Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation, 2023, Kuchler et al.

[SNT Gatchaman]

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation
Timon Kuchler; Roman Günthner; Andrea Ribeiro; Renate Hausinger; Lukas Streese; Anna Wöhnl; Veronika Kesseler; Johanna Negele; Tarek Assali; Javier Carbajo-Lozoya; Maciej Lech; Kristina Adorjan; Hans Christian Stubbe; Henner Hanssen; Konstantin Kotilar; Berhard Haller; Uwe Heemann; Christoph Schmaderer

Background
Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.

Methods
In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n=41, matched out of n = 204).

Measurements and main results
PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular §icker-induced dilation (vmax; 3.42% ± 1.77% vs. 4.64 % ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5 - 190.2] vs. 189.1 [179.4 - 197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8 - 0.9] vs. 0.88 [0.8 - 0.9], p = 0.007). When combining AVR and vmax, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R= -0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of in§ammatory parameters.

Conclusion
Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.

Trial Registration
This study was previously registered at ClinicalTrials (“All Eyes on PCS - Analysis of the Retinal Microvasculature in Patients With Post-COVID-19 Syndrome”. NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552).

Link | PDF (Preprint: Research Square)

 

[SNT Gatchaman]

Patients myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was assessed using the Canadian Consensus Criteria for ME/CFS.

We observed significantly narrower retinal arterioles in PCS patients with CFS, indicated by lower CRAE (183.5 [177.4 - 197.0] vs. 174.0 [161.5 - 181.0], p = 0.03). There was no difference in the size of retinal venules between groups (214.9 [204.1 - 221.9] vs. 211.1 [199.9 - 226.0], p = 0.98) (Fig. 3 a). AVR was significantly lower in PCS patients with CFS (0.88 [0.82 - 0.91] vs. 0.82 [0.77 - 0.86], p = 0.02), and both AVR (AUC: 0.72) and CRAE (AUC: 0.70) were good markers to distinguish between PCS patients with or without CFS.

 

[DokaGirl]

From the Conclusion: " Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients."

It appears this study adds some credence to the theory regarding circulatory problems in ME.

 

[Tom Kindlon]

This has now been published.

Free fulltext:
https://link.springer.com/article/10.1007/s10456-023-09885-6

 

[EndME]

I've heard that Scheibenbogen is using RVA as part of her Biomarker platform (apart from EndoPAT for endothelial dysfunction assessment). So hopefully we will see some replication of this work from other labs soon.

 

[EndME]

A significant factor in this study seems to be that ME/CFS Long-Covid patients are obese in this study (compared to the remaing Long-Covid patients). This has implications on the results as many other studies suggest https://pubmed.ncbi.nlm.nih.gov/29743194/. Of course this doesn't have implications on the overall results if there is decent matching amongst those cohorts (which according to the BMI results seems to be the case, but there is some obesity mismatching P=0.60).

 

[Hutan]

I'd missed this paper:

Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com

 

[Hutan]

These measures have been used in heart disease research and seem to be credible as measures of endothelial dysfunction.

Dynamic vessel (DVA) and static retinal vessel analysis (SVA) are two well-established diagnostic tools to analyze retinal microcirculation as a surrogate of pan-endothelial health [23, 24]. Assessing retinal endothelial function has been proposed as “of high potential” to quantify ED non-invasively by the European Society of Cardiology (ESC) [25]. DVA measures retinal vessel responses to flickering light over time, which is mediated by neuro-vascular coupling and subsequently flow-induced nitric oxide (NO) release from the endothelium [23]. SVA offers an accurate, quick, and reproducible method to assess impairment of microvascular integrity and vessel morphology by measuring vessel diameters. SVA and DVA have both been used and proven as valuable diagnostic tools to determine endothelial health in large cohorts with chronic cardiovascular (CV) diseases [26,27,28,29]. The Atherosclerosis Risk In Communities (ARIC) study showed that narrower central retinal arteriolar equivalent (CRAE) and wider central retinal venular equivalent (CRVE) are independent predictors for long-term CV events in a large cohort of healthy participants [26, 28]. We previously could show in a cohort of dialysis patients that impaired retinal venular dilation (vFID) is an independent predictor for all-cause mortality [30].

41 PCS
204 healthy controls - SARS CoV-2 naive - which is a shame. Healthy post Covid-19 patients would have been better

A significant factor in this study seems to be that ME/CFS Long-Covid patients are obese in this study (compared to the remaing Long-Covid patients).

The Canadian Consensus Criteria were used to identify the ME/CFS PCS patients. 25/41 were assessed as meeting the criteria.

Fatigue (95.1%), exercise intolerance (90.2%), and brain fog (90.2%) were the three most abundant symptoms.

With the high level of those particular symptoms, I think we can assume that most of the PCS patients would meet the IOM criteria.

 

[Hutan]

There is a lot of overlap between the two cohorts. The arteriolar/venular (width) ratio (AVR) shows the best separation, with a very good P value. But, still a lot of overlap.

PCS patients showed significantly narrower retinal arterioles, indicated by lower CRAE when compared with HC (178.1 [167.5–190.2] vs. 189.1 [179.4–197.2], p = 0.01). We did not observe differences in the central retinal venular equivalent (CRVE) between cohorts (213.1 [200.0–224.2] vs.212.2 [197.1–220.8], p = 0.5). Subsequently, the arteriolar venular ratio (AVR) was significantly lower in PCS patients as it is the ratio of CRAE/CRVE (0.84 [0.8–0.9] vs. 0.88 [0.8–0.9], p = 0.007) (Fig. 1 c, d and e). After controlling for potential confounders, lower venular dilation (p = 0.03) and lower AVR (p = 0.048) remained associated with PCS. The strength of association with narrower retinal arterioles was smaller after adjustment (p = 0.077) (Table E3 Online Supplement).

The association with narrower retinal arterioles became non-significant "after adjustment" for confounders. I'm not sure what confounders were adjusted for. The AVR remained significant, although only just.

I think this is a really interesting study. Yes, the issue of obesity in the more severely affected patients is a problem. Yes, more replication is needed, better controlling for the confounding of obesity.

 

[Hutan]

Concerning retinal vessel diameters, we found narrower arterioles. This is reflected in lower AVR, which proved the most reliable parameter in distinguishing PCS from HC and showed the strongest association with PCS severity. While CRAE and CRVE both display particular and separate microvascular patterns of the arterial and venous circulation, the AVR provides a non-specific measurement of the general regulatory state of retinal microcirculation [23]. Calibers of CRAE and CRVE are associated with CV risk factors such as nicotine abuse, age, diabetes, obesity, and higher blood pressure [23, 24, 42, 49]. Although the observed associations between PCS, PCS severity and AVR could be partly explained by the influence of confounding factors, analyses suggest that the effects of SARS-CoV-2 infection on microvascular integrity and endothelial function are likely to be prolonged and contribute to long-term consequences of the infection, rather than simply being a result of pre-existing cardiovascular morbidity. With a median PCS duration of 10 months in our cohort, this is a highly relevant clinical finding, especially since the severity of acute infection was mostly mild to moderate.

 

[SNT Gatchaman]

Subsequent study: Inhibition of HIF-2α Pathway as a Potential Therapeutic Strategy for Endothelial Dysfunction in Post-COVID Syndrome (2024, Preprint: MedRxiv)