Endothelial Dysfunction during Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

Figures & data

Figure 1. Flow diagram of study selection process.

Table 1. Studies included in this systematic review.

Study	Method of assessment	Measurements and scale	N	Hospitalization during AECOPD	Age	Males	FEV1%	Results
Marchetti et al. [32]	FMD and NMD	FMD% and NMD% (% proportional change from baseline)	19 (8)^a	Yes	61 ± 7 (61 ± 8)^a	12 (4)^a	33 ± 22^a	AECOPD and 3 months later (1) FMD (8 patients): 2.6 ± 1.50% vs. 5.1 ± 2.40%; p = 0.04 (2) NMD (7 patients): 5.00 ± 2.60% vs. 13.3 ± 4.50%; p = 0.02
Minet et al. [29]	PAT	RHI	44 (stable n = 34 and AECOPD n = 10)	N/a	64 ± 8	39	47 ± 17	Whole population: RHI = 0.43 [−0.14,1.30] (50% of patients exhibiting abnormal RHI≤ 0.40).After adjustment for age and sex, RHI was linked to condition (AECOPD/stable), FFMI, history of MI, FEV1, PaCO2, HR, HCO3, inflammation and walking distance (p < 0.10). In multivariate analysis: walking distance, FFMI and PaCO2 were independent contributors of RHI (p < 0.0001).
Ozben et al. [28]	FMD and NMD	FMD% and NMD% (% proportional change from baseline)	30	No	64.2 ± 10.9	22	51 ± 15	AECOPD and after resolution: (1) FMD 6.44 ± 3.99% vs. 10.42 ± 4.86%; p < 0.001 (2) NMD 20.6 ± 13.7% vs. 29.1 ± 8.5%; p = 0.225 Recovery values (FMD% and NMD%)were similar to those of healthy controls
Scherr et al. [31]	PAT	RHI	157 (of which 14 were studied also during AE)	N/a	67 [59–73]	108	52.7 [40.1–65.6]	(1) 57% of the COPD patients had endothelial dysfunction (RHI = 1.42 [1.27–1.53])] (2) Exacerbation of COPD (14 participants) was not associated with a significant change in RHI (p = 0.625) or ΑΙx (p = 0.530) (3) RHI was not associated with COPD-related outcomes (AECOPD, hospitalization, CV events, mortality)
Urban et al. [30]	FMD and NMD	FMD% and NMD% (% proportional change from baseline)	29	Yes	64 ± 7.6	8	36 ± 13	AECOPD and after resolution: (1) FMD: 6.70 ± 3.60 vs. 10.00 ± 3.40; p < 0.001 (2) NMD: 15.0 ± 5.00 vs. 18.00 ± 6.1; p = 0.006 (3) sRAGE 525 [371–770] vs. 876 [633–1371]; p < 0.001 sRAGE was positively associated with FMD

Variables are presented as mean ± SD or median [IQR].

AECOPD, acute exacerbation of COPD; AIx, augmentation index; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; FEV1, forced expiratory volume during the first second; HR, heart rate; FFMI, fat-free mass index; FMD, flow-mediated dilatation; MI, myocardial infarction; NMD, nitroglycerine-mediated dilatation; PAT, peripheral arterial tonometry; RHI, reactive hyperemia index; sRAGE, Soluble Form of Receptor for Advanced Glycation End Products.

^aParticipants including only in meta-analysis.

Figure 2. Forest plots of the difference in (A) FMD%, (B) RHI (PAT), among patients during AECOPD and patients at recovery/stable condition. AECOPD, acute exacerbation of chronic obstructive pulmonary disease; FMD, flow-mediated dilatation; RHI, reactive hyperemia index; PAT, peripheral arterial tonometry.

Figure 3. Forest plot of the difference in NMD% among patients during AECOPD and patients at recovery/stable condition. AECOPD, acute exacerbation of chronic obstructive pulmonary disease; NMD, nitroglycerine-mediated dilatation.

Figure 4. Forest plot of the difference in endothelial function among patients during AECOPD and patients at recovery/stable condition (all methods). AECOPD, acute exacerbation of chronic obstructive pulmonary disease.

Figure 5. Sensitivity analysis (included studies with NOS score ≥7): Forest plot of the difference in endothelial function among patients during AECOPD and patients at recovery/stable condition (all methods). AECOPD, acute exacerbation of chronic obstructive pulmonary disease; NOS, Newcastle-Ottawa-Scale.

Marchetti N, Ciccolella DE, Jacobs MR, et al. Hospitalized acute exacerbation of COPD impairs flow and nitroglycerin-mediated peripheral vascular dilation. COPD. 2011;8(2):60–65. DOI:https://doi.org/10.3109/15412555.2011.558541

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Minet C, Vivodtzev I, Tamisier R, et al. Reduced six-minute walking distance, high fat-free-mass index and hypercapnia are associated with endothelial dysfunction in COPD. Respir Physiol Neurobiol. 2012;183(2):128–134. DOI:https://doi.org/10.1016/j.resp.2012.06.017

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Ozben B, Eryüksel E, Tanrikulu AM, et al. Acute exacerbation impairs endothelial function in patients with chronic obstructive pulmonary disease. Turk Kardiyoloji Dernegi arsivi. Turk Kardiyoloji Derneginin Yayin Organidir. 2010;38:1–7.

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Scherr A, Schumann DM, Karakioulaki M, et al. Endothelial dysfunction is not a predictor of outcome in chronic obstructive pulmonary disease. Respir Res. 2020;21(1):90. DOI:https://doi.org/10.1186/s12931-020-01345-9

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Urban MH, Valipour A, Kiss D, et al. Soluble receptor of advanced glycation end-products and endothelial dysfunction in COPD. Respir Med. 2014;108(6):891–897. DOI:https://doi.org/10.1016/j.rmed.2014.03.013

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