findingown dataIn the phenotyping cohort, supine and upright heart rates were similar between low_MSNA and high_MSNA groups, with no difference in orthostatic tachycardia (34±8 vs 34±5 bpm; p=0.988).
“Supine and upright HR were similar in both MSNA groups (Figure 2A and Table S1), with no difference in orthostatic tachycardia (low_MSNA: 34±8 vs. high_MSNA: 34±5 bpm; p=0.988).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn the phenotyping cohort, blood pressure increased on standing in the high_MSNA group and decreased in the low_MSNA group (5±5/6±3 vs −5±3/−1±2 mmHg), but the differences in orthostatic changes between groups did not reach statistical significance (p=0.117 and p=0.070).
“Thus, BP increased on standing (i.e., orthostatic change) in the high_MSNA group and decreased in the low_MSNA group (5±5/6±3 vs. −5±3/−1±2 mmHg in the low_MSNA group), but the differences in the orthostatic changes between groups did not reach statistical significance (p=0.117 and p=0.070 for comparisons of SBP and DBP).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn the treatment cohort, supine and upright blood pressures tended to be higher in HyperPOTS patients, but only supine systolic blood pressure was statistically significant.
“Supine and upright BPs, on the other hand, tended to be higher in the HyperPOTS patients, but only supine SBP was statistically significant.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataBeta-blockers were taken by a similar number of HyperPOTS and non-HyperPOTS patients (10 vs 7; p=0.492).
“Beta-blockers were the most common concomitant medication for POTS and were taken by a similar number of patients in both groups (10 HyperPOTS and 7 non-HyperPOTS patients; p=0.492).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataBefore guanfacine treatment, all patients in the treatment cohort reported spontaneous hyperadrenergic episodes that felt like "adrenaline rushes" associated with facial flushing, an increase in BP and HR, and extreme and prolonged tiredness after an episode.
“Before guanfacine treatment, all patients reported spontaneous hyperadrenergic episodes that felt like “adrenaline rushes” associated with facial flushing, an increase in BP and HR, and feeling extreme and prolonged tiredness after an episode.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataOf all participants, 28 (74%) took guanfacine for >1 month and 10 (26%) between 1-4 weeks.
“Of all participants (n=38), 28 (74%) took guanfacine for >1 month and 10 (26%) between 1–4 weeks.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingnone givenMCAD was suspected in a minority of patients in our cohort.
“MCAD was suspected in a minority of patients in our cohort.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPatients in the highest and lower quartiles of MSNA had indistinguishable orthostatic tachycardia and identical HR changes to the Valsalva maneuver.
“Patients in the highest and lower quartiles of MSNA had indistinguishable orthostatic tachycardia and identical HR changes to the VM (Figure 2 and Table S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDespite selection bias and the open-label nature of the study, only the group of patients that met the clinical biomarker of HyperPOTS had a significant improvement on guanfacine, even though all were treated with this medication because of an apparent hyperadrenergic clinical picture.
“However, despite this and the open-label nature of our study, our results are encouraging in that only the group of patients that met our clinical biomarker of HyperPOTS had a significant improvement on guanfacine even though all were treated with this medication because of an apparent hyperadrenergic clinical picture.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBoth supine MSNA and self-reported improvement to guanfacine (PGIC score) independently identified ΔDBPVM2 as a clinical biomarker of the HyperPOTS phenotype.
“Thus, both supine MSNA and self-reported improvement to treatment with the central sympatholytic guanfacine (PGIC score) independently identified ΔDBPVM2 as a clinical biomarker of the HyperPOTS phenotype.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataIn the treatment cohort, HyperPOTS and non-HyperPOTS groups had similar age, BMI, and duration of POTS.
“Both groups had similar age, BMI, and duration of POTS (estimated from diagnosis; Table 2);”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationA high plasma norepinephrine could be due not only to a primary hyperadrenergic state but could also reflect a compensatory sympathetic activation secondary to a partial neuropathy.
“but cautioned that a high plasma norepinephrine could be due not only to a primary hyperadrenergic state but could also reflect a compensatory sympathetic activation secondary to a partial neuropathy,9 a concern shared by others.24”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [9] Jacob G, Robertson D, Mosqueda-Garcia R, Ertl AC, Robertson RM, Biaggioni I. Hypovolemia in Syncope and Orthostatic Intolerance Role of the Renin-Angiotensin System. The American Journal of Medicine. 1997; 103: 128– 133. 9274896 source
- cites [24] Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology. 1993; 43: 132– 137. 8423877 source
Classified as probably not a substantial claim.
PremisereasoningBlood pressure recovers during late Phase 2 of the Valsalva maneuver because of sympathetic-mediated vasoconstriction.
“Blood pressure recovers because of sympathetic-mediated vasoconstriction (late Phase 2).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenThe increase in intrathoracic pressure induced by the Valsalva maneuver leads to a reduction in venous return, stroke volume, and an initial decrease in blood pressure (early Phase 2), triggering sympathetic activation in ways analogous to upright posture.
“The increase in intrathoracic pressure induced by the VM leads to a reduction in venous return, stroke volume, and an initial decrease in blood pressure (early Phase 2), triggering sympathetic activation in ways analogous to upright posture.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThese hyperadrenergic episodes resemble those seen in patients with mast cell activation disorders (MCAD).
“These episodes resemble those seen in patients with mast cell activation disorders (MCAD). Indeed, we have previously reported the association of MCAD and POTS in patients with a hyperadrenergic clinical phenotype responsive to central sympatholytics.12”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Shibao C, Arzubiaga C, Roberts LJ, Raj S, Black B, Harris P, Biaggioni I. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005; 45: 385– 390. 15710782 source
May combine two claims.
Interpretationown dataThe results are consistent with the concept that POTS is caused by central sympathetic activation in a subset of patients, which can be identified clinically by an exaggerated DBP increase during phase 2 of the Valsalva maneuver and improved by central sympatholytic therapy.
“These results are consistent with the concept that POTS is caused by a central sympathetic activation in a subset of patients, which can be identified clinically by an exaggerated DBP increase during phase 2 of the Valsalva maneuver and improved by central sympatholytic therapy.”
- Also stated in: § Discussion · plain
“Taken together, our results are consistent with the concept that POTS is caused by a central sympathetic activation in a subset of patients, which can be identified clinically by an exaggerated DBP increase during phase 2 of the Valsalva maneuver and improved by central sympatholytic therapy.”
Quote in the paperSubstantial claim- Rests on an assumption: Clinical improvement reported by HyperPOTS patients during guanfacine treatment is attributable to guanfacine rather than to other factors such as placebo, concomitant treatments, or regression to the mean.
- Also stated in: § Discussion · plain
May combine two claims.
PremisecitationUpright plasma NE ≥600 pg/mL is a useful biomarker because it identifies patients who respond better to beta blockers.
“It is a useful biomarker in that it identifies patients who respond better to beta blockers.11”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Thieben MJ, Sandroni P, Sletten DM, Benrud-Larson LM, Fealey RD, Vernino S, Lennon VA, Shen W-K, Low PA. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc. 2007; 82: 308– 313. 17352367 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGaffney et al. used clonidine to treat patients with mitral valve prolapse syndrome and hyperdynamic circulatory state with orthostatic tachycardia, likely a condition similar to POTS.
“Gaffney et al. used clonidine to treat patients with mitral valve prolapse syndrome and hyperdynamic circulatory state with orthostatic tachycardia, likely a condition similar to POTS.40”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Gaffney FA, Lane LB, Pettinger W, Blomqvist CG. Effects of long-term clonidine administration on the hemodynamic and neuroendocrine postural responses of patients with dysautonomia. Chest. 1983; 83: 436– 438. 6295714 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenPatients were referred to us after having tried multiple unsuccessful therapies.
“Furthermore, patients were referred to us after having tried multiple unsuccessful therapies.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationClinically indistinguishable hyperadrenergic episodes were seen in POTS patients without MCAD and are also seen in patients with pseudopheochromocytoma.
“Clinically indistinguishable hyperadrenergic episodes were seen in POTS patients without MCAD12 and are also seen in patients with pseudopheochromocytoma.34,35”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [12] Shibao C, Arzubiaga C, Roberts LJ, Raj S, Black B, Harris P, Biaggioni I. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005; 45: 385– 390. 15710782 source
- cites [34] Kuchel O. Pseudopheochromocytoma. Hypertension. 1985; 7: 151– 158. 3980057
Not checked in the free run.
- cites [35] Mann SJ, Solanki KV. Clarifying the Cause and Treatment of Paroxysmal Hypertension (Pseudopheochromocytoma). Curr Hypertens Rep. 2022; 24: 353– 359. 35666406 source
May combine two claims.
Study design and conductreasoningAll patients included in Protocol 2 were prescribed guanfacine for a presumed hyperadrenergic phenotype, therefore introducing a selection bias.
“All patients included in Protocol 2 were prescribed guanfacine for a presumed hyperadrenergic phenotype (see Methods), therefore introducing a selection bias.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSpontaneous hyperadrenergic episodes with flushing, hypertension, and tachycardia are associated with MCAD in patients with POTS.
“We have previously reported that spontaneous hyperadrenergic episodes with flushing, hypertension, and tachycardia are associated with MCAD in patients with POTS.12”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Shibao C, Arzubiaga C, Roberts LJ, Raj S, Black B, Harris P, Biaggioni I. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005; 45: 385– 390. 15710782 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationWe previously used methyldopa in the treatment of POTS associated with mast cell activation disorders that have a similar hyperadrenergic phenotype.
“We previously used methyldopa in the treatment of POTS associated with mast cell activation disorders that have a similar hyperadrenergic phenotype.12”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Shibao C, Arzubiaga C, Roberts LJ, Raj S, Black B, Harris P, Biaggioni I. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005; 45: 385– 390. 15710782 source
The paper relies on this without support.
There is no agreement about the criteria used to identify HyperPOTS patients.
“There is, however, no agreement about the criteria used to identify them.”
The paper relies on this without support.
Clinical improvement reported by HyperPOTS patients during guanfacine treatment is attributable to guanfacine rather than to other factors such as placebo, concomitant treatments, or regression to the mean.
“In the treatment cohort, HyperPOTS patients, identified by this clinical biomarker, more often reported clinical improvement (85% vs 44% in non-hyperadrenergic; p=0.016), had better orthostatic tolerance (ΔOHDAS: −1.9±0.9 vs. 0.1±0.5; p=0.032) and reported less chronic fatigue (ΔPROMIS F-SF: −12.9±2.7 vs. −2.2±2.2; p=0.005) in response to guanfacine.”
The paper relies on this without support.
In patients whose sympathetic activation is a compensatory mechanism needed to maintain upright BP, treatment with a central sympatholytic would be expected to worsen their condition.
“because patients in whom sympathetic activation is a compensatory mechanism needed to maintain upright BP would be expected to get worse if treated with a central sympatholytic.”
The paper relies on this without support.
Orthostatic tachycardia in POTS reflects sympathetic activation.
“although orthostatic tachycardia reflects sympathetic activation in POTS”
The paper relies on this without support.
Clonidine has a short half-life, and its initial sympathetic inhibition is followed by rebound sympathetic activation.
“We used guanfacine instead of clonidine because the latter has a short half-life, and the initial sympathetic inhibition is followed by rebound sympathetic activation.”
The paper relies on this without support.
The DBP response to the Valsalva maneuver is more readily available than direct measurement of MSNA.
“The DBP response to the VM is more readily available than direct measurement of MSNA”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Reported guanfacine-response sensitivity conflicts with responder counts
MinorAt the >17 mmHg cutoff, 17 HyperPOTS patients and 8 non-HyperPOTS patients reported improvement. The cutoff therefore identified 17 of 25 responders, giving 68% sensitivity, not the reported 72%.
“The ROC analysis using PGIC also showed that a conservative cutoff of ΔDBPVM2 >17 mmHg identified a response to guanfacine with 77% specificity and 72% sensitivity (AUC 0.774 [0.627–0.920]; p=0.006).”
“During guanfacine treatment, a greater percentage of HyperPOTS patients reported an improvement in their overall health (PGIC score ≤ 3) (17 [85%]) than non-HyperPOTS (8 [44%]; p=0.016, Figure S1B).”
Cites
Freeman, R., Wieling, W., Axelrod, F. B., Benditt, D. G., Benarroch, E., Biaggioni, I., Cheshire, W. P., Chelimsky, T., Cortelli, P., Gibbons, C. H., et al. (2011) · Autonomic Neuroscience · doi:10.1016/j.autneu.2011.02.004 · Cited by 1,243 · see citing works
Self-citationSheldon, R. S., Grubb, B. P., Olshansky, B., Shen, W.-K., Calkins, H., Brignole, M., Raj, S. R., Krahn, A. D., Morillo, C. A., Stewart, J. M., et al. (2015) · Heart Rhythm · doi:10.1016/j.hrthm.2015.03.029 · Cited by 1,013 · cited 2× · see citing works
“7,8 It is a useful biomarker in that it identifies patients who respond better to beta-blockers.”
COMPASS 31: a refined and abbreviated composite autonomic symptom score
Sletten, D. M., Suarez, G. A., Low, P. A., Mandrekar, J., & Singer, W. (2012) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2012.10.013 · Cited by 741 · see citing works
General Characteristics of Sympathetic Activity in Human Skin Nerves
Hagbarth, K. E., Hallin, R. G., Hongell, A., Torebjörk, H. E., & Wallin, B. G. (1972) · Acta Physiologica Scandinavica · doi:10.1111/j.1748-1716.1972.tb05167.x · Cited by 689 · see citing works
Idiopathic postural orthostatic tachycardia syndrome: An attenuated form of acute pandysautonomia?
Schondorf, R., & Low, P. A. (1993) · Neurology · doi:10.1212/wnl.43.1_part_1.132 · Cited by 548 · see citing works
Postural orthostatic tachycardia syndrome: the Mayo clinic experience
Thieben, M. J., Sandroni, P., Sletten, D. M., Benrud-Larson, L. M., Fealey, R. D., Vernino, S., Low, P. A., Lennon, V. A., & Shen, W.-K. (2007) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(11)61027-6 · Cited by 516 · cited 2× · see citing works
“11 We and others have observed that these patients tend to have exaggerated pressor responses to the Valsalva maneuver (VM), 12 which is a readily available measurement compared with MSNA or plasma catecholamines.”
Representativeness of the Patient-Reported Outcomes Measurement Information System Internet panel
Liu, H., Cella, D. F., Gershon, R. C., Shen, J., Morales, L. S., Riley, W. T., & Hays, R. D. (2010) · Journal of Clinical Epidemiology · doi:10.1016/j.jclinepi.2009.11.021 · Cited by 447 · see citing works
The neuropathic postural tachycardia syndrome
Jacob, G., Costa, F., Shannon, J. R., Robertson, R. M., Wathen, M., Stein, M., Biaggioni, I., Ertl, A., Black, B., & Robertson, D. (2000) · New England Journal of Medicine · doi:10.1056/nejm200010053431404 · Cited by 398 · cited 10× · see citing works
“An upright plasma NE ≥ 600 pg/mL is the criterion most often used to define hyperadrenergic POTS, 4–6 and this threshold has been adapted in recent expert consensus statements.”
InfluentialSelf-citationPostural tachycardia syndrome: a heterogeneous and multifactorial disorder
Benarroch, E. E. (2012) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2012.08.013 · Cited by 370 · cited 1× · see citing works
“22,23 The heterogeneous nature of POTS represents a challenge not only in understanding the disease but also in developing an effective treatment.”
Cardiac origins of the postural orthostatic tachycardia syndrome
Fu, Q., VanGundy, T. B., Galbreath, M. M., Shibata, S., Jain, M., Hastings, J. L., Bhella, P. S., & Levine, B. D. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.02.043 · Cited by 329 · see citing works
Manoeuvres affecting sympathetic outflow in human muscle nerves
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Raj, S. R., Biaggioni, I., Yamhure, P. C., Black, B. K., Paranjape, S. Y., Byrne, D. W., & Robertson, D. (2005) · Circulation · doi:10.1161/01.cir.0000160356.97313.5d · Cited by 286 · cited 1× · see citing works
“…include partial peripheral neuropathy (neuropathic POTS), 19 a deficit in blood volume, abnormalities in the renin-angiotensin-aldosterone system, 20 physical deconditioning, 10 autoantibodies targeting peripheral adrenergic receptors, 21 and a hyperadrenergic state resulting from central…”
Self-citationThe Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale
Kaufmann, H., Malamut, R. I., Norcliffe‐Kaufmann, L., Rosa, K., & Freeman, R. L. (2011) · Clinical Autonomic Research · doi:10.1007/s10286-011-0146-2 · Cited by 245 · cited 2× · see citing works
“…flushing, hypertension, and tachycardia); the impact of POTS symptoms on orthostatic tolerance (Orthostatic Hypotension Daily Activities Scale) 16 ; autonomic symptoms burden (Composite Autonomic Symptom Score 31) 17 ; and the impact of chronic fatigue on daily activities (PROMIS Fatigue…”
Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans.
Goldstein, D. S., Eisenhofer, G., Stull, R., Folio, C. J., Keiser, H. R., & Kopin, I. J. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113298 · Cited by 245 · see citing works
Postural Orthostatic Tachycardia Syndrome
Bryarly, M., Phillips, L. T., Fu, Q., Vernino, S., & Levine, B. D. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.11.059 · Cited by 245 · see citing works
Chronic Orthostatic Intolerance: A Disorder With Discordant Cardiac and Vascular Sympathetic Control
Furlan, R., Jacob, G., Snell, M., Robertson, D., Porta, A., Harris, P., & Mosqueda-Garcia, R. (1998) · Circulation · doi:10.1161/01.cir.98.20.2154 · Cited by 229 · see citing works
Self-citationRaj, S. R., Black, B. K., Biaggioni, I., Paranjape, S. Y., Ramirez, M., Dupont, W. D., & Robertson, D. (2009) · Circulation · doi:10.1161/circulationaha.108.846501 · Cited by 225 · see citing works
Self-citationRaj, S. R., Guzman, J. C., Harvey, P., Richer, L., Schondorf, R., Seifer, C., Thibodeau-Jarry, N., & Sheldon, R. S. (2020) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2019.12.024 · Cited by 223 · cited 2× · see citing works
“7,8 It is a useful biomarker in that it identifies patients who respond better to beta-blockers.”
Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders
Shibao, C., Arzubiaga, C., Roberts, L. J., Raj, S., Black, B., Harris, P., & Biaggioni, I. (2005) · Hypertension · doi:10.1161/01.hyp.0000158259.68614.40 · Cited by 220 · cited 4× · see citing works
“12 In the present study, however, there was no difference in the number of patients with Hyper-POTS and non-HyperPOTS with a possible diagnosis of MCAD (5 versus 8 patients, respectively; P =0.506), S3) before guanfacine treatment.”
InfluentialSelf-citationQuality of Life in Patients With Postural Tachycardia Syndrome
Benrud-Larson, L. M., Dewar, M. S., Sandroni, P., Rummans, T. A., Haythornthwaite, J. A., & Low, P. A. (2002) · Mayo Clinic Proceedings · doi:10.4065/77.6.531 · Cited by 217 · see citing works
Wilkinson, D. J. C., Thompson, J. M., Lambert, G. W., Jennings, G. L., Schwarz, R. G., Jefferys, D., Turner, A. G., & Esler, M. D. (1998) · Archives of General Psychiatry · doi:10.1001/archpsyc.55.6.511 · Cited by 214 · cited 1× · see citing works
“38 Importantly, patients with documented panic disorders have normal resting MSNA levels, 39 an observation that argues against a panic disorder underlying the hyperadrenergic state in our patients with HyperPOTS.”
Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system
Jacob, G., Robertson, D., Mosqueda-Garcia, R., Ertl, A. C., Robertson, R. M., & Biaggioni, I. (1997) · The American Journal of Medicine · doi:10.1016/s0002-9343(97)00133-2 · Cited by 164 · cited 2× · see citing works
“…among the first to introduce this threshold in the literature, 9 but cautioned that a high plasma norepinephrine could be due not only to a primary hyperadrenergic state but could also reflect a compensatory sympathetic activation secondary to a partial neuropathy, 9 a concern shared by others.”
Self-citationDiedrich, A., Charoensuk, W., Brychta, R. J., Ertl, A. C., & Shiavi, R. (2003) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.2002.807323 · Cited by 138 · see citing works
Self-citationReal-life assessment of the validity of patient global impression of change in fibromyalgia
Rampakakis, E., Ste‐Marie, P. A., Sampalis, J. S., Karellis, A., Shir, Y., & Fitzcharles, M. (2015) · RMD Open · doi:10.1136/rmdopen-2015-000146 · Cited by 133 · cited 1× · see citing works
“…Material) to assess the impact of guanfacine treatment on patient-reported change in overall health (Patient Global Impression of Change [PGIC]) 15 ; the frequency and severity of spontaneous hyperad-renergic episodes (facial flushing, hypertension, and tachycardia); the impact of POTS…”
Psychiatric profile and attention deficits in postural tachycardia syndrome
Raj, V, Haman, K. L., Raj, S. R., Byrne, D., Blakely, R. D., Biaggioni, I., Robertson, D., & Shelton, R. C. (2009) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2008.144360 · Cited by 131 · cited 1× · see citing works
“38 Importantly, patients with documented panic disorders have normal resting MSNA levels, 39 an observation that argues against a panic disorder underlying the hyperadrenergic state in our patients with HyperPOTS.”
Self-citationSorkin, E. M., & Heel, R. C. (1986) · Drugs · doi:10.2165/00003495-198631040-00003 · Cited by 106 · see citing works
The Postural Tachycardia Syndrome
Medow, M. S., & Stewart, J. M. (2007) · Cardiology in Review · doi:10.1097/01.crd.0000233768.68421.40 · Cited by 105 · see citing works
Lambert, E., Eikelis, N., Esler, M., Dawood, T., Schlaich, M., Bayles, R., Socratous, F., Agrotis, A., Jennings, G., Lambert, G., et al. (2008) · Circulation: Arrhythmia and Electrophysiology · doi:10.1161/circep.107.750471 · Cited by 94 · cited 1× · see citing works
“33 It is likely that an exaggerated increase in MSNA triggered by standing will have the same limitations as upright norepinephrine in differentiating between a primary hyperadrenergic state or a compensatory response to, for example, volume depletion.”
The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine
van Zwieten, P. A., Thoolen, M. J., & Timmermans, P. B. (1984) · Hypertension · doi:10.1161/01.hyp.6.5_pt_2.ii28 · Cited by 83 · cited 1× · see citing works
“46 We previously used methyldopa in the treatment of POTS associated with mast cell activation disorders that have a similar hyperad-renergic phenotype.”
Role of adenosine in the sympathetic activation produced by isometric exercise in humans.
Costa, F., & Biaggioni, I. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117147 · Cited by 81 · see citing works
Self-citationSympathetic Nerve Activity in Response to Hypotensive Stress in the Postural Tachycardia Syndrome
Bonyhay, I., & Freeman, R. L. (2004) · Circulation · doi:10.1161/01.cir.0000147280.90339.e9 · Cited by 78 · cited 2× · see citing works
“…and tachycardia); the impact of POTS symptoms on orthostatic tolerance (Orthostatic Hypotension Daily Activities Scale) 16 ; autonomic symptoms burden (Composite Autonomic Symptom Score 31) 17 ; and the impact of chronic fatigue on daily activities (PROMIS Fatigue Short Form 7a [PROMIS F-SF]).”
Ross, A. J., Ocon, A. J., Medow, M. S., & Stewart, J. M. (2014) · Clinical Science · doi:10.1042/cs20130222 · Cited by 78 · cited 1× · see citing works
“29 Several publications have reported direct recordings of central sympathetic outflow to skeletal muscle (MSNA) in POTS, and the variability in these results likely reflects the heterogeneity of this condition.”
Blood Pressure Management in Afferent Baroreflex Failure
Biaggioni, I., Shibao, C. A., Diedrich, A., Muldowney, J. A. S., Laffer, C. L., & Jordan, J. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.10.027 · Cited by 78 · cited 1× · see citing works
“41 Slow-release clonidine and transdermal patches may be alternative therapies.”
Self-citationBaroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome
Muenter Swift, N., Charkoudian, N., Dotson, R. M., Suarez, G. A., & Low, P. A. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01243.2004 · Cited by 70 · see citing works
Jordan, J., Shannon, J. R., Diedrich, A., Black, B. K., & Robertson, D. (2002) · Hypertension · doi:10.1161/hy1201.097202 · Cited by 69 · cited 8× · see citing works
“An upright plasma NE ≥ 600 pg/mL is the criterion most often used to define hyperadrenergic POTS, 4–6 and this threshold has been adapted in recent expert consensus statements.”
InfluentialSelf-citationNewcorn, J. H., Schulz, K., Harrison, M., DeBellis, M. D., Udarbe, J. K., & Halperin, J. M. (1998) · Pediatric Clinics of North America · doi:10.1016/s0031-3955(05)70064-x · Cited by 68 · see citing works
Effect of High Dietary Sodium Intake in Patients With Postural Tachycardia Syndrome
Garland, E. M., Gamboa, A., Nwazue, V. C., Celedonio, J. E., Paranjape, S. Y., Black, B. K., Okamoto, L. E., Shibao, C. A., Biaggioni, I., Robertson, D., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.03.005 · Cited by 65 · cited 8× · see citing works
“The ROC analysis using PGIC also showed that a conservative cutoff of ∆ DBP VM2 >17 mm Hg identified a response to guanfacine with 77% specificity and 72% sensitivity (area under the curve, 0.774 [95% CI, 0.627–0.920]; P =0.006).”
InfluentialSelf-citationLiao, Y., Chen, S., Liu, X., Zhang, Q., Ai, Y., Wang, Y., Jin, H., Tang, C., & Du, J. (2010) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2010.03.034 · Cited by 58 · cited 1× · see citing works
“5,12,27 Patients with POTS have been characterized according to calf blood flow response to standing, 28 with low-flow patients probably representing those with a hyperadrenergic phenotype.”
Strawn, J. R., Compton, S. N., Robertson, B., Albano, A. M., Hamdani, M., & Rynn, M. A. (2017) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/cap.2016.0132 · Cited by 55 · cited 1× · see citing works
“A similar clinical picture can be seen in panic attacks, and we cannot exclude a nonspecific Hyperadrenergic POTS Okamoto et al anxiolytic effect of guanfacine, which has been observed in children and adolescents 36 and adults with anxiety complicating cardiac surgery.”
Kuchel, O. (1985) · Hypertension · doi:10.1161/01.hyp.7.1.151 · Cited by 54 · see citing works
Bartlett, S. J., Gutierrez, A. K., Andersen, K. M., Bykerk, V. P., Curtis, J. R., Haque, U. J., Orbai, A., Jones, M., & Bingham, C. O. (2020) · Arthritis Care & Research · doi:10.1002/acr.24501 · Cited by 52 · see citing works
Kanjwal, K., Saeed, B., Karabin, B., Kanjwal, Y., & Grubb, B. P. (2011) · Cardiology Journal · doi:10.5603/cj.2011.0008 · Cited by 46 · cited 1× · see citing works
“An upright plasma NE ≥ 600 pg/mL is the criterion most often used to define hyperadrenergic POTS, 4–6 and this threshold has been adapted in recent expert consensus statements.”
Gaffney, F. A. (1983) · CHEST Journal · doi:10.1378/chest.83.2_supplement.436 · Cited by 43 · see citing works
Spectrum of Autonomic Cardiovascular Neuropathy in Diabetes
Jacob, G., da Costa, F. A. A., & Biaggioni, I. (2003) · Diabetes Care · doi:10.2337/diacare.26.7.2174 · Cited by 34 · cited 1× · see citing works
“24 Indeed, plasma NE >600 pg/mL has been documented in healthy subjects with volume depletion, 13 in patients with diabetic neuropathy, 25 and even in patients with neuropathic orthostatic hypotension.”
Self-citationYang, M., Keller, S., & Lin, J.-M. S. (2019) · Quality of Life Research · doi:10.1007/s11136-019-02289-4 · Cited by 30 · cited 1× · see citing works
“18 In addition, the participant’s medical records were reviewed to collect data on medical history relevant to POTS and the results of autonomic testing and a 10-minute head-up tilt test at 75°, done off medications affecting BP or HR and before guanfacine treatment.”
Wilson, M. F., Haring, O., Lewin, A., Bedsole, G., Stepansky, W., Fillingim, J., Hall, D., Roginsky, M., McMahon, F. G., Jagger, P., et al. (1986) · The American Journal of Cardiology · doi:10.1016/0002-9149(86)90723-x · Cited by 29 · see citing works
Vernino, S. A., Hopkins, S., Bryarly, M. A., Hernandez, R. S., & Salter, A. R. (2024) · Clinical Autonomic Research · doi:10.1007/s10286-024-01020-9 · Cited by 28 · see citing works
Srour, H., Pandya, K., Flannery, A., & Hatton, K. (2018) · Seminars in Cardiothoracic and Vascular Anesthesia · doi:10.1177/1089253218768537 · Cited by 21 · cited 1× · see citing works
“37 However, patients with POTS typically deny a sensation of doom or panic and accept the transient nature of these episodes.”
Mamilla, D., Gonzales, M. K., Esler, M., & Pacák, K. (2019) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2019.08.004 · Cited by 21 · cited 1× · see citing works
“34,35 The magnitude of these episodes can be dramatic, with acute increases in SBP in the 180 mm Hg range.”
Clinical features of hyperadrenergic postural tachycardia syndrome in children
Zhang, Q., Chen, X., Li, J., & Du, J. (2014) · Pediatrics International · doi:10.1111/ped.12392 · Cited by 20 · cited 1× · see citing works
“5,12,27 Patients with POTS have been characterized according to calf blood flow response to standing, 28 with low-flow patients probably representing those with a hyperadrenergic phenotype.”
Stickford, A. S. L., VanGundy, T. B., Levine, B. D., & Fu, Q. (2015) · The Journal of Physiology · doi:10.1113/jp270088 · Cited by 19 · cited 2× · see citing works
“22,23 The heterogeneous nature of POTS represents a challenge not only in understanding the disease but also in developing an effective treatment.”
Mar, P. L., Shibao, C. A., Garland, E. M., Black, B. K., Biaggioni, I., Diedrich, A., Paranjape, S. Y., Robertson, D., & Raj, S. R. (2015) · Clinical Science · doi:10.1042/cs20140766 · Cited by 18 · cited 1× · see citing works
“26 Others have used a paradoxical increase in BP with upright posture as a clinical indicator of Hyper-POTS, alone or in combination with elevated norepinephrine.”
Self-citation(1988) · PubMed · Cited by 15 · see citing works
Autoimmunity in Syndromes of Orthostatic Intolerance: An Updated Review
Pena, C., Moustafa, A., Mohamed, A.-R., & Grubb, B. P. (2024) · Journal of Personalized Medicine · doi:10.3390/jpm14040435 · Cited by 13 · cited 1× · see citing works
“…POTS), 19 a deficit in blood volume, abnormalities in the renin-angiotensin-aldosterone system, 20 physical deconditioning, 10 autoantibodies targeting peripheral adrenergic receptors, 21 and a hyperadrenergic state resulting from central activation of the sympathetic nervous system (HyperPOTS).”
Clarifying the Cause and Treatment of Paroxysmal Hypertension (Pseudopheochromocytoma)
Mann, S. J., & Solanki, K. V. (2022) · Current Hypertension Reports · doi:10.1007/s11906-022-01198-1 · Cited by 7 · cited 1× · see citing works
“34,35 The magnitude of these episodes can be dramatic, with acute increases in SBP in the 180 mm Hg range.”
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Postural Orthostatic Tachycardia Syndrome: A State-of-the-Art Review
Lau, D. H., Fedorowski, A., Raj, S. R., Schild, C., Pace, L., Blitshteyn, S., Raj, V., Boris, J. R., Kavi, L., Seeley, M., et al. (2026) · Heart Lung and Circulation · doi:10.1016/j.hlc.2025.09.004 · Cited by 21 · see citing works
Carbidopa: beyond Parkinson’s disease
Lenka, A., & Vernino, S. A. (2025) · Clinical Autonomic Research · doi:10.1007/s10286-025-01122-y · Cited by 3 · see citing works
“Symptomatic improvement in the aforementioned symptoms has been reported after treatment with several medications, including ivabradine [26], beta blockers such as propranolol [27], and centrally-acting sympatholytics such as guanfacine [28].”
Dooley, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157284 · Cited by 3 · see citing works
Pediatric orthostatic intolerance – a review with focus on recent research
Hebson, C. L., Harberg, M., & Borasino, P. (2025) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000001469 · Cited by 1 · see citing works
van Campen, C. M. C., & Visser, F. C. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14113648 · Cited by 2 · see citing works
“Previous studies have shown that a subgroup of POTS patients have indeed a high level of catecholamines, mainly of norepinephrine [33–35], but also to a lesser degree of epinephrine [36].”
Approach to Postural Orthostatic Tachycardia Syndrome
Robbins, N. M., Golden, E. P., Freeman, K. J., Bhavaraju-Sanka, R. K., Snapper, H., & Cook, G. A. (2026) · Neurology Clinical Practice · doi:10.1212/cpj.0000000000200620 · Cited by 1 · see citing works
Tackling POTS Needs More Than Just a Sympathetic Approach
Dani, M., & Fedorowski, A. (2024) · Hypertension · doi:10.1161/hypertensionaha.124.23716
Hyperadrenergic postural tachycardia syndrome associated with augmented neurovascular transduction
Kulapatana, S., Okamoto, L. E., Rigo, S., Urechie, V., Cayton, T. W., Han, R. E., Jacob, G., Dupont, W. D., Furlan, R., Biaggioni, I., et al. (2026) · Clinical Autonomic Research · doi:10.1007/s10286-025-01183-z
“We identified this subset of POTS based on their hyperadrenergic responses resulting from augmented neurovascular transduction, which was distinct from patients with POTS with high resting sympathetic discharge, which we have proposed earlier [8].”
InfluentialSelf-citationToo high and too loose: dysautonomia and the hypertensive paradox in hypermobility disorders
Johnson, J. W., Mirro, I., & Kontorovich, A. (2026) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000001310
Reduced Tissue Oxygenation and Altered Valsalva Hemodynamics in Young Adults with Type 1 Diabetes
Poulsen, M. B., Julu, P. O. O., Memon, S., Shah, M., & Brock, C. (2026) · International Physiology Journal · doi:10.14302/issn.2578-8590.ipj-26-6121
Alpha 2 Agonists: Clonidine and Guanfacine
Carle, K. J. (2026) · Springer eBooks · doi:10.1007/978-981-95-7244-1_4
Orthostatic Hypertension: Clinical Spectrum and Gaps in Knowledge
Moloney, D., Jordan, J., & Biaggioni, I. (2026) · Current Hypertension Reports · doi:10.1007/s11906-026-01386-3
“…most studies have focused on the relation between oHT and hypertension, oHT has also been reported in younger patients with hyperadrenergic syndromes, such as hyperadrenergic postural orthostatic tachycardic syndrome [18, 19], but its prevalence and clinical implications have not been defined.”
Self-citationTrout, J., Lamotte, G. J., Langford, J. S., Heyliger, L., & Cortez, M. M. (2026) · Clinical Autonomic Research · doi:10.1007/s10286-026-01239-8
- Authors
- Okamoto, L. E., Urechie, V., Rigo, S., Abner, J. J., Giesecke, M., Muldowney, J. A. S., Furlan, R., Shibao, C. A., Shirey-Rice, J. K., Pulley, J. M., Diedrich, A., & Biaggioni, I.
- Affiliations
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- Humanitas University (IT)
- ORCID
- Venue
- Hypertension
- Published
- 2024-11
- Volume
- 81
- Issue
- 11
- Pages
- 2237-2247
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- PMC
- PMC11483201
- OpenAlex
- W4401398498
- Cited by
- 13
- References
- 56
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 1
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (submittedVersion)
- Funders
- Vanderbilt University
- National Institutes of Health (5ul1tr002243-09)
- National Heart, Lung, and Blood Institute (R56 HL142583, R01HL142583, R01 HL149386, R01HL159203)
- National Center for Advancing Translational Sciences (UL1-TR002243)
- Topics
- Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Keywords
- postural orthostatic tachycardia syndrome, guanfacine, sympatholytic therapy, muscle sympathetic nerve activity, plasma norepinephrine, Valsalva maneuver, diastolic blood pressure, orthostatic tolerance, chronic fatigue, biomarkers
- MeSH terms
- Adult, Blood Pressure, Female, Humans, Male, Middle Aged, Norepinephrine, Sympathetic Nervous System, Sympatholytics, Valsalva Maneuver, Biomarkers, Guanfacine, Treatment Outcome, Postural Orthostatic Tachycardia Syndrome, Young Adult, Adrenergic alpha-2 Receptor Agonists
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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