The effect of hyperbaric oxygen therapy on myocardial function in post-COVID-19 syndrome patients: a randomized controlled trial, 2023, Leitman et al.

[SNT Gatchaman]

The effect of hyperbaric oxygen therapy on myocardial function in post-COVID-19 syndrome patients: a randomized controlled trial
Leitman, Marina; Fuchs, Shmuel; Tyomkin, Vladimir; Hadanny, Amir; Zilberman-Itskovich, Shani; Efrati, Shai

Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms following SARS-CoV-2 infection. Recent evidence revealed that post-COVID-19 syndrome patients may suffer from cardiac dysfunction and are at increased risk for a broad range of cardiovascular disorders.

This randomized, sham-control, double-blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT) on the cardiac function of post-COVID-19 patients with ongoing symptoms for at least three months after confirmed infection. Sixty patients were randomized to receive 40 daily HBOT or sham sessions. They underwent echocardiography at baseline and 1–3 weeks after the last protocol session.

Twenty-nine (48.3%) patients had reduced global longitudinal strain (GLS) at baseline. Of them, 13 (43.3%) and 16 (53.3%) were allocated to the sham and HBOT groups, respectively. Compared to the sham group, GLS significantly increased following HBOT (− 17.8 ± 1.1 to − 20.2 ± 1.0, p = 0.0001), with a significant group-by-time interaction (p = 0.041).

In conclusion, post-COVID-19 syndrome patients despite normal EF often have subclinical left ventricular dysfunction that is characterized by mildly reduced GLS. HBOT promotes left ventricular systolic function recovery in patients suffering from post COVID-19 condition. Further studies are needed to optimize patient selection and evaluate long-term outcomes.

Link | PDF (Nature Scientific Reports)

 

[Hutan]

Israeli research

We've seen other papers from members of this team. There have been issues with undeclared conflicts of interest.

Hyperbaric oxygen therapy improves neurocognitive functions & symptoms of post-COVID condition: randomized controlled trial, 2022, Zilberman-Itskovich
This paper was on the same study - with the 2022 one focused on cognitive symptoms and this latest one focused on cardiac issues.

Recovery of Repressed Memories in Fibromyalgia Patients Treated With Hyperbaric Oxygen, 2018, Lev-Wiesel et al

 

[Hutan]

Out of 91 patients eligible to participate in the study, 11 patients did not complete the baseline evaluation and one patient did not meet inclusion criteria. Thus, 79 patients were randomized to either HBOT or sham arms. Two patients from the sham group withdrew their consent during treatment, and two patients did not complete the post-protocol assessments due to poor compliance. From the HBOT group, three patients did not complete post-protocol assessments due to intercurrent illness, a personal traumatic event, and withdrawal of consent. Accordingly, 37 patients from the HBOT group and 35 patients from the sham group completed the protocol and underwent post-treatment assessments. Six echocardiography examinations from the HBOT group and 4 from the sham group were not transferred appropriately and saved for analysis. One exam from each group was not suitable for speckle tracking imaging analysis due to suboptimal quality. Figure 1 shows the echocardiography examinations of the 30 patients from HBOT and the 30 patients from the sham group that were included in the final analysis.

There was some loss of data along the way - creating opportunities for biasing outcomes, so we need to trust that the authors acted properly. This is more difficult to do when no competing interests are declared (as is the case with this paper) when we know that some authors do in fact have significant competing interests.

Ethics declarations
Competing interests
The authors declare no competing interests.

For example, Efrati Shai, the senior author here, is a shareholder in Aviv Scientific and an employee of the Sagol Centre, with those organisations together rolling out a global network of hyperbaric clinics (as I noted in a comment on the 2022 paper):

Aviv Scientific is a leader in research on age-related cognitive and functional decline and novel applications of hyperbaric medicine to maximize human performance. Aviv focuses on improving the aging process by increasing cognitive and physical performance in healthy aging adults. Based on an exclusive global partnership with the world’s largest Hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Israel, Aviv Scientific is rolling out a global network of medical clinics focused on the enhancement of cognitive and physical performance with hyperbaric medicine and related technologies at its core.

 

[Hutan]

I think there were quite a lot of parameters potentially up for evaluation. Only one was found in the straight comparison of the treatment versus sham groups - GLS. I'm not sure how significant the reported mean change at baseline really is.

There were no significant differences between the two groups at baseline while GLS was mildly reduced at baseline (with a normal GLS − 20%) in both groups (− 19.1% and − 19.5%, p = 0.29). Post-HBOT, there was a statistically significant elevation of GLS (− 19.1 ± 1.8% to − 20.4 ± 2.1, p = 0.01) compared to the sham group (− 19.5 ± 2.1 to − 20.0 ± 2.1, p = 0.27). The net effect size was 0.268, and the mixed model analysis was not significant (p = 0.237) (Table 3). There were no other significant changes between the two groups (Table 3).

Another paper looked at 16 papers on GLS, covering 2,396 patients. It concluded that the mean was 20.7 and that normal should be regarded as over 18%, borderline 16 to 18% and abnormal function below 16%. So, in that case, the GLS figures in this HBOT study at baseline were normal, as they were after treatment.

Given that the GLS is the single difference, the actual changes are pretty minor. To reiterate:
HBOT - 19.1 +-1.8% to 20.4 +-2.1
sham - 19.5 +-2.1% to 20.0 +-2.1
And the mixed model analysis was not significant - I think that means that we can't conclude that the treatment made any difference to GLS.

They did a post hoc analysis, by selecting a subset of participants - which is fair enough, but again creates a whole range of opportunities to bias the outcomes. So, Figure 2 actually looks a bit convincing, in terms of the HBOT moving GLS towards that 20% mean, but we have to remember this is not in fact the primary outcome, but instead is data with post hoc selection.

 

[Jaybee00]

No bueno or לא טוב

Why would they declare a COI on the earlier paper but not this one?

 

[SNT Gatchaman]

Yes, agree there are problems with bias/conflicts. From a simplistic viewpoint I don't think we've seen any evidence of hypoxia, so what's the proposed effect mechanism here? Can a supraphysiological O2 saturation — even if a modest increase have an effect, eg via hypoxia inducible factor? See (tag HIF-1). Maybe HIF-1 is taking effect in the absence of hypoxia under pathological conditions.

There is a recent preprint linking HIF-1 and gut wall integrity but that requires hypoxia: Hypoxia Bi-directionally Regulates Gut Vascular Barrier through HIF-1α-dependent Mechanism in vitro (2023, Preprint: BioRxiv)

 

[SNT Gatchaman]

Another potential link between between impaired pathways relating to oxygen saturation and some ME findings would be WASF3.

See our thread 2022: NIH study of mitochondria in ME/CFS- WASF3, WAVE3.

He clarifies that gene product was discovered to be raised in the ME cohort of the NIH intramural study which will be published by 2023.

WASF3 is hypoxia-inducible. See —
HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions (2012, International Journal of Cancer)
referenced in Targeting WASF3 Signaling in Metastatic Cancer (2021, Int. J. Mol. Sci.)

 

[Hutan]

From the discussion:

The current randomized controlled trial demonstrates a subtle systolic dysfunction of GLS lower than − 20%, in about half (48.3%) of the post-COVID-19 syndrome patients, which was significantly improved by HBOT. This recovery in GLS by HBOT exceeded the natural recovery rate observed in the sham group.

I think this probably overstates things. From that paper I quoted above, a GLS of less than -20% is not necessarily a dysfunction, subtle or otherwise.

Also from the discussion:

In a recent systematic review, reduced GLS was reported in 30% of post-COVID-19 patients 3–6 months from infection, evaluated using cardiac MRI33.

That's interesting.
Ref 33 is Ramadan, M. S., Bertolino, L., Zampino, R., Durante-Mangoni, E. & Monaldi Hospital Cardiovascular Infection Study G. Cardiac sequelae after coronavirus disease 2019 recovery: a systematic review. Clin. Microbiol. Infect. 27(9), 1250–1261 (2021).
We haven't looked at that paper yet. I note it's a review paper, so it will be citing another paper when it talks about that specific finding.

 

[Hutan]

Ref 33 is Ramadan, M. S., Bertolino, L., Zampino, R., Durante-Mangoni, E. & Monaldi Hospital Cardiovascular Infection Study G. Cardiac sequelae after coronavirus disease 2019 recovery: a systematic review. Clin. Microbiol. Infect. 27(9), 1250–1261 (2021).
We haven't looked at that paper yet. I note it's a review paper, so it will be citing another paper when it talks about that specific finding.

I won't make a separate thread for that paper, as it doesn't relate specifically to Long Covid. It just evaluates cardiac parameters in people who had had Covid-19.

Here's the link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220864/

Figure 2 of the Ramadan paper summarises reports from various papers. I found references to three papers mentioning GLS:
Brito - 0% of the sample was hospitalised. 11% had a reduced GLS
Li - 100% of the sample had been hospitalised. 70% had a reduced GLS
Wang - 100% of the sample had been hospitalised. 30% had a reduced right ventricle peak GLS.
Figure 2 suggests that only 2% of people who had had COVID-19 had reduced GLS in the 0 to 3 month post-infection period. I didn't see where theRamadan et al authors got that figure from.

We'd have to look at those specific papers to see if anything was said about the likely pre-infection heart condition of the samples, and what exactly constituted a reduced GLS. Regardless, just on the information in the Ramadan paper, I think we can say that it's rather misleading to say, as this 2023 Leitman paper did, that "reduced GLS was reported in 30% of post-COVID patients 3-6 months from infection". I think that's, at best, only a reasonable conclusion for hospitalised patients, and we don't really know if that was a result of the infection or a pre-disposing factor for a serious infection.

The Ramadan paper doesn't provide any evidence that reduced GLS is relevant to people with persisting symptoms after a Covid-19 infection.