Cardiac consequences of intermittent hypoxia: a matter of dose? A systematic review and meta-analysis in rodents

Elise Belaidi; Charles Khouri; Olfa Harki; Sébastien Baillieul; Gilles Faury; Anne Briançon-Marjollet; Jean-Louis Pépin; Claire Arnaud

doi:10.1183/16000617.0269-2021

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FIGURE 1
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) study flowchart.
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FIGURE 2
Characteristics of intermittent hypoxia (IH) protocols. NR: not reported.
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FIGURE 3
Risk of bias assessment according to the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) (overall score).
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FIGURE 4
Orchard plots of the effect of intermittent hypoxia (IH) on a) mean arterial blood pressure (MAP); b) heart rate (HR); and c) ejection fraction (EF). Data were extracted in IH and control groups from primary studies and expressed as standardised mean differences. The pooled estimate (yellow) indicates an increase in MAP and HR and a reduction in EF upon IH exposure compared to control normoxic groups.
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FIGURE 5
Orchard plots of the effect of intermittent hypoxia (IH) on cardiac remodelling. a) cardiac dimensions; b) fibrosis and c) apoptosis. Data were extracted in IH and control groups from primary studies and expressed as standardised mean differences. The pooled estimate (yellow) indicates that IH induces an overall cardiac hypertrophy (HW_TL: heart weight to tibia length; CSA: cross-sectional area) and dilation (LVDd: left ventricular diameter in diastole), associated with increased perivascular (PVF) and interstitial fibrosis (IF) and apoptosis (Casp3: caspase 3). CTGF: connective tissue growth factor; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labelling.
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FIGURE 6
Impact of intermittent hypoxia (IH) on myocardial infarct size. a) Orchard plot indicates a high heterogeneity of IH response to ischaemia and reveals two distinct groups, one exhibiting a reduction in infarct size and the other an increase. Data were extracted in IH and control groups from primary studies and expressed as standardised mean differences (SMDs). Univariate analysis demonstrated that b) inspired oxygen fraction (F_IO₂) and c) IH duration per day were key parameters influencing myocardial infarct size.
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FIGURE 7
Impact of intermittent hypoxia (IH) on cardiac function, structure and response to ischaemia–reperfusion. a) Deleterious effect of IH characterised by a decrease in left ventricle (LV) ejection fraction, an increase in diastolic left ventricular diameter (LVDd), as well as hypertrophy, fibrosis and apoptosis. b) Dual effect of IH on infarct size following ischaemia–reperfusion depending on F_IO₂ severity and IH duration per day. F_IO₂: inspired oxygen fraction.

TABLE 1

Study characteristics

	Animal characteristics					IH protocol characteristics					Haemodynamic parameter	Cardiac function	Cardiac remodelling							Response to ischaemia
Article^#	Species	Strain	Sex	Body weight (g)	Age (weeks)	F_IO₂ (%)	Hypoxia/Reox (s)	IH duration (h per day)	Protocol duration (day)	MAP	HR	Ejection fraction	Structure	Hypertrophy		Fibrosis		Apoptosis		Infarct size
Article^#	Species	Strain	Sex	Body weight (g)	Age (weeks)	F_IO₂ (%)	Hypoxia/Reox (s)	IH duration (h per day)	Protocol duration (day)	MAP	HR	Ejection fraction	LVDd	HW/TL	CSA	PVF	IF	Casp3	TUNEL	Infarct size
*Bao et al. 2020 [S1]*	Mice	C57Bl6J	M	nd	9	5	30/30	12	28			x		x	x		x		x
*Béguin et al. 2005 [S2]*	Rat	Wistar	M	350	nd	5–10	40/20	0.5–4.0	1											x
*Béguin et al. 2007 [S3]*	Rat	Wistar	M	350	nd	10	40/20	4	1											x
*Belaidi et al. 2008 [S4]*	Rat	Wistar	M	340	nd	10	40/20	4	1											x
*Belaidi et al. 2009 [S5]*	Rat	SHR and WKY	M	nd	9	5	40/20	8	14	x										x
*Belaidi et al. 2016 [S6]*	Mice	S129 and C57Bl6J	M	nd	8	5	30/30	8	14											x
*Bober et al. 2018 [S7]*	Rat	SD	M	340	nd	6.5	80/120	8	7
*Bourdier et al. 2016 [S8]*	Rat	Wistar	M	325	8	5	30/30	8	21	x	x							x		x
*Cai et al. 2003 [S9]*	Mice	nd	M	25	nd	6	360/360	1	1											x
*Castro-Grattoni et al. 2016 [S10]*	Mice	C57Bl6J	M	nd	6	5	20/40	6	42						x	x
*Castro-Grattoni et al. 2019 [S11]*	Mice	C57Bl6J	F	nd	8–72	5	20/40	6	56							x
*Chen et al. 2005 [S12]*	Rat	SD	M	250	nd	5	30/30	8	35	x	x	x	x
*Chen et al. 2008 [S13]*	Rat	SD	M	185	nd	5	20/100	8	42	x	x							x	x
*Chen et al. 2010 [S14]*	Mice	C57Bl6J	M	nd	26	4.5	45	10	56	x	x	x	x		x		x		x
*Chen et al. 2011 [S15]*	Rat	SD	M	290	9	4	30/45	6	12									x
*Chen et al. 2011 [S16]*	Rat	WKY and SHR	M	255	9	4	30/45	6	10–30									x
*Chen et al. 2015 [S17]*	Rat	SD	M	325	9	6	30/45	6	12			x	x
*Chen et al. 2016 [S18]*	Rat	SD	M	nd	9	4	30/45	8	14			x	x
*Chen et al. 2016 [S19]*	Rat	SD	M	nd	16	4	30/45	8	14								x
*Del Rio et al. 2016 [S20]*	Rat	SD	M	250	nd	5	nd	8	28	x	x						x
*Détrait et al. 2020 [S21]*	Mice	C57Bl6J	M	nd	19	5	30/30	8	28–42		x	x	x	x	x		x
*Ding et al. 2014 [S22]*	Rat	Wistar	M	215	8	5.5	60/60	8	35		x	x	x					x	x
*Ding et al. 2014 [S23]*	Rat	Wistar	M	nd	8	5.5	20/100	nd	35								x
*Du et al. 2019 [S24]*	Mice	C57Bl6J	M	nd	4	5.5	120/60	12	56			x
*Farré et al. 2018 [S25]*	Mice	C57Bl6J	nd	nd	8–72	6	20/40	6	42
*Fu et al. 2016 [S26]*	Rat	SD	M	225	9	4.5	120/120	nd	21–56			x	x						x
*Guan et al. 2019 [S27]*	Rat	SD	M	205	nd	9	15/90	8	35			x			x		x		x
*Guo et al. 2015 [S28]*	Rat	Wistar	M	210	8	7	120/120	8	7–28	x
*Han et al. 2014 [S29]*	Rat	SD	M	151	nd	10	240/120	6	14–28									x
*Han et al. 2018 [S30]*	Rat	SD	M	165	nd	10	240/120	8	42			x	x				x	x	x
*Hayashi et al. 2008 [S31]*	Mice	C57Bl6J	M	nd	10	5	30/30	8	10	x		x	x				x
*Hayashi et al. 2011 [S32]*	Mice	C57Bl6J	M	nd	8	5	60/60	8	7						x	x
*Imano et al. 2018 [S33]*	Mice	C57Bl6J	M	nd	8	5	90/300	8	28			x	x		x	x
*Inamoto et al. 2010 [S34]*	Mice	C57Bl6J	M	nd	8	5	30/30	8	10							x
*Jiang et al. 2020 [S35]*	Rat	SD	M	225	nd	5	90/90	8	28			x	x					x
*Joyeux-Faure et al. 2005 [S36]*	Rat	Wistar	M	230	nd	5	40/20	8	35	x										x
*Lai et al. 2015 [S37]*	Mice	C57Bl6J	nd	nd	22	7	60/60	8	56				x	x					x
*Lai et al. 2015 [S38]*	Mice	C57Bl6J	M	nd	22	7	60/60	8	56				x	x				x	x
*Li et al. 2016 [S39]*	Rat	Wistar	M	nd	16	5	30/90	8	28			x
*Li et al. 2017 [S40]*	Rat	SD	M	225	nd	9	240/350	8	42						x		x		x
*Lu et al. 2020 [S41]*	Rat	SD	M	200	6	7.5	90/90	8	42							x
*Lucking et al. 2014 [S42]*	Rat	Wistar	M	225	nd	5	90/210	8	14	x	x		x
*Ma et al. 2020 [S43]*	Rat	SD	M	190	8	8	210/90	6	42	x		x	x				x
*Maeda et al. 2013 [S44]*	Rat	SD	M	nd	7	4	nd	8	21		x
*Matsumoto et al. 2009 [S45]*	Mice	C57Bl6J	M	nd	10	5	30/30	8	10							x
*Milano et al. 2013 [S46]*	Mice	C57Bl6J	M	nd	9	7	180/120	1.7	14											x
*Morand et al. 2018 [S47]*	Rat	Wistar	M	340	8	5	30/30	8	14	x	x
*Moreau et al. 2015 [S48]*	Rat	SD	M	nd	nd	6.5	80/120	8	7–95	x	x
*Moulin et al. 2020 [S49]*	Mice	Swiss×S129	M	nd	nd	5	30/30	8	21										x	x
*Moulin et al. 2020 [S50]*	Mice	Swiss×S129	M	nd	10	5	30/30	8	21										x	x
*Naghshin et al. 2009 [S51]*	Mice	C57Bl6J	M	23	11	5	30/30	12	28		x	x	x
*Naghshin et al. 2012 [S52]*	Mice	FVB	M	nd	11	5.5	30/30	12	28		x	x
*Nakagawa et al. 2019 [S53]*	Mice	nd	M	nd	nd	5	60/300	8	14
*Nishioka et al. 2013 [S54]*	Mice	C57Bl6J	M	nd	8	5	30/30	8	10		x					x
*Pai et al. 2016 [S55]*	Rat	SD	M	nd	20	5	40/40	8	28		x		x	x					x
*Park et al. 2007 [S56]*	Mice	C57Bl6J	M	nd	10	6	120/120	8	7–28	x	x									x
*Ramirez et al. 2012 [S57]*	Rat	SD	M	nd	nd	10	180/180	8	7						x	x
*Ramond et al. 2007 [S58]*	Rat	Wistar	M	300	nd	5	40/20	4	1											x
*Ramond et al. 2013 [S59]*	Rat	Wistar	M	300	nd	5	30/30	8	14	x										x
*Ray et al. 2015 [S60]*	Rat	Wistar	M	nd	nd	5	90/330	8	14	x	x				x
*Rodriguez et al. 2014 [S61]*	Mice	C57Bl6J and ob/ob	M	nd	10	5.5	30/30	12	28		x		x
*Sun et al. 2020 [S62]*	Rat	SD	M	220	nd	9	15/30	8	35			x							x
*Tao et al. 2019 [S63]*	Mice	C57Bl6J	M	nd	8	5	30/30	8	28			x					x	x	x
*Tong et al. 2019 [S64]*	Mice	C57Bl6J	M	22	6	5	20/40	8	13							x
*Totoson et al. 2013 [S65]*	Rat	Wistar	M	290	nd	5	30/30	8	14–28											x
*Wang et al. 2013 [S66]*	Rat	Wistar	M	250	nd	7.6	30/30	4	1–28										x	x
*Wang et al. 2017 [S67]*	Rat	SD	nd	260	nd	9	90/90	8	21
*Wang et al. 2017 [S68]*	Rat	SD	M	200	nd	9	90/90	8	21		x		x
*Wang et al. 2018 [S69]*	Mice	C57Bl6J	M	23	nd	5.5	60/60	8	84										x
*Wang et al. 2018 [S70]*	Rat	SD	M	225	9	8	90/210	5	28			x	x				x
*Wang et al. 2020 [S71]*	Mice	C57Bl6J	M	nd	8	8	20/40	12	56			x	x	x			x
*Wei et al. 2017 [S72]*	Rat	SD	M	250	10	7.6	30/30	8	35			x	x
*Williams et al. 2010 [S73]*	Rat	SD	M	180	nd	5	30/30	8	10		x		x						x
*Xie et al. 2015 [S74]*	Rat	SD	M	200	nd	8	240/350	8	42						x		x		x
*Xu et al. 2015 [S75]*	Rat	SD	M	200	nd	8.5	10/80	8	35	x
*Yang et al. 2011 [S76]*	Mice	C57Bl6J and ob/ob	M	nd	10	5	30/30	12	28			x	x	x
*Yang et al. 2018 [S77]*	Rat	SD	M	200	8	6	120	8	42			x	x					x	x
*Yang et al. 2019 [S78]*	Rat	SD	M	200	9	6	80/40	8	42
*Yeung et al. 2015 [S79]*	Rat	SD	M	70	4	5	15/45	8	28								x			x
*Yin et al. 2014 [S80]*	Mice	FVB and 129S1	M	nd	9	8	20/100	12	7–56			x	x	x
*Yuan et al. 2014 [S81]*	Rat	Wistar	M	200	nd	5	30/30	8	42
*Yuan et al. 2015 [S82]*	Rat	SD	M	235	nd	8	240/350	8	42										x
*Zhang et al. 2018 [S83]*	Rat	SD	M	300	nd	8	nd	6	30			x	x				x
*Zhang et al. 2017 [S84]*	Mice	C57Bl6J	M	22	6	5	20/40	8	84			x	x			x
*Zhang et al. 2018 [S85]*	Rat	SD	M	nd	nd	8	nd	6	30			x	x
*Zhang et al. 2018 [S86]*	Rat	SD	M	nd	nd	8	nd	6	30			x	x				x
*Zhao et al. 2019 [S87]*	Rat	SD	M	205	nd	9	90/90	8	35			x	x
*Zhou et al. 2014 [S88]*	Mice	129S1 and FVB	M	nd	9	8	60/60	nd	21–28									x	x
*Zhou et al. 2017 [S89]*	Mice	C57Bl6J and FVB	M	nd	nd	8	20/100	12	3–28			x	x
*Zhou et al. 2018 [S90]*	Mice	129s1 and C57Bl6J	nd	nd	nd	8	30/30	12	28			x	x				x
*Zhou et al. 2018 [S91]*	Rat	SD	M	165	nd	4.5	30/60	8	21			x	x					x	x
*Zhu et al. 2020 [S92]*	Rat	SD	M	190	nd	10	30/60	8	35			x

^#: For full details of the studies included in the meta-analysis see supplementary file S3, references listed in this table refer to this file. Casp3: caspase 3; CSA: cross-sectional area; F: female; F_IO₂: inspired oxygen fraction (in percentage); HR: heart rate; Hypoxia/Reox (s): duration of hypoxia and reoxygenation (in seconds); HW/TL: heart weight to tibia length ratio; IF: interstitial fibrosis; IH: intermittent hypoxia; LVDd: left ventricular diameter in diastole; M: male; MAP: mean arterial pressure; nd: no data; PVF: perivascular fibrosis; SD: Sprague–Dawley; SHR: spontaneously hypertensive rat; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labelling; WKY: Wistar Kyoto.

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Supplementary material ERR-0269-2021.SUPPLEMENT