Cited by 420Heart Rate Variability and Autonomic ControlCardiovascular Function and Risk FactorsDiabetes Management and Research

The DOI matches its Crossref record; 101 of the 101 references it cites were found in a registry or an index; none of the 13 sources its claims cite is checked for support yet.

Heart rate variability in type 2 diabetes mellitus: A systematic review and meta–analysis

Open access

Abstract

BACKGROUND: Cardiac autonomic neuropathy in type 2 dibetes mellitus (T2DM) patients is frequent and associated with high cardiovascular mortality. Heart rate variability (HRV) is the gold standard to measure cardiac autonomic neuropathy. We aimed to conduct a systematic review and meta-analysis to evaluate the impact of T2DM on HRV parameters. METHODS: The PubMed, Cochrane Library, Embase and Science Direct databases were searched on 1st October 2017 using the keywords "diabetes" AND ("heart rate variability" OR "HRV"). Included articles had to report HRV parameters in T2DM patients and healthy controls measured during 24 hours with a Holter-electrocardiogram. Measurements of HRV retieved were: RR-intervals (or Normal to Normal intervals-NN), standard deviation of RR intervals (SDNN), percetange of adjacent NN intervals differing by more than 50 milliseconds (pNN50), square root of the mean squared difference of successive RR intervals (RMSSD), total power, Low Frequency (LF), High Frequency (HF) and LF/HF ratio, as per Task Force recommendations. RESULTS: We included twenty-five case-control studies with 2,932 patients: 1,356 with T2DM and 1,576 healthy controls. T2DM patients had significantly (P<0.01) lower RR-intervals (effect size = -0.61; 95%CI -1.21 to -0.01), lower SDNN (-0.65; -0.83 to -0.47), lower RMSSD (-0.92; -1.37 to -0.47), lower pNN50 (-0.46; -0.84 to -0.09), lower total power (-1.52; -2.13 to -0.91), lower LF (-1.08; -1.46 to -0.69]), and lower HF (-0.79; -1.09 to -0.50). LF/HF did not differ between groups. Levels of blood glucose and HbA1c were associated with several HRV parameters, as well as Time from diagnosis of T2DM. CONCLUSIONS: T2DM was associated with an overall decrease in the HRV of T2DM patients. Both sympathetic and parasympathetic activity were decreased, which can be explained by the deleterious effects of altered glucose metabolism on HRV, leading to cardiac autonomic neuropathy.

Overview

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TL;DR

This systematic review and meta-analysis found that type 2 diabetes mellitus (T2DM) is associated with an overall decrease in heart rate variability (HRV), with both sympathetic and parasympathetic activity reduced. The authors attribute this to deleterious effects of altered glucose metabolism leading to cardiac autonomic neuropathy.

Key findings

Twenty-five case-control studies with 2,932 patients (1,356 T2DM, 1,576 healthy controls) showed significantly lower HRV in T2DM for RR intervals (effect size = –0.61; 95%CI –1.21 to –0.01), SDNN (–0.65; –0.83 to –0.47), RMSSD (–0.92; –1.37 to –0.47), pNN50 (–0.46; –0.84 to –0.09), total power (–1.52; –2.13 to –0.91), LF (–1.08; –1.46 to –0.69), and HF (–0.79; –1.09 to –0.50). LF/HF did not differ between groups (effect size = 0.02; 95%CI –0.38 to 0.43; P = 0.914). Meta-regressions found age and male gender associated with decreased LF and HF; blood glucose and total cholesterol associated with increased LF and HF; higher HbA1c associated with shorter RR intervals; and time from T2DM diagnosis linked with higher SDNN and lower total power.

Methods

Systematic review and meta-analysis of case-control studies reporting 24-hour Holter-electrocardiogram HRV parameters in T2DM patients and healthy controls, following Task Force recommendations. Databases searched were PubMed, Cochrane Library, Embase, and Science Direct (search date reported as 1 October 2017; text also states between 30 October 2015 and 1 October 2017). Random-effects meta-analyses (DerSimonian and Laird) calculated standardised mean differences, with heterogeneity assessed by I² and meta-regressions for clinically relevant variables; study quality was assessed with STROBE and CONSORT.

Limitations

The paper states that meta-analyses inherit limitations of included studies and are subject to selection bias; included studies varied in quality, most were cross-sectional, measurement conditions differed, and inclusion criteria were not identical. The paper also states that control health status was not detailed in all studies, some studies were monocentric, the final number of patients was not very high, and missing or declarative data were potential biases. Evident from the text: heterogeneity was significant for all meta-analyses (e.g., I² = 91.6% for RR intervals, 94.0% for RMSSD, 93.5% for total power), and many variables (HbA1c, BMI, blood pressure, insulin, HOMA-IR, neuropathy scores) were missing or unreported across studies, limiting meta-regression analyses.

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Integrity signals

Registry

Crossref · 10.1371/journal.pone.0195166

Cites

101 of 101 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Fig 1 Search strategy.
Fig 1 Search strategy.CC BY · PubMed Central
Fig 2 Meta–analysis of RR intervals of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; RR: RR intervals; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.
Fig 2 Meta–analysis of RR intervals of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; RR: RR intervals; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.CC BY · PubMed Central
Fig 3 Meta–analysis of SDNN of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; SDNN: Standard Deviation of RR intervals; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.
Fig 3 Meta–analysis of SDNN of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; SDNN: Standard Deviation of RR intervals; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.CC BY · PubMed Central
Fig 4 Meta–analysis of RMSSD of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; RMSSD: square root of mean squared differences of successive RR intervals; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.
Fig 4 Meta–analysis of RMSSD of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; RMSSD: square root of mean squared differences of successive RR intervals; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.CC BY · PubMed Central
Fig 5 Meta–analysis of pNN50 of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; pNN50: percentage of RR intervals with more than 50 ms variation; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.
Fig 5 Meta–analysis of pNN50 of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; pNN50: percentage of RR intervals with more than 50 ms variation; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.CC BY · PubMed Central
Fig 6 Meta–analysis of total power of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; TP: Total Power; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.
Fig 6 Meta–analysis of total power of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; TP: Total Power; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.CC BY · PubMed Central
Fig 7 Meta–analysis of the LF of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; LF: Low Frequency; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.
Fig 7 Meta–analysis of the LF of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; LF: Low Frequency; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.CC BY · PubMed Central
Fig 8 Meta–analysis of the HF of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; HF: High Frequency; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.
Fig 8 Meta–analysis of the HF of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; HF: High Frequency; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.CC BY · PubMed Central
Fig 9 Meta–analysis of LF/HF of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; LF/HF: Low Frequency/High Frequency ratio; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.
Fig 9 Meta–analysis of LF/HF of type 2 diabetes mellitus patients compared with controls. -: non reported data (missing SD were also non reported). 95% CI: 95% confident intervals; BMI: Body Mass Index; LF/HF: Low Frequency/High Frequency ratio; T2DM: Type 2 Diabetes Mellitus; SD: Standard Deviation.CC BY · PubMed Central
Fig 10 Meta–regression of factors influencing heart rate variability in type 2 diabetes mellitus. 95% CI: 95% confident intervals; RR: RR intervals; SDNN: Standard Deviation of RR intervals; pNN50: percentage of RR intervals with more than 50 ms variation; RMSSD: square root of mean squared differences of successive RR intervals; TP: Total Power; LF: Low Frequency; HF: High Frequency; LF/HF: Low Frequency/High Frequency ratio.
Fig 10 Meta–regression of factors influencing heart rate variability in type 2 diabetes mellitus. 95% CI: 95% confident intervals; RR: RR intervals; SDNN: Standard Deviation of RR intervals; pNN50: percentage of RR intervals with more than 50 ms variation; RMSSD: square root of mean squared differences of successive RR intervals; TP: Total Power; LF: Low Frequency; HF: High Frequency; LF/HF: Low Frequency/High Frequency ratio.CC BY · PubMed Central

Verification

Claims the paper makes

37 Own result · 18 Own method · 14 Own interpretation · 10 Not checked yet · 1 No basis given

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  • It may state two separate claims as one. 9
  • The quote only partly states this claim. 1
  • Probably not a substantial claim. 11
19 of 19
  • The paper relies on this without support.

    HRV is the gold standard to measure cardiac autonomic neuropathy.

    “Heart rate variability (HRV) is the gold standard to measure cardiac autonomic neuropathy.”
  • The paper relies on this without support.

    HRV parameters are associated with high inter- and intra-individual variability.

    “with different measurement conditions for HRV parameters associated with a high inter and intra–individual variability.”
2 of 2

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Citations

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  1. L Boer-Martins, 2012, Leptin and aldosterone in sympathetic activity in resistant hypertension with or without type 2 diabetes, Arq Bras Cardiol, 99, 642

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Metadata

Authors
Benichou, T., Pereira, B., Mermillod, M., Tauveron, I., Pfabigan, D., Maqdasy, S., & Dutheil, F.
Affiliations
  • Centre Hospitalier Universitaire de Clermont-Ferrand (FR)
  • Centre National de la Recherche Scientifique (FR)
  • Peking University (CN)
Corresponding author
Dutheil, Frédéric
Venue
PLOS ONE
Published
2018-04-02
Volume
13
Issue
4
Pages
e0195166
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2888208815
Cited by
419
References
101
Citations by year
2026: 43 · 2025: 63 · 2024: 72 · 2023: 59 · 2022: 66 · 2021: 54 · 2020: 33 · 2019: 23 · 2018: 5
FWCI
5.36
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
type 2 diabetes, heart rate variability, cardiac autonomic neuropathy, autonomic dysfunction, sympathetic activity, parasympathetic activity, blood glucose, HbA1c, cardiovascular mortality, Holter electrocardiogram, RR interval, spectral analysis of HRV, autonomic reinnervation
MeSH terms
Adult, Aged, Diabetes Mellitus, Type 2, Female, Heart Rate, Humans, Male, Middle Aged, Regression Analysis, Risk Factors, Body Mass Index, Case-Control Studies

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