Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID with and w/o POTS..., 2023, Mahdi et al

Full Title: Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 with and without POTS syndrome; a multi-omic profiling study, 2023, Ali Mahdi et al

Abstract
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.

https://www.nature.com/articles/s41598-023-47539-1

 

The other thing is the definition of POTS vs orthostatic intolerance. Ie they were doing head-up tilt-testing, classifying as POTS +ve if >+30 bpm or 120 bpm. That doesn't capture the group (per van Campen et al) who have a drop in cerebral blood flow without tachycardia, eg due to reduction in stroke volume index.

 

"Declaring" here means they were diagnosed with "depression/anxiety/clinical burnout". Often tachycardia is ascribed to anxiety. I wonder if POTS is now being more frequently diagnosed but if you don't have the overt tachycardia of orthostatic intolerance you get labelled as "depression" or "clinical burnout".

 

Having read through initially I think this paper has useful data. Despite sub-typing in terms of POTS vs orthostatic intolerance, they found no difference between the groups and so combined the data. This combined data showed clear differences from HCs.

They highlight: upregulated sphingolipid species (ceramides), plasminogen-activator-1 (PAI1, SERPINE1), VEGF, CCL5; on a background of up-regulated amino acid metabolism and apoptotic pathways.

 

Rather than differences in the dysregulation of pathways (not shown here), I wonder whether there is no difference in the metabolic pathology but that there are differences in the compensatory responses. Ie it was the orthostatic intolerance at inclusion that was not adequately discriminated on the basis of presence/absence of tachycardia. Such differences could be predicated on such things like size of patient, premorbid fitness, muscle mass etc. General vascular sex differences don't apply here as these patients were nearly all female, though the POTS+ group were slightly younger: 39 ± 11 vs 44 ± 11.

It would be interesting to have evaluated this cohort using measures of cerebral blood flow and assessment of stroke volume index, à la van Campen.

 

That previous paper is —

Microvasular Dysfunction and Reduced Cardiac Stress Reactivity in Postural Orthostatic Tachycardia Associated With Postacute COVID-19 (2023, Circulation: Arrhythmia and Electrophysiology)

Some of the references relating to this are —

Ceramides and other sphingolipids as drivers of cardiovascular disease (2021, Nature Reviews Cardiology)

S1PR1 Sphingosine-1-Phosphate Receptor 1 Signaling Regulates Blood Flow and Pressure (2017, Hypertension)

Sphingosine-1-phosphate signalling—a key player in the pathogenesis of Angiotensin II-induced hypertension (2017, Cardiovascular Research)

Dual Effect of Ceramide on Human Endothelial Cells (2002, Circulation)

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Sphingosine-1-Phosphate receptor signalling was related to TLR-4 signalling in cancer-induced cognitive dysfunction, noted in this 2022 thread —

Sphingosine-1-phosphate receptor 1 activation in the central nervous system drives cisplatin-induced cognitive impairment (2022, The Journal of Clinical Investigation)

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Also, here are two very recent threads for papers on sphingolipid/ceramide/lipid droplet/general lipid metabolism dysregulation induced with Covid —

A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants (2022, Nature Communications)

Dynamic label-free analysis of SARS-CoV-2 infection reveals virus-induced subcellular remodeling. (2023, Preprint: BioRxiv)