Long-Term Impact of COVID-19 on Heart Rate Variability: A Systematic Review of Observational Studies
Round 1
Reviewer 1 Report
The study investigating the association between post-COVID-19 syndrome and heart rate variability was interesting. The manuscript is generally well-structured and adheres to the PRISMA checklist. However, the rationale for the importance of this study is lacking, and improving this aspect could enhance the significance of the research.
Author Response
- Response to Comments from Reviewer 1
Comment 1:
The study investigating the association between post-COVID-19 syndrome and heart rate variability was interesting. The manuscript is generally well-structured and adheres to the PRISMA checklist.
However, the rationale for the importance of this study is lacking, and improving this aspect could enhance the significance of the research.
Response:
Thank you for your careful review and insightful comments that have significantly enhanced our manuscript. We supplemented the rationale for the importance of this study.
“Heart rate variability (HRV) is considered a non-invasive, objective and validated measurement method for evaluating cardiovascular health and autonomic nervous system (ANS) function [16]. Accordingly, HRV has also been considered as an index for some clinical conditions related to ANS dysfunction, including POTS [17], posttraumatic stress disorder [18], and somatic symptom disorders [19]. Also, several studies have reported that HRV was associated with health-related outcomes in COVID-19 [20-23]. In this regards, some studies suggest that monitoring HRV can improve the management of patients with COVID-19 and their clinical outcomes [24,25]. Importantly, it has been hypothesized that the symptoms and signs of long COVID overlap with those of ANS dysfunction such as POTS, and that this pattern may be explained by autonomic instability [26]. Although other underlying mechanisms of long COVID include immune dysregulation, gut microbiota imbalance, and autoimmunity, ANS dysfunction is still considered a promising therapeutic target for this clinical condition [27]. Although there has been a recent systematic review investigating changes in HRV parameters in individuals currently positive for SARS-CoV-2 [28], there has been no attempt to comprehensively investigate the relationship between HRV parameters and the long-term effects of SARS-CoV-2 infection, including long COVID.
Therefore, this systematic review of observational studies aimed to investigate the long-term association between COVID-19 and HRV parameters.”
(Please see in page 2, red words)
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Authors performed a systematic literature review to investigate the association between having COVID-19 disease in the past, either a short or long disease. The search strategy is provided, including the use of author keywords and MeSH terms to identify relevant articles from selected databases. Characteristics of studies included are described in detail as well as discussion of potential causes of reduced heart rate after COVID-19. However, some parts should be improved:
- inclusion and exclusion criteria used to select articles for examination should be more detailed.
- Outcome definitions should be clearly stated.
- Authors included only available observational studies, all of them were cross-sectional. Apart from a very arguable design of studies included, comparison of only after-Covid heart parameters without knowing baseline values introduces a huge bias. This should be at least addressed in limitations. In this light, it can not be concluded that “a long-term reduction in SDNN after COVID-19 was observed” and that “changes in HRV associated with COVID-19 68 would be related to its long-term effects”.
- In the abstract, line 18, “we included an observation study” seems like you have included only one observational study. I assume the authors intended that study design considered for the review was observational design?
- Supplementary files are inverted, i.e., files do not correspond to the mentions in the text.
- Line 88 – I would rather say “Individuals who reported absent or unclear clinical symptoms after COVID-19 recovery were not excluded, but they were analyzed separately from those with long COVID”.
- Line 367: Clinical implications are more comparison with literature, real clinical implications shold be added.
- Conclusions should be reworded to present better what was done in the study; “long-term reduction in SDNN after COVID-19” was not assessed.
Author Response
- Response to Comments from Reviewer 2
General comment:
Authors performed a systematic literature review to investigate the association between having COVID-19 disease in the past, either a short or long disease. The search strategy is provided, including the use of author keywords and MeSH terms to identify relevant articles from selected databases. Characteristics of studies included are described in detail as well as discussion of potential causes of reduced heart rate after COVID-19. However, some parts should be improved:
Response:
Thank you for your careful review and insightful comments that have significantly enhanced our manuscript.
Comment 1:
- inclusion and exclusion criteria used to select articles for examination should be more detailed.
Response:
Thank you for the comment. We have described the inclusion and exclusion criteria in more detail.
“The eligibility criteria of this systematic review can be summarized as the following PICOS format. (1) Population: Individuals who recovered from COVID-19 or individuals with long COVID were included as the population of interest in this review. The recovery usually means the negative conversion of SARS-CoV-2 infection. And long COVID was defined as clinical symptoms developing at usually 3 months from the onset of COVID-19 and existing for more than 2 months [5]. Individuals who reported absent or unclear clinical symptoms after COVID-19 recovery were not excluded, but they were analyzed separately from those with long COVID. There was no restriction on the participant’s clinical condition, language, sex, age, or ethnicity. (2) Intervention: Not applicable. (3) Comparator: Healthy (or uninfected) individuals were included as control groups. (4) Outcome: The outcomes of interest in this review were HRV parameters. The parameters are classified into time-domain measures and frequency-domain measures. The HRV time-domain measures include the standard deviation of normal-to-normal RR intervals (SDNN), root mean square of the successive differences (RMSSD), standard deviation of the average NN intervals for each 5 min segment of a 24 h HRV recording (SDANN), SDNN index, and percentage of successive RR intervals that differ by more than 50 ms (pMM50) [30]. On the other hand, HRV frequency-domain measures include the low-frequency band (LF), the high-frequency band (HF), and LF/HF ratio [30]. (5) Study design: Observational studies, including observational cohort studies, cross-sectional studies, and case-control studies, were included in this review. However, case reports and case series were excluded. Also, animal studies, reviews, and intervention studies were excluded from this review.”
(Please see in pages 2-3, red words)
Comment 2:
- Outcome definitions should be clearly stated.
Response:
Thank you for the comment. We have more clearly described the HRV-related parameters (i.e., the outcome of interest) by classifying them into time-domain and frequency-domain.
“(4) Outcome: The outcomes of interest in this review were HRV parameters. The parameters are classified into time-domain measures and frequency-domain measures. The HRV time-domain measures include the standard deviation of normal-to-normal RR intervals (SDNN), root mean square of the successive differences (RMSSD), standard deviation of the average NN intervals for each 5 min segment of a 24 h HRV recording (SDANN), SDNN index, and percentage of successive RR intervals that differ by more than 50 ms (pMM50) [30]. On the other hand, HRV frequency-domain measures include the low-frequency band (LF), the high-frequency band (HF), and LF/HF ratio [30].”
(Please see in page 3, red words)
Comment 3:
- Authors included only available observational studies, all of them were cross-sectional. Apart from a very arguable design of studies included, comparison of only after-Covid heart parameters without knowing baseline values introduces a huge bias. This should be at least addressed in limitations. In this light, it can not be concluded that “a long-term reduction in SDNN after COVID-19 was observed” and that “changes in HRV associated with COVID-19 68 would be related to its long-term effects”.
Response:
Thank you for the comment. We totally agree with the comment. We should have interpreted the findings in this manuscript more carefully. Therefore, in this revised manuscript, the following corrections were made to reflect the reviewer's comments.
“The included studies generally found decreased SDNN and parasympathetic activity in post-COVID-19 individuals. Compared to controls, decreases in SDNN were observed in individuals who recovered from COVID-19 or had long COVID.”
(Please see in page 1, red words)
“Therefore, this systematic review of observational studies aimed to investigate the long-term association between COVID-19 and HRV parameters.”
(Please see in page 2, red words)
“Second, we could not investigate causal relationships because the included studies were cross-sectional. Because the included studies only used uninfected or healthy controls as their control groups, it was not possible to analyze longitudinal changes in HRV parameters in individuals before and after SARS-CoV-2 infection. Also, the comparability of the controls and infected patients can also be pointed out as a limitation of this review. Although the majority of included studies adjusted for key potential confounding variables between exposed and control groups [39-41,43,45-47], there were also some studies that did not. Thus, the authors admit that the findings of this review may have been biased. Some authors of the primary studies concluded that autonomic imbalance could explain the pathology of long-COVID-19 [38,39], but this conclusion would require further longitudinal cohort studies.”
(Please see in page 14, red words)
“Compared to uninfected or healthy controls, decreases in SDNN were observed in individuals who recovered from COVID-19 or had long COVID. On the other hand, consistent differences between the groups were not observed in RMSSD, LF, and HF.”
(Please see in page 14, red words)
Comment 4:
- In the abstract, line 18, “we included an observation study” seems like you have included only one observational study. I assume the authors intended that study design considered for the review was observational design?
Response:
Thank you for the comment. That expression has been modified as follows.
“We included observational studies comparing HRV parameters …”
(Please see in page 1, red words)
Comment 5:
- Supplementary files are inverted, i.e., files do not correspond to the mentions in the text.
Response:
Thank you for the comment. We found that Supplementary 1 and 2 previously submitted were interchanged. We corrected the Supplementary file names in the correct order in this revised manuscript.
Comment 6:
- Line 88 – I would rather say “Individuals who reported absent or unclear clinical symptoms after COVID-19 recovery were not excluded, but they were analyzed separately from those with long COVID”.
Response:
Thank you for the comment. That sentence was corrected with the sentence suggested by the reviewer.
“Individuals who reported absent or unclear clinical symptoms after COVID-19 recovery were not excluded, but they were analyzed separately from those with long COVID.”
(Please see in page 3, red words)
Comment 7:
- Line 367: Clinical implications are more comparison with literature, real clinical implications shold be added.
Response:
Thank you for the comment. We added the following to bring the findings of this review to clinical implications.
“Several studies have reported an acute effect of COVID-19 on the ANS [24,50]. Specifically, a previous systematic review showed mixed results of changes in SDNN and RMSSD in patients with acute COVID-19 [51], while LF and HF were generally lower in COVID-19 patients compared to healthy controls [51]. However, this review suggests a consistent finding of reduced SDNN in the long-term impact of COVID-19 and no consistent findings in RMSSD, LF, and HF. Given that SDNN is considered a gold standard indicator for cardiac risk [30], a possible association between long-term effects of COVID-19 and cardiac risk may be raised. A study that followed more than 150,000 individuals with COVID-19 for one year found that the risks and burdens of cardiovascular disease are substantial in the COVID-19 survivors [11]. In addition, some risk factors including pre-existing cardiovascular comorbidities may increase cardiovascular risk in these patients [52]. Therefore, HRV parameters such as SDNN, which can be measured non-invasively and conveniently, are considered clinically worthy of attention for the purpose of monitoring the long-term effects of COVID-19 and cardiovascular risk of COVID-19 survivors.
…
The COVID-19 pandemic is considered to have triggered a huge shift in the popularization of telemedicine in the delivery of healthcare [54,55]. And the use of wearable health devices plays an important role in terms of telemedicine [54]. Importantly, HRV is one of the popular health indicators for the wearable health devices [55]. Therefore, if telemedicine using wearable health devices becomes more popular in the post-COVID-19 era, establishing the clinical significance of HRV parameters from the perspective of evidence-based medicine is clinically relevant. In this context, the findings of this review could be used to promote better patient-doctor communication, or to facilitate the successful implementation of the wearable health devices [56].”
(Please see in page 13, red words)
Comment 8:
- Conclusions should be reworded to present better what was done in the study; “long-term reduction in SDNN after COVID-19” was not assessed.
Response:
Thank you for the comment. Based on the reviewer's advice, we have amended our conclusions as follows.
“Compared to uninfected or healthy controls, decreases in SDNN were observed in individuals who recovered from COVID-19 or had long COVID. On the other hand, consistent differences between the groups were not observed in RMSSD, LF, and HF. Most included studies emphasized parasympathetic inhibition in post-COVID-19 conditions, including long COVID-19. However, the studies included in this review are cross-sectional and do not guarantee causality. Moreover, due to the methodological limitations of studies, including the measurement of HRV parameters, the findings should be further validated by more robustly designed prospective longitudinal studies.”
(Please see in page 2, red words)
Author Response File: Author Response.pdf
Reviewer 3 Report
The authors reviewed long-term impact of COVID-19 on heart rate variability. There are several issues needing to consider before possible publish.
1. The definition of long-term COVID-19: how to identify the association between COVID-19 and these symptoms? Reference 6 might overestimate the incidence rate of long COVID. I don’t recommend to cite this data.
2. Almost the whole population has infected SARS-CoV-2. Even there is an association between heart rate variability and COVID-19, how to apply this discovery to COVID-19 prevention or heart disease treatment? The clinical application of the association of heart rate variability and COVID-19 needs to be addressed.
3. The comparability of the controls and those infected needs to be provided.
Author Response
- Response to Comments from Reviewer 3
General comment:
The authors reviewed long-term impact of COVID-19 on heart rate variability. There are several issues needing to consider before possible publish.
Response:
Thank you for your careful review and insightful comments that have significantly enhanced our manuscript.
Comment 1:
- The definition of long-term COVID-19: how to identify the association between COVID-19 and these symptoms? Reference 6 might overestimate the incidence rate of long COVID. I don’t recommend to cite this data.
Response:
Thank you for the comment. We have added the definition of long COVID, and the reference 6 has been replaced with the latest research.
“Therefore, a set of persistent or new symptoms after COVID-19 is called “long COVID” or “post-acute COVID-19 syndrome.” According to a WHO-led Delphi consensus, long COVID refers to a complex symptom cluster developing 3 months from the onset of COVID-19 that last more than 2 months, and cannot be explained by an alternative diagnosis. [5]. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction; these symptoms fluctuate or relapse over time [5]. According to a meta-analysis of 50 studies, the prevalence of the post-COVID-19 condition or long COVID (symptomatic at 28+ days from the infection) reached 43% [6]. Thus, the long-term impact of COVID-19 is a cause for concern.”
(Please see in pages 1-2, red words)
[6] Chen, C.; Haupert, S.R.; Zimmermann, L.; Shi, X.; Fritsche, L.G.; Mukherjee, B. Global Prevalence of Post-Coronavirus Disease 2019 (COVID-19) Condition or Long COVID: A Meta-Analysis and Systematic Review. J Infect Dis 2022, 226, 1593-1607, doi:10.1093/infdis/jiac136.
Comment 2:
- Almost the whole population has infected SARS-CoV-2. Even there is an association between heart rate variability and COVID-19, how to apply this discovery to COVID-19 prevention or heart disease treatment? The clinical application of the association of heart rate variability and COVID-19 needs to be addressed.
Response:
Thank you for the comment. We added the following to bring the findings of this review to clinical implications.
“Several studies have reported an acute effect of COVID-19 on the ANS [24,50]. Specifically, a previous systematic review showed mixed results of changes in SDNN and RMSSD in patients with acute COVID-19 [51], while LF and HF were generally lower in COVID-19 patients compared to healthy controls [51]. However, this review suggests a consistent finding of reduced SDNN in the long-term impact of COVID-19 and no consistent findings in RMSSD, LF, and HF. Given that SDNN is considered a gold standard indicator for cardiac risk [30], a possible association between long-term effects of COVID-19 and cardiac risk may be raised. A study that followed more than 150,000 individuals with COVID-19 for one year found that the risks and burdens of cardiovascular disease are substantial in the COVID-19 survivors [11]. In addition, some risk factors including pre-existing cardiovascular comorbidities may increase cardiovascular risk in these patients [52]. Therefore, HRV parameters such as SDNN, which can be measured non-invasively and conveniently, are considered clinically worthy of attention for the purpose of monitoring the long-term effects of COVID-19 and cardiovascular risk of COVID-19 survivors.
…
The COVID-19 pandemic is considered to have triggered a huge shift in the popularization of telemedicine in the delivery of healthcare [54,55]. And the use of wearable health devices plays an important role in terms of telemedicine [54]. Importantly, HRV is one of the popular health indicators for the wearable health devices [55]. Therefore, if telemedicine using wearable health devices becomes more popular in the post-COVID-19 era, establishing the clinical significance of HRV parameters from the perspective of evidence-based medicine is clinically relevant. In this context, the findings of this review could be used to promote better patient-doctor communication, or to facilitate the successful implementation of the wearable health devices [56].”
(Please see in page 13, red words)
Comment 3:
- The comparability of the controls and those infected needs to be provided.
Response:
Thank you for the comment. That comparability is probably one of the limitations of this review due to the limitations of the included studies. In this regard, we have added the following discussion.
“Second, we could not investigate causal relationships because the included studies were cross-sectional. Because the included studies only used uninfected or healthy controls as their control groups, it was not possible to analyze longitudinal changes in HRV parameters in individuals before and after SARS-CoV-2 infection. Also, the comparability of the controls and infected patients can also be pointed out as a limitation of this review. Although the majority of included studies adjusted for key potential confounding variables between exposed and control groups [39-41,43,45-47], there were also some studies that did not. Thus, the authors admit that the findings of this review may have been biased. Some authors of the primary studies concluded that autonomic imbalance could explain the pathology of long-COVID-19 [38,39], but this conclusion would require further longitudinal cohort studies.”
(Please see in page 14, red words)
Author Response File: Author Response.pdf
