Meta-analysis on inflammation and autonomic nervous system of coronary heart disease combined with depression

Abstract

Objectives

This meta-analysis aimed to explore the association between inflammatory factors, heart rate variability (HRV) and the coexistence of coronary heart disease (CHD) and depression.

Design

Systematic review and meta-analysis. Complying with the Meta-analysis Of Observational Studies in Epidemiology statement.

Data sources

We searched PubMed, Web of Science and EMBASE for the data from the inception date to 16 March 2023.

Eligibility criteria

We included cross-sectional and cohort studies with inclusion criteria: (1) patients with CHD; (2) depression measurement and (3) including inflammatory factors or cardiac biomarkers or HRV.

Data extraction and synthesis

Two authors searched the databases independently. The effect estimates and heterogeneity were synthesised by Review Manager V.5.3. Sensitivity analysis and publication bias were analysed by STATA software. The quantitative synthesis outcomes were presented by mean difference (MD) or standard MD (SMD) with 95% CI.

Results

By searching the databases, we identified a total of 6750 articles. There were 22 articles left after selection, including 6344 participants. This meta-analysis indicated that patients with CHD with depression had higher levels of C reaction protein (CRP) (SMD 0.50, 95% CI (0.19 to 0.81), p=0.001), high-sensitivity C reactive protein (hs-CRP) (SMD 0.28, 95% CI (0.07 to 0.48), p=0.008), IL-6 (SMD 0.49, 95% CI (0.05 to 0.92), p=0.03) and a lower level of the mean RR interval and the SD of all RR intervals (SMD −0.64, 95% CI (−1.11 to –0.17), p=0.008), SD of the 5 min averages of all normal RR intervals (MD −12.77 ms, 95% CI (–21.20 to –4.33), p=0.003), overage of the SD of all normal RR intervals for each 5 min segment (MD −13.83 ms, 95% CI (–15.94 to –11.72), p<0.00001), root mean square of successive differences (MD: −8.02 ms, 95% CI (–13.62 to –2.43), p=0.005), proportion of adjacent cycles differing by >50 ms (pNN50) (SMD −0.86, 95% CI (−1.41 to –0.31), p=0.002), than those without depression.

Conclusions

This study underscores the association between elevated CRP, hs-CRP, IL-6 and lower HRV in patients with CHD with depression. It emphasises the importance of clinicians assessing CRP, hs-CRP, IL-6 and HRV in patients with CHD to potentially identify depressive conditions.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• A number of articles on this topic were searched from the three key databases.

• Publication bias was dealt with Duval’s trim-and-fill method.

• The quantitative synthesis outcomes were presented by mean difference (MD) or standard MD.

• Limited availability of cohort studies investigating biomarkers for depression in coronary heart disease.

Introduction

Both cardiovascular disease (CVD) and depression are prevalent and life-threatening and burdened disease worldwide. In China alone, the updated Report on Cardiovascular Health and Diseases in China 2021 reports 330 million patients with CVD.¹ While smoking, hypertension, diabetes and other traditional risk factors play a significant role, emerging data highlight the influence of psychological factors on CVD development.² Notably, depression is on track to become the second leading health hazard by 2030.³ The WHO reports that 340 million people worldwide suffer from depression. This mental health condition is a predictor of cardiac events in symptomatic women with suspected myocardial ischaemia.⁴ Furthermore, depression has been identified as a crucial risk factor of coronary heart disease (CHD), and significantly increases the mortality in patients with CHD.⁵ Accumulated evidence demonstrates a high prevalence of depression among patients with CHD.⁶ Fortunately, psychological therapies have the potential to reduce the risk of cardiac events.⁷

Several potential mechanisms connect CHD and depression. These include genetic variants,⁸ endothelial dysfunction,⁹ inflammation response,¹⁰ the imbalance of sympathetic and parasympathetic nerves,¹¹ dysregulation of the hypothalamic–pituitary–adrenal axis,¹² 5-hydroxytryptamine (5-HT) system dysfunction¹³ and thrombocyte aggregation abnormalities.¹⁴ Elevated proinflammatory factors point towards an increased inflammatory response in both CHD and depression. Heart rate variability (HRV) serves as a readily available and convenient method to assess the impairment of the sympathetic and parasympathetic nervous systems. Reduced HRV is associated with adverse prognoses in patients with both depression and CVD.^{15 16} Moreover, the interplay between inflammation and HRV is well established. Proinflammatory states are linked to reduced HRV.¹⁷ For example, Euteneuer et al ¹⁸ demonstrated that patients with major depressive disorder (MDD) exhibit higher levels of C reactive protein (CRP), interleukin (IL)-6 and tumour necrosis factor-α (TNF-α), alongside reduced 24 hours and daytime HRV. What is worse, autonomic nervous system (ANS) dysfunction and inflammatory response contribute to higher cardiac mortality in patients with depression.¹⁹

Currently, cardiologists rely on self-evaluation scales to assess depressive symptoms in patients with CVD. However, these scales are susceptible to subjectivity. We believe that incorporating biological markers into the assessment could offer a more objective measure, reducing the influence of subjective bias. Therefore, this meta-analysis focuses on the role of inflammatory factors and HRV in understanding the co-occurrence of CHD and depression.

Methods

Registration

We conducted this meta-analysis in accordance with the Meta-analysis Of Observational Studies in Epidemiology statement (online supplemental material 1).²⁰ The meta-analysis was registered in the International Prospective Register of Systematic Reviews network, with registration number CRD42023405320.

Search strategy

We searched PubMed, Web of Science and EMBASE for relevant data from database inception to 16 March 2023. The search strategy details were shown in online supplemental material 2.

Study selection process

Eligibility criteria

Inclusion criteria: (1) patients diagnosed with CHD; (2) measurement of depression and (3) inclusion of inflammatory factors, cardiac biomarkers or HRV.

Exclusion criteria: (1) pregnant patients; (2) studies lacking full text; (3) studies with unextractable data; (4) studies with duplicate data repeated; (5) non-English language studies; (6) case reports, letters or reviews and (7) animal studies.

Data collection process

Two authors (GL and LZ) independently searched the databases. We selected eligible studies based on the predefined inclusion and exclusion criteria. In cases of disagreement, a third author was consulted for further evaluation. References were managed using EndNote V.20 software (Thomson Scientific).

Coronary heart disease

We used the following keywords to search for studies related to CHD: coronary artery disease, coronary atherosclerotic heart disease, CHD, ischaemic heart disease, acute coronary syndrome (ACS), unstable angina, stable angina pectoris, silent myocardial ischaemia and myocardial infarction.

Depression measurement

The following depression measurement instruments were included: Beck Depression Inventory, Composite International Diagnostic Interview, Clinical Global Impressions Severity of Depressive Illness, Interview Schedule-Revised, Computerised National Institute of Mental Health Diagnostic Interview Schedule-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Hamilton Depression Scale and Hamilton Depression Rating Scale-17.

Data extraction

We extracted critical information from the included studies, including first author, publish year, study type, country, sample size, type of CHD, depression measurement instrument, biomarkers and detection method of biomarkers (table 1).

Table 1.

Basic characteristics of the studies

First author	Publish year	Study type	Country	Sample	CHD	Depression measurement	Predictors	Study quality assessment
Alizadeh23	2021	Cross-sectional study	Iran	116	Post-MI	BDI-II	Hs-CRP	Combie:A
Aydin24	2017	Cross-sectional study	Turkey	119	Stable CAD	DSM-IV-TR	Fibrinogen CRP NT-proBNP SDNN SDANN SDNNIDX pNN50 RMSSD	Combie:A
Bankier25	2009	Cross-sectional study	USA	72	Stable CHD	DSM-IV	CRP NT-proBNP	Combie:A
Carney26	1995	Cross-sectional study	USA	38	CAD	NIMHDIS DSM-IV	SDANN SDNNIDX pNN50 RMSSD	Combie:A
Duivis27	2011	Prospective cohort study	Netherlands USA	581	Stable CHD	PHQ-9 DSM-IV	Fibrinogen	NOS:high
Frasure- Smith28	2009	Cross-sectional study	Canada	682	AMI	BDI-II DSM-IV	SDNN	Combie:A
Gehi29	2005	Cross-sectional study	USA	873	Stable CHD	DSM-IV PHQ-9 CDIS-IV	SDNN SDANN	Combie:A
Guinjoan30	2004	Cross-sectional study	Argentina	56	UA or AMI	DSM-IV, HAMD	SDNN pNN50 rMSNN	Combie:A
Lafitte31	2015	Cohort study	France	87	Post ACS	MINI DSM-IV ICD-10 HDRS-17 MADRS	Hs-CRP Fibrinogen	NOS:high
Lespérance32	2004	Cross-sectional study	Montreal	481	ACS	DSM-IV	IL-6 CRP	Combie:A
Luo33	2018	Cross-sectional study	China	189	Stable CAD	5-Item Geriatric Depression	SDNN SNANN SDNNIDX RMSSD pNN50	Combie:A
Martens34	2008	Cross-sectional study	Netherlands	78	Post-MI	CIDI BDI	SDANN SDNN RMSSD	Combie:A
Ren35	2017	Cross-sectional study	China	103	Post-AMI	SDS	NT-proBNP	Combie:A
Roohafza36	2018	Cross-sectional study	Iran	162	AMI	BDI	IL-6 CRP	Combie:A
Schins37	2005	Cross-sectional study	Netherlands	103	Post-MI	BDI CIDI-auto	IL-6 CRP	Combie:A
Sforzini38	2019	Cohort study	London	89	CHD	CIS-R PHQ-9	Hs-CRP	NOS:high
Stein39	2000	Cross-sectional study	USA	50	Stable CAD	NIMHDIS DSMIV BDI	SDNN SDANN SDNNIDX RMSSD pNN50	Combie:A
Whooley40	2007	Prospective cohort study	USA	984	Stable CHD	CDIS-IV DSM-IV PHQ-9	Fibrinogen	NOS:high
Whooley41	2008	Prospective cohort study	USA	1017	Stable CHD	PHQ-9 DSM-IV CDIS-IV	SDANN	NOS:high
Wilkowska42	2019	Cross-sectional study	Poland	22	Post-MI	BDI DSM-IV TR criteria	SDNN	Combie:B
Yang43	2012	Prospective observational study	China	232	Post-CABG	PHQ-9	Hs-CRP	Combie:A
Ye44	2022	Cross-sectional study	China	210	CHD	HAMD	CRP IL-6	Combie:A

Combie tool: grade A (6.0–7.0 points, high quality), grade B (4.0–5.5 points, medium quality) and grade C (<4 points, low quality).

NOS: high quality, 7–9 stars; medium quality, 5–6 stars and poor quality, 0–4 stars.

ACS, acute coronary syndrome; AMI, acute myocardial infarction; BDI-II, Beck depression inventory II Scale; CAD, coronary artery disease; CDIS-IV, Computerised National Institute of Mental Health Diagnostic Interview Schedule; CHD, coronary heart disease; CIDI, Composite International Diagnostic Interview; CIS-R, Clinical Global Impressions Severity of Depressive Illness Interview Schedule-Revised; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; HAMD, Hamilton Depression Scale; HDRS-17, 17 item Hamilton Depression Rating Scale; hs-CRP, high-sensitivity C reactive protein; IHD, ischaemia heart disease; MADRS, The Montgomery-Åsberg Depression Rating Scale; MI, myocardial infarction; MINI, Mini-International Neuropsychiatric Interview; NIMHDIS, National Institute of Mental Health Diagnostic Interview Schedule; NOS, Newcastle-Ottawa Scale; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PHQ-9, Patient Health Questionnaire-9; pNN50, proportion of adjacent cycles differing by >50 ms; rMSSD, root mean square of successive differences; SCID, Structured Clinical Interview for DSM-III-R Diagnoses; SDANN, SD of the 5 min averages of all normal RR intervals.; SDNN, the mean RR interval and the SD of all RR intervals; SDNNIDX, overage of the SD of all normal RR intervals for each 5 min segment; SDS, Zung Self-rating Depression Scale; UA, unstable angina.

Study quality assessment

We assessed the quality of cross-sectional studies using the Combie tool,²¹ and the quality of cohort studies using with the Newcastle-Ottawa Scale.²² The results of the quality assessment are presented in table 1.

Statistic analysis

We synthesised effect estimates and heterogeneity using Review Manager V.5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark). The choice of a random-effects model (p<0.10 or I²>50%) or fixed-effects model (p>0.10 and I²≤50%) was based on the results of the Cochran’s Q-test and the I² index. The quantitative synthesis outcomes were presented by mean difference (MD) or standard MD (SMD) with 95% CI. MD would be chosen when the unit was consistent, and the data heterogeneity was small. While SMD would be used when the units were different, or the data heterogeneity was big. In this study, SMD was used when analysing CRP, hs-CRP, IL-6, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), the mean RR interval and the SD of all RR intervals (SDNN), PNN50. MD was used when analysing fibrinogen, SD of the 5 min averages of all normal RR intervals (SDANN), SDANNIDX, root mean square of successive differences (RMSSD). Sensitivity analysis and publication bias were assessed using STATA software V.8 (STATA). Egger’s test was used to analyse publication bias. Duval’s trim-and-fill method would be used if there was publication bias.

Patient and public involvement

None.

Results

Data inclusion

We identified a total of 6750 articles through database searches. After reviewing titles, abstracts and full texts, and excluding duplicates and ineligible studies, 22 articles^23–44 remained for analysis, representing 6344 participants. Thirteen studies23 28 31 32 34–39 42–44 were approved by the ethics committees of their institutions. Five studies (Bankier et al,²⁵ Duivis et al,²⁷ Gehi et al,²⁹ Whooley et al,⁴⁰ Whooley et al ⁴¹) were approved by their institutional review boards and obtained the informed consent from all patients. Four studies (Aydin Sunbul et al,²⁴ Carney et al,²⁶ Guinjoan et al,³⁰ Luo et al ³³) did not include ethical statements yet obtained the patients’ consents. The flow chart of this meta-analysis is presented in figure 1.

Figure 1.

Flow chart of this meta-analysis.

Inflammatory factors

C reaction protein

Six articles24 25 32 36 37 ⁴⁴with a total of 1147 participants (360 with CHD and depression, and 787 with CHD only) were included in the meta-analysis of CRP and CHD combined with depression. Although significant heterogeneity was observed (I²=78%, p=0.0004), a random-effects model revealed that patients with CHD with depression had significantly higher CRP levels than those without depression (SMD 0.50, 95% CI (0.19 to 0.81), p=0.001) (table 2, figure 2, online supplemental material 3). Subgroup analysis of CRP in patients with ACS: There were two studies^{32 36} included in this subgroup analysis. But there was no significant difference between patients with depression and those without depression (SMD 0.43, 95% CI (−0.14 to 1.01), p=0.14) (table 2, online supplemental material 3).

Table 2.

The results of this meta-analysis

	Sample				Heterogeneity				Test for overall effect
	CHD+D	CHD	SMD/MD	Fix/Random	Tau2	Chi2	df (p value)	I2	Z	P value
CRP	360	787	0.50 (0.19, 0.81)	Random	0.11	22.35	5 (0.0004)	78%	3.18	0.001
CRP subgroup	118	525	0.43 (−0.14, 1.01)	Random	0.14	6.07	1 (0.01)	84%	1.48	0.14
Hs-CRP	122	402	0.28 (0.07, 0.48)	Fix	–	5.37	3 (0.15)	44%	2.66	0.008
IL-6	265	691	0.49 (0.05, 0.92)	Random	0.17	20.79	3(0.0001)	86%	2.18	0.03
IL-6 subgroup	118	525	0.54 (−0.36, 1.44)	Random	0.40	14.46	1 (0.0001)	93%	1.17	0.24
Fibrinogen	445	1326	0.11 (−0.22, 0.44)	Random	0.10	38.16	3 (<0.00001)	92%	0.64	0.52
NT-proBNP	131	163	1.83 (−0.69, 4.34)	Random	4.84	141.18	2 (＜0.00001)	99%	1.42	0.15
SDNN	607	1462	−0.64 (−1.11, –0.17)	Random	0.40	118.29	7 (＜0.00001)	94%	2.67	0.008
SDANN	517	1658	−12.77 (−21.20, –4.33)	Random	81.06	24.80	5 (0.0002)	80%	2.97	0.003
SDNNIDX	194	202	−13.83 (−15.94, –11.72)	Fix	–	0.36	3 (0.95)	0%	12.83	＜0.00001
RMSSD	213	261	−8.02 (−13.62, –2.43)	Random	32.20	30.84	4 (＜0.00001)	87%	2.81	0.005
pNN50	213	239	−0.86 (−1.41, –0.31)	Random	0.32	26.61	4 (＜0.0001)	85%	3.09	0.002

CHD, coronary heart disease; CHD+D, CHD combined with depression; hsCRP, high-sensitivity C reactive protein; MD, mean difference; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; RMSSD, root mean square of successive differences; SDANN, SD of the 5 min averages of all normal RR intervals; SDNN, the mean RR interval and the SD of all RR intervals; SDNNIDX, overage of the SD of all normal RR intervals for each 5 min segment; SMD, standard MD.

Figure 2.

Forest plot of CRP and CHD combined with depression

High-sensitivity-CRP

Four articles23 31 38 43 with a total number of 524 participants (122 with CHD and depression, 402 with CHD only) were included in the meta-analysis of hs-CRP and CHD combined with depression. Low heterogeneity was observed (I²=44%, p=0.15), allowing for a fixed-effects model. The analysis revealed that patients with CHD with depression had significantly higher hs-CRP levels than those without depression (SMD 0.28, 95% CI (0.07 to 0.48), p=0.008) (table 2, figure 3, online supplemental material 3).

Figure 3.

Forest plot of hs-CRP and CHD combined with depression.

Interleukin-6

Four articles32 36 37 44 with a total number of 956 participants (265 with CHD and depression group, and 691 with CHD only) were included in a meta-analysis of IL-6 and CHD combined with depression. High heterogeneity was observed (I²=86%, p=0.0001), prompting the use of a random-effects model. Interestingly, there was a significant difference in IL-6 levels between patients with CHD with and without depression (SMD 0.49, 95% CI (0.05 to 0.92), p=0.03) (table 2, online supplemental material 3). Subgroup analysis of IL-6 in patients with ACS: There were two studies^{32 36} included in this subgroup analysis. However, there was no significant difference between patients with depression and those without depression (SMD 0.54, 95% CI (−0.36 to 1.44), p=0.24).

Fibrinogen

Four articles24 27 31 40 with a total number of 1771 patients (445 with CHD and depression group, and 1326 with CHD only) were included in the meta-analysis of fibrinogen and CHD combined with depression. High heterogeneity was also observed (I²=92%, p<0.00001), prompting the use of a random-effects model. No significant difference in fibrinogen levels was found between patients with CHD with and without depression (MD 0.11 mg/dL, 95% CI (−0.22 to 0.44), p=0.52) (table 2, online supplemental material 3).

Natriuretic peptide-proBNP

Three articles,^{24 25 35} encompassing 294 patients (131 with CHD and depression, and 163 with CHD only), were included in the meta-analysis of NT-proBNP and CHD combined with depression. Despite substantial heterogeneity (I²=99%, p<0.00001), necessitating a random-effects model, no significant difference in NT-proBNP levels was observed between patients with CHD with and without depression (SMD 1.83, 95%CI (−0.69 to 4.34), p=0.15) (table 2, online supplemental material 3)

Autonomic nervous system

SD of all RR intervals

Eight articles24 28–30 33 34 39 42 comprising 2069 patients (607 with CHD and depression, and 1462 with CHD alone) were analysed in the meta-analysis of SDNN and CHD combined with depression. High heterogeneity (I²=94%, p<0.00001) dictated the use of a random-effects mode. Notably, patients with CHD with depression exhibited lower SDNN compared with those without depression (SMD −0.64, 95% CI (−1.11 to –0.17), p=0.008) (table 2, online supplemental material 3).

SD of the SDANN

Six articles,24 26 29 34 39 41 including 2175 patients (517 with CHD and depression, and 1658 with CHD only), were included in the meta-analysis of SDANN and CHD combined with depression. Again, considerable heterogeneity (I²=80%, p=0.0002) necessitated a random-effects model. Similar to the previous findings, patients with CHD with depression demonstrated lower SDANN compared with those without deprion (MD −12.77 ms, 95% CI (−21.20 to –4.33), p=0.003) (table 2, online supplemental material 3).

Average of the SDNN intervals for each 5 min segment

Four articles,24 26 33 39 with a total of 396 patients (194 with CHD and depression group, and 202 with CHD alone), contributed to the meta-analysis of average of the SD of all normal RR intervals for each 5 min segment (SDNNIDX) and CHD combined with depression. Notably, this analysis exhibited no heterogeneity (I²=0%, p=0.95), allowing for a fixed effects model. Consistent with prior findings, patients with CHD with depression displayed lower SDNNIDX compared with those without depression (MD −13.83 ms, 95% CI (−15.94 to –11.72), p<0.00001) (table 2, online supplemental material 3)

Root mean square of successive differences

Five articles,24 26 33 34 39 with a total number of 474 patients (213 with CHD and depression, and 261 with CHD alone), contributed to the meta-analysis of RMSSD and CHD combined with depression. Considerable heterogeneity (I²=87%, p<0.00001) necessitated a random-effects model. Similar to the previous findings, patients with CHD with depression demonstrated lower RMSSD compared with those without depression (MD −8.02 ms, 95% CI (−13.62 to –2.43), p=0.005) (table 2, online supplemental material 3).

Proportion of adjacent cycles differing by >50 ms (pNN50)

Five articles,24 26 30 33 39 with a total number of 452 patients, (213 with CHD and depression group, and 239 with CHD alone), contributed to the meta-analysis of PNN50. Considerable heterogeneity (I²=85%, p<0.0001), necessitated a random-effects model. Patients with CHD with depression demonstrated lower pNN50 compared with those without depression (SMD −0.86, 95% CI (−1.41 to –0.31), p=0.002) (table 2, online supplemental material 3).

Sensitivity analysis

Sensitivity analyses for each biomarker were conducted using Stata software. The corresponding figures are presented in online supplemental material 4. The results for CRP could be influenced by excluding the study by Ye et al.⁴⁴ The results of hs-CRP could be affected by omitting Yang et al.⁴³ The results of IL-6 could be affected by omitting Ye et al.⁴⁴ The results of NT-proBNP could be affected by omitting Ren.³⁵ The forest plot showed Ren’s study weighted high in the meta-analysis. The results were consistent with other biomarkers (table 3, online supplemental material 4).

Table 3.

The results of sensitivity analysis

Meta-analysis of CRP and CHD combined with depression
Omitting article	Schins 200537		Aydin Sunbul 201724	Bankier 200925	Lespérance 200432		Roohafza 201836	Ye 202244
SMD (95% CI)	0.57(0.25 to 0.90)		0.52(0.15 to 0.89)	0.49(0.14 to 0.85)	0.58(0.26 to 0.90)		0.45(0.08 to 0.82)	0.38(0.14 to 0.62)
Subgroup analysis of CRP in ACS patients
Omitting article	Lespérance 200432			Roohafza 201836
SMD (95%CI)	0.73(0.41 to 1.04)			0.14(−0.21 to 0.48)
Meta-analysis of hs-CRP and CHD combined with depression
Omitting article	Alizadeh 202123			Lafitte 201531	Sforzini 201938			Yang 201243
SMD (95% CI)	0.34(0.11 to 0.58)			0.35(0.13 to 0.58)	0.27(0.04 to 0.50)			0.11(−0.14 to 0.37)
Meta-analysis of IL-6 and CHD combined with depression
Omitting article	Schins 200537			Lespérance 200432		Roohafza36 2018	Ye 202244
SMD (95% CI)	0.60(0.10 to 1.11)			0.62(0.16 to 1.09)		0.32(−0.13 to 0.76)	0.40(−0.21 to 1.02)
Subgroup analysis of IL-6 in ACS patients
Omitting article	Lespérance 200432			Roohafza 201836
SMD (95% CI)	1.00(0.67 to 1.33)			0.08(−0.27 to 0.42)
Meta-analysis of fibrinogen and CHD combined with depression
Omitting article	Aydin Sunbul 201724			Duivis 201127	Lafitte 201531			Whooley 200740
MD (95% CI)	0.12(−0.29 to 0.52)			0.08(−0.34 to 0.51)	0.01(−0.33 to 0.34)			0.23(0.06 to 0.39)
Meta-analysis of NT-proBNP and CHD combined with depression
Omitting article	Aydin Sunbul 201724			Bankier 200925			Ren 201735
SMD (95% CI)	2.72(−2.94 to 8.39)			2.86(−2.53 to 8.25)			0.02(−0.26 to 0.31)
Meta-analysis of SDNN and CHD combined with depression
Omitting article	Aydin Sunbul 201724	Frasure-Smith 200928	Gehi 200529	Guinjoan 200430	Luo 201833	Martens 200834	Stein 200039	Wilkowska 201942
SMD (95% CI)	−0.61 (−1.12 to −0.09)	−0.74 (−1.36 to −0.11)	−0.75 (−1.35 to 0−.15)	−0.68 (−1.20 to −0.16)	−1.83 (−2.17 to −1.48)	−0.65 (−1.18 to −0.12)	−0.60 (−1.10 to −0.09)	−0.65 (−1.15 to −0.15)
Meta-analysis of SDANN and CHD combined with depression
Omitting article	Aydin Sunbul 201724		Carney 199526	Gehi 200529	Martens 200834		Stein 200039	Whooley 200841
MD (95% CI)	−9.53 (−17.08 to −1.99)		−11.74 (−20.74 to −2.74)	−16.17 (−25.94 to −6.39)	−11.73 (−20.82 to −2.64)		−12.22 (−21.74 to −2.71)	−15.57 (−27.30 to −3.85)
Meta-analysis of SDNNIDX and CHD combined with depression
Omitting article	Aydin Sunbul 201724		Carney 199526		Luo 201833		Stein 200039
MD (95% CI)	−14.00(−16.26 to –11.73)		−13.87(−16.00 to –11.73)		−12.77(−16.91 to –8.63)		−13.93(−16.17 to –11.69)
Meta-analysis of RMSSD and CHD combined with depression
Omitting article	Aydin Sunbul 201724		Carney 199526	Luo 201833		Martens 200834		Stein 200039
MD (95% CI)	−7.28(−14.44 to –0.12)		−7.65(−13.78 to –1.53)	−6.09(−11.09 to –1.08)		−10.11(−14.62 to –5.60)		−8.87(−15.66 to –2.07)
Meta-analysis of pNN50 and CHD combined with depression
Omitting article	Aydin Sunbul 201724		Carney 199526	Guinjoan 200430		Luo 201833		Stein 200039
SMD (95% CI)	−0.88(−1.60 to –0.16)		−0.92(−1.56 to –0.29)	−0.91(−1.56 to –0.26)		−0.65(−0.90 to –0.40)		−0.96(−1.57 to –0.34)

ACS, acute coronary syndrome; CHD, coronary heart disease; hsCRP, high-sensitivity C reactive protein; MD, mean difference; NT-proBNP, N-terminal prohormone of brain natriuretic peptide ; RMSSD, root mean square of successive differences; SDANN, SD of the 5 min averages of all normal RR intervals; SDNN, the mean RR interval and the SD of all RR intervals; SDNNIDX, overage of the SD of all normal RR intervals for each 5 min segment; SMD, standard MD.

Publication bias

No evidence of publication bias was detected in the meta-analysis of CRP (p=0.229), hs-CRP (p=0.196), IL-6 (p=0.357), fibrinogen (p=0.812), NT-proBNP (p=0.265), SDNN (p=0.117), SDNNIDX (p=0.403), RMSSD (p=0.149) or pNN50 (p=0.147) in relation to CVD combined with depression. However, the meta-analysis of SDANN did reveal publication bias (p=0.012). Duval’s trim-and-fill method presented no indications of publication in the meta-analysis of SDANN (Q=24.803, p=0.000; OR 0.000, 95% CI 0.000 to 0.013). The funnel plots for each biomarker are provided in online supplemental material 5.

Discussion

This meta-analysis suggests that patients with CHD with depression exhibit higher levels of CRP, hs-CRP and IL-6, and display lower HRV compared with those without depression. These findings implicate inflammation and impaired function of sympathetic and parasympathetic nerves as key factors in the link between CHD and depression.

Inflammation is implicated in the pathophysiology of CVD.⁴⁵ In the process of atherosclerosis, proinflammatory factors such as TNF-α, IL-1, IL-6 and CRP induce endothelial dysfunction and promote the formation of lipid plaques.⁴⁶ CRP, released from hepatocytes, reflects the acute phase response of inflammation.⁴⁷ Hs-CRP, detected through an ultrasensitive technique, can reveal even lower levels of CRP. CRP has been associated with both CVD and major adverse cardiac events.⁴⁸ Additionally, a higher level of IL-6 is associated with an increased risk of atherosclerotic CVD.⁴⁹

Furthermore, inflammation has been established as a crucial factor linking CHD and depression.⁵⁰ Proinflammatory cytokines interfere with the kynurenine pathway, leading to reduced serotonin synthesis. This reduction in 5-HT is closely linked to the pathophysiology of depression.⁵¹ Anti-inflammatory drugs such as cytokine inhibitors, non-steroidal anti-inflammatory drugs, polyunsaturated fatty acids and statins benefit both CHD and depression. Moreover, antidepressant drugs can not only alleviate depressive symptoms in patients with CHD but also decrease the release of inflammatory factors.⁵²

This meta-analysis reveals higher levels of CRP, hs-CRP and IL-6 in patients with CHD with depression. Supporting our findings, studies by Bankier et al,²⁵ Ye et al,⁴⁴ and Roohafza et al ³⁶ demonstrated a link between elevated inflammatory factors (such as CRP and IL-6) and depression in patients with CHD. Bankier et al’s²⁵ cross-sectional study of 72 patients with CHD showed significantly higher CRP levels in those with MDD. Notably, stepwise multiple regression analyses, excluding other demographic and medical variables, confirmed this association. Similarly, Ye et al’s study⁴⁴ concluded that depression increased CRP and IL-6 concentrations in patients with CHD. Their measurements of lipid metabolism indexes and carotid artery intima–media thickness further reinforced the connection between inflammatory factors, lipid levels and arteriosclerosis. Consequently, they concluded that depression can trigger aggressive inflammation and elevate arteriosclerosis risk. Finally, Roohafza et al’s³⁶ repeated-measure cross-sectional study of 162 acute myocardial infarction (AMI) patients also linked depression to higher CRP and IL-6 values. This suggests that treating depression could improve the prognosis of AMI patients, with anti-inflammatory therapy holding promise for alleviating depression in this population.

However, our meta-analysis found no statistically significant association between other proinflammatory factors and the co-occurrence of CHD and depression. Some studies show conflicting results. For example, Alizadeh et al’s²³ investigation of 154 postmyocardial infarction patients found no link between hs-CRP and depression, attributing this to potential influences from genetic, environmental and socioeconomic factors. Similarly, Lafitte et al’s³¹ 9-month evaluation of 87 patients with ACS did not detect an association between hs-CRP, fibrinogen and the co-occurrence of CHD and depression. Such discrepancies could be attributed to variations in biomarker detection methods. For instance, Schins et al’s study³⁷ measured serum CRP concentration using ELISA kits from ICN Pharmaceuticals (Orangeburg, New York, USA). Aydin et al ²⁴ employed BioSystems’ CRP latex kit with A&B reagents. Additionally, medication use might play a role. Lespérance et al ³² discovered that depression was associated with higher CRP levels in post-ACS patients not taking statins, but not in those taking them. These findings highlight the need for further research to understand the interplay between depression, inflammation and CHD, considering methodological factors and potential medication interactions.

A strong link exists between inflammation and the ANS. Impaired ANS function could promote inflammation, while the proinflammatory process disrupts the balance of sympathetic and parasympathetic tone.⁵³ HRV serves as a non-invasive method to assess the function of these nerves. Recognising the interconnectedness of HRV and inflammation, some researchers propose HRV as a potential measure of anti-inflammatory reflex.⁵⁴ Lower HRV reflects the activation of sympathetic nerves, which is associated with vasospasm and myocardial ischaemia.⁵⁵ Additionally, lower HRV is generally linked to a higher risk of CVD and all-cause morbidity.⁵⁶ Notably, patients with depression exhibit lower HRV, and this reduction can predict adverse prognoses of CVD.⁵⁷

Our meta-analysis demonstrates that patients with CHD with depression have significantly lower values of SNDD, SDANN, SDNNIDX, RMSSD and pNN50 compared with those without depression. Several published studies report similar findings. Aydin Sunbul et al’s study²⁴ exploring depression and HRV in patients with spontaneous coronary artery dissection (SCAD) revealed lower levels of flow-mediated dilatation (FMD) and HRV parameters (including RR interval, SDNN, SDNN index, SDANN, pNN50 and RMSSD) in patients with depression and SCAD. The lower FMD suggests endothelial dysfunction in these patients, implying a potential connection between reduced HRV and endothelial dysfunction in the context of depression and SCAD. Carney et al’s study,²⁶ used SDNN as a representative of HRV, evaluated differences between depressed and non-depressed CAD patients, and found lower SDNN in the depression group. However, Frasure-Smith et al’s study²⁸ did not observe a significant association between depression and HRV, although lower HRV was significantly correlated with higher levels of IL-6 and CRP.

Limitation

However, there are some methodological limitations of this study. (1) Most selected studies are observational studies, only six cohort studies. (2) We changed the model to reduce the heterogeneity. It could not only influence the heterogeneity itself but also deviate the interpretation of variability in data. (3) Omitting one study could affect the indicators of CRP, hs-CRP, IL-6, NT-proBNP, which may influence the results. (4) There was a publication bias in the meta-analysis of SDANN. These limitations demonstrate that more clinical studies are needed to strengthen the results.

Conclusions

This study underscores the association between elevated CRP, hs-CRP, IL-6 and lower HRV in patients with CHD with depression. It emphasises the importance of clinicians assessing CRP, hs-CRP, IL-6 and HRV in patients with CHD to potentially identify depressive conditions. Consequently, this suggests the potential benefits of considering anti-inflammatory and antidepressant therapy for patients with CHD with depression.

Data availability statement

Data are available on reasonable request.

Ethics statements

Patient consent for publication

Not applicable.