Microvasular Dysfunction and Reduced Cardiac Stress Reactivity in Postural Orthostatic Tachycardia Associated With Postacute COVID-19

Mahdi, Ali; Lodin, Klara; Reistam, Ulrika; Fedorowski, Artur; Nygren-Bonnier, Malin; Runold, Michael; Bruchfeld, Judith; Desta, Liyew; Pernow, John; Nickander, Jannike; Ståhlberg, Marcus

doi:10.1161/circep.123.011881

Cited by 4 publications

(4 citation statements)

References 5 publications

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“…Our results suggest that alterations in hemostasis and apoptosis might play a key role in the PACS pathophysiology as several proteins involved in platelet activation and coagulation were dysregulated in PACS. This supports previous observations of COVID-19 convalescents who demonstrated microvascular endothelial dysfunction 7,24 associated with a hypercoagulable state including platelet activation and micro-clotting 25,26 . Interestingly, previous studies have also shown dysregulation of proteins involved in platelet activation and coagulation in POTS patients without PACS 27 highlighting the importance of hemostasis in POTS.…”

Section: Discussionsupporting

confidence: 92%

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Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study

Mahdi,

Zhao,

Fredengren

et al. 2023

Sci Rep

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Post-acute COVID-19 (PACS) are associated with cardiovascular dysfunction, especially postural orthostatic tachycardia syndrome (POTS). Patients with PACS, both in the absence or presence of POTS, exhibit a wide range of persisting symptoms long after the acute infection. Some of these symptoms may stem from alterations in cardiovascular homeostasis, but the exact mechanisms are poorly understood. The aim of this study was to provide a broad molecular characterization of patients with PACS with (PACS + POTS) and without (PACS-POTS) POTS compared to healthy subjects, including a broad proteomic characterization with a focus on plasma cardiometabolic proteins, quantification of cytokines/chemokines and determination of plasma sphingolipid levels. Twenty-one healthy subjects without a prior COVID-19 infection (mean age 43 years, 95% females), 20 non-hospitalized patients with PACS + POTS (mean age 39 years, 95% females) and 22 non-hospitalized patients with PACS-POTS (mean age 44 years, 100% females) were studied. PACS patients were non-hospitalized and recruited ≈18 months after the acute infection. Cardiometabolic proteomic analyses revealed a dysregulation of ≈200 out of 700 analyzed proteins in both PACS groups vs. healthy subjects with the majority (> 90%) being upregulated. There was a large overlap (> 90%) with no major differences between the PACS groups. Gene ontology enrichment analysis revealed alterations in hemostasis/coagulation, metabolism, immune responses, and angiogenesis in PACS vs. healthy controls. Furthermore, 11 out of 33 cytokines/chemokines were significantly upregulated both in PACS + POTS and PACS-POTS vs. healthy controls and none of the cytokines were downregulated. There were no differences in between the PACS groups in the cytokine levels. Lastly, 16 and 19 out of 88 sphingolipids were significantly dysregulated in PACS + POTS and PACS-POTS, respectively, compared to controls with no differences between the groups. Collectively, these observations suggest a clear and distinct dysregulation in the proteome, cytokines/chemokines, and sphingolipid levels in PACS patients compared to healthy subjects without any clear signature associated with POTS. This enhances our understanding and might pave the way for future experimental and clinical investigations to elucidate and/or target resolution of inflammation and micro-clots and restore the hemostasis and immunity in PACS.

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Section: Discussionsupporting

confidence: 92%

“…A recent study estimates the prevalence of POTS to be 30% in severely affected PACS patients referred to a tertiary specialist center 6 . More recently we have shown that POTS associated with PACS is accompanied with microvascular endothelial dysfunction which translates into reduced endothelial dependent cardiac stress perfusion 7 .…”

mentioning

confidence: 97%

Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study

Mahdi,

Zhao,

Fredengren

et al. 2023

Sci Rep

Self Cite

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“…Table 1 lists some of them, implying elements of a common origin. Of particular interest is the evidence for endothelial microvascular dysfunction [50], which can occur via the microclot-mediated blockage of red cell flow to tissues.…”

Section: Occurrence and Comorbidities Of Potsmentioning

confidence: 99%

“…Autoimmune disorders and Autoimmunity Some strong associations [16,[22][23][24][25][26] Cognitive function Large amount of literature; improved by plasma exchange [27] [27-30] Fatigue [31][32][33][34][35][36][37][38] HPV or other antiviral vaccination An example of induction by a viral protein [39][40][41][42][43][44][45] but cf. [46] Inflammation [47] Irritable bowel disease [48] Long COVID A very common occurrence and a focus of our interest [16][17][18][19][20][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]<...…”

Section: Introduction Orthostasis Orthostatic Intolerance and Potsmentioning

confidence: 99%

Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID

Kell,

Khan,

Kane

et al. 2024

JPM

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Postural orthostatic tachycardia syndrome (POTS) is a common accompaniment of a variety of chronic, inflammatory diseases, including long COVID, as are small, insoluble, ‘fibrinaloid’ microclots. We here develop the argument, with accompanying evidence, that fibrinaloid microclots, through their ability to block the flow of blood through microcapillaries and thus cause tissue hypoxia, are not simply correlated with but in fact, by preceding it, may be a chief intermediary cause of POTS, in which tachycardia is simply the body’s exaggerated ‘physiological’ response to hypoxia. Similar reasoning accounts for the symptoms bundled under the term ‘fatigue’. Amyloids are known to be membrane disruptors, and when their targets are nerve membranes, this can explain neurotoxicity and hence the autonomic nervous system dysfunction that contributes to POTS. Taken together as a system view, we indicate that fibrinaloid microclots can serve to link POTS and fatigue in long COVID in a manner that is at once both mechanistic and explanatory. This has clear implications for the treatment of such diseases.

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Cardiovascular autonomic dysfunction in post-COVID-19 syndrome: a major health-care burden

Fedorowski,

Fanciulli,

Raj

et al. 2024

Nat Rev Cardiol

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Microvasular Dysfunction and Reduced Cardiac Stress Reactivity in Postural Orthostatic Tachycardia Associated With Postacute COVID-19

Cited by 4 publications

References 5 publications

Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study

Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study

Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID

Cardiovascular autonomic dysfunction in post-COVID-19 syndrome: a major health-care burden

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