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

Mij

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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
 
Karolinska , Sweden
This looks like an interesting study; relatively small numbers.

There was a large overlap (> 90%) with no major differences between the PACS groups.
This doesn't surprise me, as I think POTS symptoms are something that comes and goes in many people with ME/CFS. And so, whether a person is given the label of POTS can depend a lot on chance, on how the person was on the day of testing. I take the fact that there was no differences between the two groups but differences between the two groups and healthy controls as a sign that the researchers may have found some real differences relevant to the PACS pathology.

It will be good to see if any of the findings line up with other similar studies.
 
The PACS patients were free from comorbidities except for a subset of PACS-POTS (40%) who declared depression/anxiety. For this reason, a larger proportion of patients in this group were on sedative and hypnotics.

"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.

It has previously been shown that sphingolipids, in particular ceramides, represent potential drivers of cardiovascular disease through various actions [...]. A proposed key-mechanism by which sphingolipids act as mediators of cardiovascular disease is through their pleiotropic effect as inhibitors of nitric oxide formation and increased production of reactive oxygen species. Since our previous work showed that PACS + POTS patients frequently presented with microvascular dysfunction (MVD), we hypothesized that sphingolipid-related dysregulation could accompany POTS and/or MVD in PACS patients.

Compared to healthy controls, we found 16 and 19 dysregulated lipids out of 88 in the PACS+POTS and PACS-POTS groups, respectively. Moreover, no significant differences were detected between PACS-POTS and PACS+POTS groups. A few of the most upregulated sphingolipids in both PACS groups are sphingosine (d18:1) and sphingosine (d16:1) which are the basis of sphingolipids, and sphingosine 1-phosphate (S1P) with diverse bioactive actions including critical roles in the immune system, blood pressure and endothelial function.

Collectively, our data show clear dysregulation of the molecular plasma profile in PACS patients. This is most pronounced in cardiometabolic proteins but also in cytokines and sphingolipids compared to healthy controls. Interestingly, all analyses showed a similar picture with absence of major differences between PACS patients with and without POTS. The common denominator for the outcomes of all molecular analysis is the up-regulation of pro-inflammatory proteins/molecules of importance for maintaining hemostasis, metabolism, clot formation and vascular function.
 
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we sought to provide a foundation for future mechanistic studies by applying an unbiased, multiomic approach analyzing cardiometabolic plasma proteins, proinflammatory cytokines/chemokines and sphingolipids in patients with PACS with and without POTS compared to healthy controls. Our hypothesis posits significant molecular changes in PACS, particularly in cases associated with POTS, aiming to lay a foundation for future mechanistic studies and enhance our understanding of these intricate conditions.

we hypothesized that sphingolipid-related dysregulation could accompany POTS and/or MVD in PACS patients.

Contrary to our hypothesis, this suggests that PACS is associated with distinct molecular changes regardless of POTS occurrence. Therefore, the presence of POTS in PACS may not be related with dysregulation of plasma proteins, cytokines, or sphingolipids, at least not at the discrimination level used in the current study.

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.

van Campen et al said:
Time velocity integral (VTI) frames were obtained in the resting supine position and while upright in the final minutes of the 30-minute tilt. The aortic VTI was measured using a continuous wave Doppler pencil probe connected to a Vivid I machine with the transducer positioned in the suprasternal notch. [...] SVI was calculated by the equation: corrected left ventricular outflow tract cross-sectional area times the aortic VTI, divided by the body surface area (BSA; DuBois formula). SVI’s of the separate cardiac cycles were averaged. CI [cardiac index] was calculated as: HR times SVI.

The change in stroke volume index was significantly larger in ME/CFS patients than in healthy controls (p < 0.0001).
 
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.

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)

The bioactive sphingolipids, ceramides, are known to act as secondary messengers and mediate important cellular and molecular signaling. It has been shown that several ceramides predict adverse cardiovascular events with high accuracy possibly through their diverse regulatory effects on vascular reactivity. More specifically, S1P, which was upregulated in our cohort, is associated with elevated blood pressure and proinflammatory biomarkers.

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)
 
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