Open-chest Animals Research Articles

Different strokes for different folks

Atrial fibrillation (AF) remains the most common arrhythmia since William Harvey’s observation of fibrillating auricles in open chest animal models in 1628. Willem Einthoven first documented ECG tracing of AF in 1906. Fast forward several hundred years since its first observation, AF remains a mystery from its pathogenesis and sustenance to treatment options in the

Assessment of myocardial viability using a minimally invasive laser Doppler flowmetry on pig model

The intra-operative real-time assessment of tissue viability can potentially improve therapy delivery and clinical outcome in cardiovascular therapies. Cardiac ablation therapy for the treatment of supraventricular or ventricular arrhythmia continues to be done without being able to assess if the intended lesion and lesion size have been achieved. Here, we report a method for continuous measurements of cardiac muscle microcirculation to provide an instrument for real-time ablation monitoring. We performed two acute open chest animal studies to assess the ability to perform real-time monitoring of creation and size of ablation lesion using a standard RF irrigated catheter. Radiofrequency ablation and laser Doppler were applied to different endocardial areas of alive open-chest pig. We performed two experiments at three different RF ablation energy setting and different ablation times. Perfusion signals before and after ablation were found extensively and distinctively different. By increasing the ablation energy and time, the perfusion signal was decreasing. In vivo assessing the local microcirculation during RF ablation by laser Doppler can potentially be useful to differentiate between viable and nonviable ablated beating heart in real time.

Contact-force recovery predicts the absence of cardiac perforation during steam pops.

Cardiac perforation (CP) is an uncommon but clinically important complication of radiofrequency ablation (RFA). We previously showed that contact-force recovery after a steam pop predicts the absence of CP in an open-chest animal model after pericardial dissection. We attempted to determine whether this also applies when pericardium is present. In 5 open-chest sheep, left atrial RFA was performed under direct observation with a 7.5F ThermoCool SmartTouch force-sensing catheter (Biosense Webster Inc., Irvine, CA, USA). The catheter's contact force was measured every 50ms during RFA. After each steam pop, the presence (+) or absence (-) of CP was noted, as well as whether pericardium was present over the ablation site. Contact-force signals were analyzed to detect contact-force recovery. Perforation rates were compared between sites with or without pericardium. Ninety-six steam pops occurred: 77 with pericardium and 19 without. For the pericardial steam pops, contact-force recovery occurred in 31/60 CP- events (52%) and 1/17 CP+ events (6%; P = 0.0006). For nonpericardial steam pops, contact-force recovery occurred in 4/9 CP- events (44%) and 1/10 CP+ events (P = 0.14). The rate of CP was 22% with pericardium and 52% without (P = 0.02). Pericardial tissue charred extensively during steam pop induction, even in the absence of CP. Contact-force recovery predicts the absence of CP during RFA independently of whether the pericardium is present. The presence of the pericardium may decrease the likelihood of perforation, perhaps by acting as a thermal sink. Additional studies are needed to correlate these results with clinical experience.

Multiple abdominal burst patterns observed during tracheobronchial coughing in anesthetized cats

The cough motor pattern is classically defined as a neuromechanical sequence of inspiration, compression, and expulsion. This definition is most applicable to single coughs. However, humans routinely produce multiple expulsions per each inspiratory effort during single or repetitive coughing. The functional significance of this coughing pattern is not fully understood, but it could represent a mechanism to facilitate the stairstep movement of particulates and mucus up the airway tree against gravity in humans. This repetitive expulsion pattern following single inspiratory cough efforts has not been reported in animal models of coughing. In the anesthetized cat, repetitive coughing can be produced by either mechanical or chemical stimulation of airway afferents. We hypothesized that expulsive cough motor patterns consistent with those seen in humans could be observed in the anesthetized cat. Further, we have previously observed that thoracotomy depresses cough excitability, presumably though a decrease in pulmonary volume‐related feedback. We also hypothesized that thoracotomy would reduce the occurrence of coughs in which multiple expiratory bursts were observed. We investigated the cough patterns of 9 cats pre‐ (n=5) and post‐thoracotomy (n=4) for multiple abdominal bursting patterns during cough. Thoracotomized animals were artificially ventilated at a positive end expiratory pressure of 5 cmH2O. Electromyograms (EMGs) were recorded from the diaphragm, thyroarytenoid, and internal oblique muscles. Repetitive coughing was produced by mechanical stimulation of the intrathoracic airway. The percentage of cough epochs that contained at least one cough with a multiple bursting pattern was similar for closed (CC, 44±18%) and open chested (OC, 42±11%) animals. These patterns consisted of double abdominal bursts (71%), three abdominal bursts (23%) and four bursts (5%). Corresponding abdominal bursts had similar amplitudes in both CC and OC animals. In OC animals, the amplitude of the second abdominal burst (CC − 45±11 to 31±7%, p=n.s.; OC − 43±4 to 28±5, p<0.05) was significantly lower than the first. Thoracotomy prolonged E2 duration for coughs with only 1 expiratory burst (CC 1±0.2s; OC 2±0.4 s, p < 0.05), but not for multiple expiratory bursts (CC 0.6±0.1 s; OC 0.9±0.4 s). The time between multiple abdominal bursts (CC 232±16 msec; OC 233±32 msec) was not different after thoracotomy. In some animals, small amplitude bursts in thyroarytenoid EMGs occurred out of phase with multiple abdominal bursting, consistent with adductor/abdominal oscillations. We conclude that the anesthetized cat is capable of expressing multiple abdominal bursting following a single inspiratory effort during tracheobronchial coughing. Our results support the existence of multiple oscillatory patterns during repetitive tracheobronchial coughing in the cat. This pattern may be analogous to that exhibited by awake humans.Support or Funding InformationSupported by NIH HL 103415 and 1OT20D001983.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Percutaneous Pericardial Resection: A Novel Potential Treatment for Heart Failure With Preserved Ejection Fraction.

People with heart failure and preserved ejection fraction develop increases in left ventricular (LV) end-diastolic pressures during exercise that contribute to dyspnea. In normal open-chest animal preparations, the pericardium restrains LV filling when central blood volume increases. We hypothesized that resection of the pericardium using a minimally invasive epicardial approach would mitigate the increase in LV end-diastolic pressure that develops during volume loading in normal and diseased hearts with the chest intact. Invasive hemodynamic assessment was performed at baseline and after saline load before and after pericardial resection in normal canines with open (n=3) and closed chest (n=5) and in a pig model with features of human heart failure and preserved ejection fraction with sternum intact (n=4). In closed-chest animals, pericardiotomy was performed using a novel subxiphoid procedure. In both experimental preparations of normal dogs, pericardiotomy blunted the increase in LV end-diastolic pressure with saline infusion, while enhancing the saline-mediated increase in LV end-diastolic volume. With chest intact in the pig model, percutaneous pericardial resection again blunted the increase in LV end-diastolic pressure secondary to volume expansion (+4±3 versus +13±5 mm Hg; P=0.014), while enhancing the saline-mediated increase in LV end-diastolic volume (+17±1 versus +10±2 mL; P=0.016). This proof of concept study demonstrates that pericardial resection through a minimally invasive percutaneous approach mitigates the elevation in LV filling pressures with volume loading in both normal animals and a pig model with diastolic dysfunction. Further study is warranted to determine whether this method is safe and produces similar acute and chronic hemodynamic benefits in people with heart failure and preserved ejection fraction.

Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems.

It has been documented that adaptation to hypoxia increases myocardial tolerance to ischemia-reperfusion (I/R) injury depending on the regimen of adaptation. Reactive oxygen species (ROS) formed during hypoxia play an important role in the induction of protective cardiac phenotype. On the other hand, the excess of ROS can contribute to tissue damage caused by I/R. Here we investigated the relationship between myocardial tolerance to I/R injury and transcription activity of major antioxidant genes, transcription factors, and oxidative stress in three different regimens of chronic hypoxia. Adult male Wistar rats were exposed to continuous normobaric hypoxia (FiO2 0.1) either continuously (CNH) or intermittently for 8 h/day (INH8) or 23 h/day (INH23) for 3 wk period. A control group was kept in room air. Myocardial infarct size was assessed in anesthetized open-chest animals subjected to 20 min coronary artery occlusion and 3 h reperfusion. Levels of mRNA transcripts and the ratio of reduced and oxidized glutathione (GSH/GSSG) were analyzed by real-time RT-PCR and by liquid chromatography, respectively. Whereas CNH as well as INH8 decreased infarct size, 1 h daily reoxygenation (INH23) abolished the cardioprotective effect and decreased GSH/GSSG ratio. The majority of mRNAs of antioxidant genes related to mitochondrial antioxidant defense (manganese superoxide dismutase, glutathione reductase, thioredoxin/thioredoxin reductase, and peroxiredoxin 2) were upregulated in both cardioprotective regimens (CNH, INH8). In contrast, INH23 increased only PRX5, which was not sufficient to induce the cardioprotective phenotype. Our results suggest that the increased mitochondrial antioxidant defense plays an important role in cardioprotection afforded by chronic hypoxia.

Quantitative assessment of mitral inflow and aortic outflow stroke volumes by 3-dimensional real-time full-volume color flow doppler transthoracic echocardiography: an in vivo study.

Noninvasive quantification of left ventricular (LV) stroke volumes has an important clinical role in assessing circulation and monitoring therapeutic interventions for cardiac disease. This study validated the accuracy of a real-time 3-dimensional (3D) color flow Doppler method performed during transthoracic echocardiography (TTE) for quantifying volume flows through the mitral and aortic valves using a dedicated offline 3D flow computation program compared to LV sonomicrometry in an open-chest animal model. Forty-six different hemodynamic states in 5 open-chest pigs were studied. Three-dimensional color flow Doppler TTE and 2-dimensional (2D) TTE were performed by epicardial scanning. The dedicated software was used to compute flow volumes at the mitral annulus and the left ventricular outflow tract (LVOT) with the 3D color flow Doppler method. Stroke volumes by 2D TTE were computed in the conventional manner. Stroke volumes derived from sonomicrometry were used as reference values. Mitral inflow and LVOT outflow derived from the 3D color flow Doppler method correlated well with stroke volumes by sonomicrometry (R = 0.96 and 0.96, respectively), whereas correlation coefficients for mitral inflow and LVOT outflow computed by 2D TTE and stroke volumes by sonomicrometry were R = 0.84 and 0.86. Compared to 2D TTE, the 3D method showed a smaller bias and narrower limits of agreement in both mitral inflow (mean ± SD: 3D, 2.36 ± 2.86 mL; 2D, 10.22 ± 8.46 mL) and LVOT outflow (3D, 1.99 ± 2.95 mL; 2D, 4.12 ± 6.32 mL). Real-time 3D color flow Doppler quantification is feasible and accurate for measurement of mitral inflow and LVOT outflow stroke volumes over a range of hemodynamic conditions.

Sensitivity of epicardial electrical markers to acute ischemia detection

IntroductionWe hypothesize that electrocardiographic measurements from the intramyocardial space contain more sensitive markers of ischemia than those detectable on the epicardium. The goal of this study was to evaluate different electrical markers for their potential to detect the earliest phases of acute myocardial ischemia. MethodsWe conducted acute ischemia studies in open chest animal, by creating finely controlled demand or supply ischemic episodes and recording intramyocardial and epicardial potentials. ResultsUnder the conditions of mild perfusion deficit, acute ischemia induced changes in the T wave that were larger and could be detected earlier on the epicardial surface than ST-segment changes. ConclusionsOur findings indicate that in the setting of very acute ischemia, epicardial T waves have higher sensitivity to mild degrees of acute ischemia than epicardial ST potentials. These results suggest that changes in the T wave shape may augment shifts in ST segments to improve ECG based localization of ischemia.

Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia

AimsThe objective of this study was to examine the involvement of endogenous opioid peptides and opioid receptor (OR) subtypes in the cardioprotective effect of adaptation to chronic hypoxia in rats. Main methodsRats were exposed to continuous normobaric hypoxia (CNH; 12% oxygen) for 3 weeks. Myocardial ischemia was induced by 20-min coronary artery occlusion followed by 3-h reperfusion in anesthetized open-chest animals. Various OR antagonists were administered to rats prior to ischemia. The size of myocardial infarction and the incidence of ischemic ventricular arrhythmias were assessed. Myocardial and plasma concentrations of opioid peptides (met-enkephalin, β-endorphin, and endomorphins) were determined. Key findingsAdaptation to CNH significantly increased myocardial and plasma concentrations of opioids, potentiated their further elevation by ischemia/reperfusion, and reduced myocardial infarct size, but it did not affect the incidence of ischemic arrhythmias. The infarct size-limiting effect of CNH was abolished by OR antagonists naltrexone (non-selective), naloxone methiodide (non-selective peripherally acting), TIPP[ψ] (δ-OR), naltriben (δ2-OR), or CTAP (μ-OR), while BNTX (δ1-OR) and nor-binaltorphimine (κ-OR) had no effect. SignificanceThe results suggest that the infarct size-limiting effect afforded by adaptation to CNH is mediated by activation of peripheral δ2- and μ-ORs by elevated levels of endogenous opioid peptides.

Short-Term Fasting Reduces the Extent of Myocardial Infarction and Incidence of Reperfusion Arrhythmias in Rats

The effect of three-day fasting on cardiac ischemic tolerance was investigated in adult male Wistar rats. Anesthetized open-chest animals (pentobarbitone 60 mg/kg, i.p.) were subjected to 20-min left anterior descending coronary artery occlusion and 3-h reperfusion for infarct size determination. Ventricular arrhythmias were monitored during ischemia and at the beginning (3 min) of reperfusion. Myocardial concentrations of beta-hydroxybutyrate and acetoacetate were measured to assess mitochondrial redox state. Short-term fasting limited the infarct size (48.5+/-3.3 % of the area at risk) compared to controls (74.3+/-2.2 %) and reduced the total number of premature ventricular complexes (12.5+/-5.8) compared to controls (194.9+/-21.9) as well as the duration of ventricular tachycardia (0.6+/-0.4 s vs. 18.8+/-2.5 s) occurring at early reperfusion. Additionally, fasting increased the concentration of beta-hydroxybutyrate and beta-hydroxybutyrate/acetoacetate ratio (87.8+/-27.0) compared to controls (7.9+/-1.7), reflecting altered mitochondrial redox state. It is concluded that three-day fasting effectively protected rat hearts against major endpoints of acute I/R injury. Further studies are needed to find out whether these beneficial effects can be linked to altered mitochondrial redox state resulting from increased ketogenesis.

Initial feasibility testing of limited field of view magnetic resonance thermometry using a local cardiac radiofrequency coil

The visualization of lesion formation in real time is one potential benefit of carrying out radiofrequency ablation under magnetic resonance (MR) guidance in the treatment of atrial fibrillation. MR thermometry has the potential to detect such lesions. However, performing MR thermometry during cardiac radiofrequency ablation requires high temporal and spatial resolution and a high signal-to-noise ratio. In this study, a local MR coil (2-cm diameter) was developed to investigate the feasibility of performing limited field of view MR thermometry with high accuracy and speed. The local MR coil allowed high-resolution (1 × 1 × 3 mm(3)) image acquisitions in 76.3 ms with a field of view 64 × 32 mm(2) during an open-chest animal experiment. This represents a 4-fold image acquisition acceleration and an 18-fold field of view reduction compared to that achieved using external MR coils. The signal sensitivity achieved using the local coil was over 20 times greater than that achievable using external coils with the same scan parameters. The local coil configuration provided fewer artifacts and sharper and more stable images. These results demonstrate that MR thermometry can be performed in the heart wall and that lesion formation can be observed during radiofrequency ablation procedures in a canine model.

Protective effects of dexrazoxane against acute ischaemia/reperfusion injury of rat hearts

Dexrazoxane (DEX), an inhibitor of topoisomerase II and intracellular iron chelator, is believed to reduce the formation of reactive oxygen species (ROS) and protects the heart from the toxicity of anthracycline antineoplastics. As ROS also play a role in the pathogenesis of cardiac ischaemia/reperfusion (I/R) injury, the aim was to find out whether DEX can improve cardiac ischaemic tolerance. DEX in a dose of 50, 150, or 450 mg·(kg body mass)(-1) was administered intravenously to rats 60 min before ischaemia. Myocardial infarct size and ventricular arrhythmias were assessed in anaesthetized open-chest animals subjected to 20 min coronary artery occlusion and 3 h reperfusion. Arrhythmias induced by I/R were also assessed in isolated perfused hearts. Only the highest dose of DEX significantly reduced infarct size from 53.9% ± 4.7% of the area at risk in controls to 37.5% ± 4.3% without affecting the myocardial markers of oxidative stress. On the other hand, the significant protective effect against reperfusion arrhythmias occurred only in perfused hearts with the dose of DEX of 150 mg·kg(-1), which also tended to limit the incidence of ischaemic arrhythmias. It is concluded that DEX in a narrow dose range can suppress arrhythmias in isolated hearts subjected to I/R, while a higher dose is needed to limit myocardial infarct size in open-chest rats.

Experimental research on safety of myocardial contrast echocardiography

Objective To evaluate the myocardium damage of myocardial contrast echocardiography (MCE) and the impact on regional left ventricular mechanics by imaging and pathology techniques.Methods Eleven open-chest animal models of Beagle were employed to collect the short-axis views of mitral annular,papillary muscle and apical level of three complete cardiac cycles using gray-scale imaging at the baseline and blank irradiation 5 min later(transmitting frequency 1.7/3.4 M Hz,mechanical index 1.0).After that,5 ml of SonoVue was gotten a shot by intravenous bolus injection,the heart was exposed by ultrasonic wave for 5 min continuously,and then the same images collected were at the point-in-time irradiation immediately,20 min,40 min and 60 min later.The short-axis circumferential strain and strain rate,radial strain and strain rate were measured and calculated by EchoPAC multi-parameter workstation,meanwhile including conventional of cardiac function.All the dogs were killed after the experiments and the myocardium was harvested for HE staining and observed with transmission electron microscope for the tissue microstructure.Results ①Conventional parameters of cardiac function:there was no significant difference before and after MCE in the heart rate,blood pressure,ejection fraction,left ventricular end-systolic volume and end-diastolic volume,stroke volume,cardiac output,mitral flow spectrum prior to the E/A,tissue Doppler mitral annular e/a and E/e ( P ＞0.05).During the whole process of experiment,the dogs’ vital signs were stable.②Compared the segmental circumferential strain and strain rate,radial strain and strain rate between baseline and each treatment groups,these parameters had a trend of increase in most segments,but the difference was not statistically significant in most segments (P ＞0.05).③HE staining at the light microscope demonstrated a small amount of myocardial cell infiltration of inflammatory cells near the outer membrane (21.2％),and very few part of the muscle fibers dissolved and fractured (6.1％).④The section of transmission electron microscope showed all the structures were normal except that a small amount of endothelial cells were mild swelling,some red blood cells were leaked,some myofilaments were regional dissolved,the relevance ratio were 28.6 ％,42.9 ％ and 21.4 ％ respectively,and the abnormal area was less than 10％ of the entire field of vision.Conclusions MCE has no significant impact for the global function of heart and the regional mechanical state,and furthermore there is no serious pathological damage on the myocardium. Key words: Echocardiography; Microbubbles; Ventricular function; Safety

Acute but not chronic tempol treatment increases ischemic and reperfusion ventricular arrhythmias in open-chest rats

The effect of the chronic and acute antioxidant tempol (superoxide dismutase mimetic) treatment on cardiac ischemic tolerance was investigated in adult male Wistar rats. The first experimental group was given tempol (1 mM) in drinking water for three weeks, the second group received tempol (100 mg/kg, i.v.) 10 min before test ischemia, and control rats received the same volume of solvent. Anesthetized open-chest animals (pentobarbitone 60 mg/kg, i.p.) were subjected to 20-min coronary artery occlusion and 3-h reperfusion for infarct size determination. Ventricular arrhythmias were monitored during ischemia and at the beginning (5 min) of reperfusion. Acute tempol administration shifted the time profile of ischemic arrhythmias to the later phase and significantly increased the number of ischemic and reperfusion premature ventricular complexes, respectively (504 +/- 127 and 84 +/- 21) as compared with the chronically treated group (218 +/- 36 and 47 +/- 7) or controls (197 +/- 26 and 31 +/- 7). Acute tempol-treated rats exhibited a tendency to decrease infarct size (P = 0.087). The mechanism of proarrhythmic tempol action during ischemia and reperfusion remains to be elucidated.

Alterations in Lateral Left Ventricular Wall Transmural Strains During Acute Circumflex and Anterior Descending Coronary Occlusion

Increased circumferential-radial shear in the midlateral left ventricle adjacent to ischemic myocardium has been observed during acute midcircumflex ischemia in open-chest animals. Extending this work, we studied transmural strains in closed-chest animals during acute proximal-circumflex (pCX) and proximal-left anterior descending (pLAD) occlusions. Six sheep had radiopaque markers implanted to silhouette the left ventricle and measure regional systolic fractional area shortening; three transmural bead columns were inserted into the midlateral wall for transmural myocardial strain analysis. After 8 weeks, three-dimensional marker coordinates were obtained using biplane videofluoroscopy, both before and during separate 1-minute pLAD and pCX balloon occlusions. Systolic strains were assessed along circumferential, longitudinal, and radial axes, and then transformed into fiber strains using quantitative microstructural measurements. Acute pLAD occlusion and pCX occlusion caused similar hemodynamic insults. Systolic fractional area shortening revealed that the beads were in the ischemic territory during pCX occlusion, but adjacent to the ischemic myocardium during pLAD occlusion. Transmural circumferential strain and fiber shortening fell in the ischemic region during pCX occlusion, but remained normal when adjacent to the ischemic myocardium during pLAD occlusion. Circumferential-radial shear strain increased in the lateral left ventricle during pCX occlusion, but reversed in this same region during pLAD occlusion. Longitudinal-radial shear also decreased during pLAD occlusion. Reversal of lateral wall circumferential-radial shear and decreased longitudinal-radial shear during acute pLAD occlusion reflects altered mechanical interaction between ischemic and nonischemic myocardium. Increased circumferential-radial shear during pCX occlusion also reflects mechanical interaction. The direction of circumferential-radial shear deformation depends on the location of the adjacent ischemic territory.

Detection of recent myocardial ischaemia by molecular imaging of P-selectin with targeted contrast echocardiography

We hypothesized that molecular imaging of endothelial P-selectin expression with targeted myocardial contrast echocardiography (MCE) could identify recently ischaemic myocardium without infarction. The microvascular behaviour of P-selectin-targeted (MB(p)) and control (MB(c)) microbubbles was assessed by intravital microscopy of the cremaster muscle in mice. Targeted MCE imaging with MB(p) and MB(c) was performed in mice after brief left anterior descending (LAD) occlusion and reperfusion and in open- and closed-chest controls. Regional wall motion and perfusion by MCE were assessed during occlusion and after reperfusion. On intravital microscopy, ischaemia-reperfusion produced a 10-fold increase (P < 0.01) in venular attachment for MB(p). Attachment for MB(c) was rare. With myocardial ischaemia-reperfusion, LAD occlusion produced hypoperfusion and wall motion abnormalities that resolved after 45 min of reperfusion. At 45 min, signal enhancement in the post-ischaemic region was four-fold greater (P < 0.05) for MB(p) vs. MB(c). MB(p) produced low-level enhancement in non-ischaemic myocardium in all open-chest animals, suggesting P-selectin expression from surgical cardiac exposure. Molecular imaging of P-selectin with targeted MCE can identify the presence of recently ischaemic myocardium in the absence of necrosis and after resolution of hypoperfusion and post-ischaemic stunning. This technique can potentially provide a method for risk stratifying patients with acute chest pain.

Alveolar instability caused by mechanical ventilation initially damages the nondependent normal lung.

BackgroundSeptic shock is often associated with acute respiratory distress syndrome, a serious clinical problem exacerbated by improper mechanical ventilation. Ventilator-induced lung injury (VILI) can exacerbate the lung injury caused by acute respiratory distress syndrome, significantly increasing the morbidity and mortality. In this study, we asked the following questions: what is the effect of the lung position (dependent lung versus nondependent lung) on the rate at which VILI occurs in the normal lung? Will positive end-expiratory pressure (PEEP) slow the progression of lung injury in either the dependent lung or the nondependent lung?Materials and methodsSprague–Dawley rats (n = 19) were placed on mechanical ventilation, and the subpleural alveolar mechanics were measured with an in vivo microscope. Animals were placed in the lateral decubitus position, left lung up to measure nondependent alveolar mechanics and left lung down to film dependent alveolar mechanics. Animals were ventilated with a high peak inspiratory pressure of 45 cmH2O and either a low PEEP of 3 cmH2O or a high PEEP of 10 cmH2O for 90 minutes. Animals were separated into four groups based on the lung position and the amount of PEEP: Group I, dependent + low PEEP (n = 5); Group II, nondependent + low PEEP (n = 4);Group III, dependent + high PEEP (n = 5); and Group IV, nondependent + high PEEP (n = 5). Hemodynamic and lung function parameters were recorded concomitant with the filming of alveolar mechanics. Histological assessment was performed at necropsy to determine the presence of lung edema.ResultsVILI occurred earliest (60 min) in Group II. Alveolar instability eventually developed in Groups I and II at 75 minutes. Alveoli in both the high PEEP groups were stable for the entire experiment. There were no significant differences in arterial PO2 or in the degree of edema measured histologically among experimental groups.ConclusionThis open-chest animal model demonstrates that the position of the normal lung (dependent or nondependent) plays a role on the rate of VILI.

EFFECT OF PERINATAL HYPOXIA ON CARDIAC TOLERANCE TO ACUTE ISCHAEMIA IN ADULT MALE AND FEMALE RATS

1. The number of adult patients undergoing surgery for congenital cyanotic defects in childhood has increased significantly. Therefore, the aim of the present study was to examine the effect of perinatal hypoxia on the tolerance of the adult myocardium to acute ischaemia-reperfusion injury. 2. Pregnant Wistar rats were exposed to intermittent hypobaric hypoxia 7 days before delivery; pups were born under normoxic conditions and exposed to hypoxia again for 10 postnatal days. After the last hypoxic exposure, all animals were kept for an additional 3 months under normoxic conditions. All experiments were performed on 90-day-old rats. 3. Ventricular arrhythmias were assessed on isolated perfused hearts during 30 min occlusion of the left anterior descending coronary artery. Infarct size was measured on isolated hearts (40 min regional ischaemia and 120 min reperfusion) and on open-chest animals (20 min regional ischaemia and 3 h reperfusion). 4. Perinatal exposure to hypoxia significantly increased cardiac tolerance to ischaemic injury in adult females, as evidenced by the lower incidence and severity of ischaemic ventricular arrhythmias, compared with the normoxic group. The effect of perinatal hypoxia on ischaemic arrhythmias in males was quite the opposite. Myocardial infarct size measured in open-chest animals only was significantly smaller in normoxic females compared with normoxic males. Perinatal exposure to hypoxia had no effect on infarct size in either setting or sex. 5. The results of the present study support the hypothesis that perinatal hypoxia is a primary programming stimulus in the heart that may lead to sex-dependent changes in cardiac tolerance to acute ischaemia in later adult life. This would have important implications for patients who have experienced prolonged hypoxaemia in early life.

Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions &lt;45 min

Brief episodes of ischemia and reperfusion after a lethal ischemic insult confer cardioprotection, a phenomenon termed "ischemic postconditioning." However, all studies reported to date have been conducted in open-chest animal models. We sought to determine whether postconditioning occurs in conscious animals and whether it protects against severe myocardial injury. Chronically instrumented rats were assigned to a 30- (Subset 1), 45- (Subset 2), or 60-min (Subset 3) coronary occlusion followed by 24 h of reperfusion. In each subset, rats received no further intervention (control), were preconditioned with 12 cycles of 2-min occlusion/2-min reperfusion immediately (early preconditioning; EPC) or 24 h (late preconditioning; LPC) before myocardial infarction, or were postconditioned with 20 cycles of 10-s occlusion/10-s reperfusion immediately after myocardial infarction (20-10 PostC). With a 30-min occlusion, infarct size (54.4 +/- 2.3% of risk region in control-30) was significantly reduced in EPC-30, LPC-30, and 20-10 PostC-30 groups (by 72, 70, and 47%, respectively; all P < 0.05 vs. control-30). With a 45-min occlusion, infarct size (62.2 +/- 2.4% in control-45) was reduced in EPC-45 and LPC-45 groups (by 47 and 41%, respectively; all P < 0.05 vs. control-45) but not in the 20-10 PostC-45 group [55.4 +/- 2.3%, P = not significant (NS) vs. control-45]. With a 60-min occlusion, infarct size (72.7 +/- 2.2% in control-60) was reduced in the EPC-60 (by 20%, P < 0.05) but not in the LPC-60 (63.6 +/- 2.5%, P = NS) or in the 20-20 PostC group (71.5 +/- 3.4%, P = NS). Both early and late ischemic preconditioning as well as ischemic postconditioning confer protection in conscious rats; however, unlike early preconditioning, postconditioning protects only against coronary occlusions <45 min. In the conscious rat, the cardioprotection afforded by postconditioning is limited to mild to moderate myocardial injury.

Myocardial infarct size-limiting effect of chronic hypoxia persists for five weeks of normoxic recovery.

We examined cardioprotective effect of chronic hypoxia and the time course of its recovery under normoxic conditions. Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (7000 m, 8 h/day, 35 exposures) and susceptibility of their hearts to ischemia-induced ventricular arrhythmias and myocardial infarction was evaluated in anesthetized open-chest animals subjected to 30-min coronary artery occlusion and 4-h reperfusion on the day after the last hypoxic exposure and at 7, 35 and 90 days of normoxic recovery. The infarct size was reduced from 69.2+/-1.7 % of the area at risk in normoxic controls to 48.0+/-2.2 % in the chronically hypoxic group and to 61.6+/-2.3 % in the group recovered for 7 days. This residual protection persisted for at least 35 days of normoxic recovery but it was absent after 90 days. In contrast to the infarct size-limitation, the antiarrhythmic protection disappeared already during the first week; the incidence of ventricular fibrillation was even significantly increased 7 and 90 days after the last hypoxic exposure. In conclusion, the duration of cardioprotection induced by chronic hypoxia differs markedly, depending on the end point of ischemia/reperfusion injury examined. Whereas the increased tolerance to lethal myocardial injury persists for at least 5 weeks after the termination of hypoxia, the antiarrhythmic protection rapidly vanishes, being replaced with transient proarrhythmic effect.