Review Reports

Round 1

Reviewer 1 Report

I read the article named „Long-term myocardial involvement and outcome in the post 2 COVID-19 Condition “ by Miltiadis Georgiadis and colleagues with great interest.

In the study, they compared 94 post-COVID-19 patients with 100 matched healthy controls using CMR and compared their outcome over a median of 269 days. Despite their ongoing symptoms and an event rate of 0.063, CMR was not able to find substantial abnormalities, only small differences in radial/circumferential strain.

I think the study is of interest. One might ask if the small deviations in strain measurements are of functional relevance for the patients or just point towards a different cause of the patients symptoms (see below). Nevertheless, the study planning and conduction are thorough, the conclusion is relevant, and the manuscript is nicely written.

Before publication, I would recommend some changes:

General aspects:

• I think the main question that remains when reading your publication is: do we really believe that these subtle changes in strain are relevant and the pathophysiological correlate of the persisting symptoms? I would argue that it is not relevant since the strain values, although statistically lower, remain normal. It is not very likely that these small changes in radial strain translate to symptoms like significant shortness of breath. There is likely another cause. One recent publication (1) is quite similar to yours (strain differences but LVEF etc similar) and constitutes “patients … demonstrate normal functional and morphological cardiac parameters”. Looking at possible alternative explanations a recent publication (2) indicates microvascular dysfunction (which can also be assessed indirectly through CMR) as a possible reason for persisting symptoms. I would either town down the conclusion or explicitly discuss why your conclusion is different to previous publications. In both cases, different causes of the persisting symptoms like microvascular dysfunction should be discussed.
• The relatively high event rate of 0.063 in a group of patients with no previous CV diseases at a mean age 48 years is extremly high. In my opinion, none of the found CMR changes explain such an elevated risk. Please discuss in more detail. Do you have any explanation?

 

1) Salatzki J, Ochs A, Weberling LD, Heins J, Zahlten M, Whayne JG, Stehning C, Giannitsis E, Denkinger CM, Merle U, Buss SJ, Steen H, André F, Frey N. Absence of cardiac impairment in patients after severe acute respiratory syndrome coronavirus type 2 infection: A long-term follow-up study. J Cardiovasc Magn Reson. 2024 Winter;26(2):101124. doi: 10.1016/j.jocmr.2024.101124. Epub 2024 Nov 15. PMID: 39549839; PMCID: PMC11663758.

2) Weberling LD, Hillier E, Friedrich MG, Zahlten M, Frey N, André F, Steen H. Abnormal coronary vascular response in patients with long COVID syndrome - a case-control study using oxygenation-sensitive cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2025 Summer;27(1):101890. doi: 10.1016/j.jocmr.2025.101890. Epub 2025 Apr 2. PMID: 40185235; PMCID: PMC12182812.

• It would be of interest to report the troponin and NTproBNP values for all participants, even when they are normal. Your materials state that these were measured in all patients, but results are not given.
• Did you use high-sensitivity troponin assays?
• Please give more details about how you matched the controls. Looking at group differences of age and gender (although not statistically significant) I would guess you did not use exact matching, but the details would be of interest for the readers.
• Please explicitly state the type of study you were performing in the methods section, I guess “prospective, observational, case-control study” would be correct?
• Figure 1 lists a minimum of 12 weeks after infection before CMR was performed. However, the methods state that CMR was done 99 days (IQR 64-110) after diagnosis – how can the 64 days as 1. quartile be explained?  Also, results mention that the first quartile was 62 days (is one a typo?)
• The abbreviation “CMR” is explained four times: three times as “cardiovascular MR” (introduction, 2.2 and discussion) and once in the materials as “cardiac MR”, please correct.
• Patients with a known but asymptomatic DCM or NDLVC would not have been excluded in your study and control cohort as per inclusion / exclusion critera – is that correct? Please discuss if that is the case or explicitly state so if these were excluded
• Is it really believable that controls had no history of Covid-19 infection? Considering that the highest number of new infections per day was in march 2020 and inclusion for this study started in Jan 2021? I do not think this invalidates the conclusion of your study since it remains of interest why in some patients symptoms persist whilst in most it does not.
• It seems a little excessive to quote 5 publications (of 36 in total) just for the validation of the edema sequences
• “Major adverse cardiac events (MACE)—defined as a composite of heart failure, 90 stroke, and all-cause mortality—were recorded for all patients.” This definition does not include MI or myocarditis. Nevertheless, these events were counted as MACE in the results.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

The relevance of the presented study is determined, first of all, by the quite long period after coronavirus infection, as well as the assessment of the outcomes in comparison with MRI data. This period was a little more than 3 months, after which they usually talk about post-COVID or long-COVID. Thus, the study aimed to identify post-COVID changes in cardiac MRI.

The authors are very careful in designating heart damage. This is justified, since MRI does not provide a comprehensive understanding of the nature of pathological processes, but only allows one to assume it.

Some questions and comments.

1. Among the exclusion criteria are congenital heart disease - does this also include cardiomyopathy? If patients with cardiomyopathy were not excluded from the study, it is very difficult to interpret both the symptoms and the MRI data.
2. The exclusion criteria for the comparison group are broader - any heart disease at all. In the main group, only some heart diseases are specified - this could create the initial inequality and partially explain the differences in the MRI data.
3. It is not clear why the authors list all patients excluded for various reasons - it is enough to indicate those patients who met the inclusion criteria and did not have exclusion criteria.
4. In the "healthy controls" group, family history of heart disease, diabetes, obesity, hyperlipidemia were significantly more common - should they be called healthy?
5. The symptoms that served as the basis for suspecting myocarditis are not described in sufficient detail. I would like to see a comparative table for each of the symptoms (not only shortness of breath, pain, but also arrhythmia, for example, melon ECG).
6. It would be appropriate to present figures with MRI data in the main and "healthy" groups.
7. The authors talk about a perimyocarditis-like injury, however, the MRI data are not enough to diagnose myocarditis. This diagnosis can only be verified by endomyocardial biopsy (as was done in individual patients in the study by Puntmann VO et al.). The MRI data itself was not analyzed in full accordance with the 2018 LL criteria. For those MRI criteria of myocarditis that were analyzed, the authors did not obtain any significant differences with the “healthy” group.
8. Differences were obtained only in strain indices, the interpretation of which at the diagnostic level is impossible. One can only very cautiously speak about minimal structural and functional changes in the myocardium.
9. When describing MACE in the main group, a case of myocarditis is presented – what do the authors mean? How was this diagnosis verified? Only one?

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

All comments have been adressed properly - thank you.

Typo line 390 with an extra "." behind the citation no 34 in the middle of the sentence.

Reviewer 2 Report

Dear Editor!
I am completely satisfied with the clarifications the authors have made and can recommend the paper for publication.

no