Table 2.
Overview of Animal Experimental Studies Characterizing Sleep-disordered Breathing and Cardiac Structural and Electrophysiologic Indices
| Study | Animal Type | Groups (No.) | Intervention | Outcome |
|---|---|---|---|---|
| Hypoxia and hypercapnia | ||||
| De Daly and Scott53 | Dog | Spontaneous breathing (32), artificial ventilation (20) | Normoxia vs hypoxia with or without hypocapnia | Decreased heart rate with hypoxemia that did not vary with hypocapnia |
| Daly and Scott52 | Dog | Anesthetized dogs (19) | Normoxia vs hypoxia | Increase in minute ventilation, decreased BP with hypoxia |
| Campen et al114 | Mouse | Acute hypoxia (6) vs CIH (8) | Acute hypoxia vs CIH × 5 wk | Decreased BP and increased RV pressure in acute hypoxia; increased BP, LV mass, and RV mass in CIH |
| Lesske et al115 | Rat | Control subjects (15) vs CIH 20 d (8) vs 30 d (7) vs 25 d (7) | 20 vs 30 vs 35 d of CIH | Increased LV mass and mean BP correlating with CIH duration |
| Lesske et al115 | Rat | Control subjects (13) vs CIH (9) vs CIH + hypercapnia (10) vs CIH + hypocapnia (9) | CIH × 30 d with eucapnia, hypocapnia, or hypercapnia | Increase in BP and LV hypertrophy with CIH. No additional change in BP or LV hypertrophy with changes in Pco2; increase in RV hypertrophy in hypercapnia + CIH |
| Peng et al45 | Rat | CIH vs normoxia control subjects | CIH for 8 h per day for 10 d vs normoxia | Increased indices of oxidative stress and mitochondrial dysfunction in CIH |
| Chen et al48 | Rat | CIH (22) vs normoxia control subjects (22) | CIH for 8 h per day for 5 wk | Increased LV and heart weight, LV dilation, LV end-diastolic pressure, myocardial lipid peroxides; lower myocardial superoxide dismutase in CIH |
| Peng et al44 | Mouse | Wild-type vs HIF-1α- deficient heterozygotes | 10 days CIH vs 10 d normoxia | Increased carotid body response, increased ROS, augmented hypoxic ventilator response, elevated BP in wild-type but not heterozygous mice |
| Park and Suzuki49 | Mouse | Normoxic control subjects (19) vs 1 wk (15) vs 2 wk (14) vs 4 wk (20) isolated heart under ischemia-reperfusion | CIH 8 h per day | Increased myocardial injury at 1 and 2 wk but not 4 wk; increased oxidative stress at 2 wk resolved by 4 wk |
| Chen et al47 | Rat | CIH vs handled normoxic control subjects | CIH 8 h per day for 6 wk | Elevations in mean arterial pressure, LV end-diastolic pressure, LV cell injury markers |
| Souvannakitti et al54 | Rat | Intermittent hypoxia (18) vs sustained hypoxia (12) vs control (17) | Acute hypoxia after intermittent or sustained hypoxia | Facilitation of catecholamine secretion by intermittent hypoxia and attenuation by sustained hypoxia |
| Stevenson et al57 | Sheep | Control (6), hypercapnia (5), hypoxemia (6) | Control vs hypercapnia vs hypoxemia | ERP lengthening, increased conduction time with hypercapnia; increased AF vulnerability with a return to eucapnia. No changes in ERP, atrial conduction time, or AF vulnerability in hypoxia and control |
| Intrathoracic pressure swings | ||||
| Linz et al36 | Pig | Intubated anesthetized pig (21) | NTP | Right atrial ERP shortening and increased AF vulnerability during maneuvers, which were completely inhibited by amiodarone followed by atropine |
| Linz et al39 | Pig | Anesthetized animals (20) | NTP vs NTP + renal denervation vs NTP + atenolol | Atrial ERP shortening, increased AF inducibility, BP increases in NTP that was mitigated by renal denervation but not atenolol |
| Linz et al116 | Pig | NTP (24) vs renal denervation + NTP (26) vs control (8) | NTP ± renal denervation | Increased BP and prolongation of spontaneous AF episodes with NTP; denervation inhibited BP increases, decreased plasma renin and aldosterone, reduction of occurrence and duration of AF episodes |
| Autonomic function | ||||
| Fletcher et al117 | Rat | Control (13) vs CIH (13) vs denervation (11) vs CIH + denervation (8) | CIH × 40 d, sympathetic denervation | Increased BP in CIH only, all others decreased BP. Increased LV mass in all CIH groups |
| Lesske et al115 | Rat | Control subjects (13) vs CIH (8) vs CIH + denervation (11) vs denervation (8) | CIH × 30 d, chemoreceptor denervation | Increased BP, LV hypertrophy in CIH, no BP change from baseline and lower catecholamines with denervation |
| Bao et al118 | Rat | Hypoxia vs hypoxia + hypocapnia vs hypoxia + prazosin vs hypoxia + yohimbine vs hypoxia + atropine | Hypoxia, hypocapnia, effect of prazosin, yohimbine, atropine on hypoxia | Increased BP and decreased heart rate with CIH alone vs CIH + hypocapnia. Mitigation of BP increase after prazosin and mitigation of heart rate elevation after atropine. No effect of yohimbine |
| Ghias et al38 | Dog | Atrial and pulmonary vein pacing (14) plexus ablation and cardiac pacing (16) |
Ganglionated plexus ablation with induced apnea | Increased ganglionated plexus activity during apnea, autonomic blockade prevented AF; pacing-induced AF mitigated by neural ablation |
| Linz et al36 | Pig | Intubated anesthetized pig (21) | NTP | Right atrial ERP shortening and increased AF vulnerability during maneuvers, which were completely inhibited by amiodarone followed by atropine |
| Linz et al39 | Pig | Anesthetized animals (20) | NTP vs NTP + renal denervation vs NTP + atenolol | Atrial ERP shortening, increased AF inducibility, BP increases in NTP that were mitigated by renal denervation but not atenolol |
| Linz et al116 | Pig | OSA (24) vs renal denervation + OSA (26) vs control (8) | NTP ± renal denervation | Increased BP and prolongation of spontaneous AF episodes with OSA; denervation inhibited BP increases, decreased plasma renin and aldosterone, reduction of occurrence and duration of AF episodes |
| Gao et al119 | Rabbit | Simulated apnea and LLVS (6) Simulated apneas (5) |
Tracheostomy clamped every 6 min over 4 h; LLVS or not | Suppression of ERP shortening and decreased AF duration mitigated with LLVS compared to apnea alone |
| Linz et al40 | Pig | Low-level (n = 8) vs high-level (n = 8) baroreceptor stimulation vs control (n = 5) | NTP × 3 h + baroreceptor stimulation | Low-level stimulation: shortening atrial ERP, decreased AF inducibility; high-level stimulation: lengthening atrial ERP, no change in AF inducibility |
| Mixed physiology | ||||
| Revelli and Allessie120 | Rabbit | Langendorff-perfused hearts with intra-atrial septal perforation (15) | Increasing bi-atrial pressure | Increased atrial ERP, decreased monophasic action potentials, increased AF vulnerability with increasing atrial pressure |
| Lu et al35 | Dog | Experiment (10) Control (5) |
10 s apnea every 30 s breathing × 1 h | Decreased heart rate variability, increased ERP; reverted after 1 h normal ventilation |
| Iwasaki et al42 | Rat | OSA (no ventilation, closed airway) (11) vs no ventilation, open airway (7) vs continued ventilation (8) | Duration and inducibility of AF, atrial conduction, LV metrics | Increased AF duration and inducibility; atrial conduction slowing; and LV hypertrophy, dilation, and diastolic dysfunction in OSA |
| Iwasaki et al121 | Rat | Lean (12) and obese (12) rats | No ventilation, closed airway vs no ventilation, open airway | Increased inducibility of AF in simulated OSA compared with control subjects, particularly in obese rats |
HIF = hypoxia-inducible factor; LLVS = low-level vagosympathetic trunk stimulation; NTP = negative tracheal pressure; ROS = reactive oxygen species. See Table 1 legend for expansion of other abbreviations.