Inflammatory Biomarkers in Postural Orthostatic Tachycardia Syndrome with Elevated G-Protein-Coupled Receptor Autoantibodies

Gunning, William T.; Stepkowski, Stanislaw M.; Kramer, Paula M.; Karabin, Beverly; Grubb, Blair P.

doi:10.3390/jcm10040623

Cited by 28 publications

(21 citation statements)

References 72 publications

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“…In conclusion, we have validated results described in a previous report that POTS patients have elevated biomarkers of an activated innate immune system [11]. Although we postulated that POTS is an autoimmune disease mediated by T cells, similar to RA, psoriasis, systemic sclerosis, multiple sclerosis, and type-1 diabetes [42,51,56,57], the data provided herein suggest that POTS is a mixed inflammatory pattern disease.…”

Section: Discussionsupporting

confidence: 90%

“…The disorder was likely first described in 1871 by Da Costa, who described all of the features of POTS mentioned above; it was formally monikered in 1993 by Schondorf and Low, yet, even today, it is not well recognized in the medical community, nor has an etiology been established [ 1 , 7 ]. Unfortunately, as many as 75% of affected individuals are misdiagnosed or referred for psychological consultation [ 8 , 9 , 10 , 11 ]. The diagnosis requires the presence of chronic orthostatic intolerance associated with an increased heart rate of ≥30 beats per minute (BPM) from the supine or sitting basal rate, or a rate that exceeds 120 BPM when standing or by an upright tilt test that occurs within 10 min [ 1 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Platelet Storage Pool Deficiency and Elevated Inflammatory Biomarkers Are Prevalent in Postural Orthostatic Tachycardia Syndrome

Gunning

Kramer

Cichocki

et al. 2022

Cells

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A significant number of postural orthostatic tachycardia syndrome (POTS) patients have platelet delta granule storage pool deficiency (δ-SPD). The etiology of POTS is unknown but a number of laboratories, including ours, have reported elevations of G-protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies in POTS patients, detected by a variety of techniques, suggesting that the disorder is an autoimmune condition. Thus, it could also be considered an inflammatory disease. In a pilot study, we investigated a limited number of platelet-related cytokines and chemokines and discovered many that were elevated. This case–control study validates our pilot study results that POTS patients have an activated innate immune system. Plasma of 35 POTS patients and 35 patients with unexplained bleeding symptoms and categorized as “non-POTS” subjects was analyzed by multiplex flow cytometry to quantify 16 different innate immune system cytokines and chemokines. Electron microscopy was used to quantify platelet dense granules. Ten of 16 biomarkers of inflammation were elevated in plasma from POTS patients compared to non-POTS subjects, with most of the differences extremely significant, with p values < 0.0001. Of particular interest were elevations of IL-1β and IL-18 and decreased or normal levels of type 1 interferons in POTS patients, suggesting that the etiology of POTS might be autoinflammatory. All POTS patients had δ-SPD. With a growing body of evidence that POTS is an autoimmune disease and having elevations of the innate immune system, our results suggest a potential T-cell-mediated autoimmunity in POTS characteristic of a mixed-pattern inflammatory disease similar to rheumatoid arthritis.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Platelet Storage Pool Deficiency and Elevated Inflammatory Biomarkers Are Prevalent in Postural Orthostatic Tachycardia Syndrome

Gunning

Kramer

Cichocki

et al. 2022

Cells

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“…While the true etiology of POTS has yet to be de ned, endothelial dysfunction has been suggested as the pathophysiology (36). There is also evidence that POTS maybe be associated with G-proteincoupled receptor autoantibodies (37). Interestingly, since CCR5 and fractalkine receptor are also G-protein-coupled receptors (9,38), it is possible that antagonism of these receptors could also inhibit the autonomic effects of these autoantibodies.…”

Section: Machine Learning Classi Er Validates the Labelling Of Indivi...mentioning

confidence: 99%

Targeting the Monocytic-Endothelial-Platelet Axis with Maraviroc and Pravastatin as a Therapeutic Option to Treat Long COVID/ Post-Acute Sequelae of COVID (PASC)

Patterson¹,

Yogendra²,

Jose³

et al. 2022

Preprint

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Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. The pathophysiology behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We believe targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants’ response to treatment, we observed significant clinical improvement in six to twelve weeks on a combination of maraviroc 300mg PO BID and pravastatin 10 mg PO daily. Subjective neurological (p=0.002), autonomic (p<0.0001), respiratory (p=0.0153), cardiac (p=0.002) and fatigue (p<0.0001) symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.

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“…[18][19][20] Additionally, antibodies against angiotensin II type 1 receptors and abnormal levels of inflammatory biomarkers were reported. 21,22 Despite the presence of these antibodies, their role in the complex pathophysiology of autonomic dysfunction in POTS remains unknown. 15 Immunomodulatory treatment with intravenous immunoglobulins has shown a positive effect on the symptoms of patients with POTS, further supporting an immune-mediated genesis.…”

Section: Introductionmentioning

confidence: 99%

Tolerability of COVID-19 mRNA vaccines in patients with postural tachycardia syndrome: a cross-sectional study

et al. 2022

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Background: Postural tachycardia syndrome (POTS) is a form of autonomic dysregulation. There is increasing evidence that the etiology may be immune-mediated in a subgroup of patients. Patients with POTS often experience an exacerbation of their symptoms associated with (viral) infections and often fear the same symptom aggravation after vaccination. In this report we describe the tolerability of messenger ribonucleic acid (mRNA) vaccines against coronavirus disease 19 (COVID-19) and the consequences of a COVID-19 infection on POTS symptoms in our cohort of patients with neuropathic POTS. Methods: We conducted a standardized, checklist-based interview with 23 patients and recorded the acute side effects of mRNA vaccination, acute symptoms of COVID-19 infection as well as the effects of vaccination and COVID-19 infection on POTS symptoms. Results: Of all included patients, 20 patients received two mRNA vaccines without having had a previous COVID-19 infection, and five patients in total had suffered a COVID-19 infection. Of these, three had COVID-19 without and two after being vaccinated. No increased frequency of side effects after both doses of mRNA vaccines was observed. Six patients reported a mild and short-term aggravation of their POTS symptoms beyond the duration of acute vaccine side effects. All five patients who suffered a COVID-19 infection subsequently reported a pronounced and persistent exacerbation of POTS symptoms. Conclusions: Our observations suggest that mRNA vaccines are not associated with a higher frequency of acute side effects in patients with POTS. Symptom exacerbation as a consequence of mRNA vaccination seems to be less frequent and of shorter duration compared to patients who suffered a COVID-19 infection.

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Inflammatory Biomarkers in Postural Orthostatic Tachycardia Syndrome with Elevated G-Protein-Coupled Receptor Autoantibodies

Cited by 28 publications

References 72 publications

Platelet Storage Pool Deficiency and Elevated Inflammatory Biomarkers Are Prevalent in Postural Orthostatic Tachycardia Syndrome

Platelet Storage Pool Deficiency and Elevated Inflammatory Biomarkers Are Prevalent in Postural Orthostatic Tachycardia Syndrome

Targeting the Monocytic-Endothelial-Platelet Axis with Maraviroc and Pravastatin as a Therapeutic Option to Treat Long COVID/ Post-Acute Sequelae of COVID (PASC)

Tolerability of COVID-19 mRNA vaccines in patients with postural tachycardia syndrome: a cross-sectional study

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