Aquaporin-4 Mediates Permanent Brain Alterations in a Mouse Model of Hypoxia-Aged Hydrocephalus

Aquaporin-4 (AQP4) is the principal water channel in the brain being expressed in astrocytes and ependymal cells. AQP4 plays an important role in cerebrospinal fluid (CSF) homeostasis, and alterations in its expression have been associated with hydrocephalus. AQP4 contributes to the development of hydrocephalus by hypoxia in aged mice, reproducing such principal characteristics of the disease. Here, we explore whether these alterations associated with the hydrocephalic state are permanent or can be reverted by reexposure to normoxia. Alterations such as ventriculomegaly, elevated intracranial pressure, and cognitive deficits were reversed, whereas deficits in CSF outflow and ventricular distensibility were not recovered, remaining impaired even one month after reestablishment of normoxia. Interestingly, in AQP4−/− mice, the impairment in CSF drainage and ventricular distensibility was completely reverted by re-normoxia, indicating that AQP4 has a structural role in the chronification of those alterations. Finally, we show that aged mice subjected to two hypoxic episodes experience permanent ventriculomegaly. These data reveal that repetitive hypoxic events in aged cerebral tissue promote the permanent alterations involved in hydrocephalic pathophysiology, which are dependent on AQP4 expression.

Effect of a reduced donor heart right ventricular distensibility on post-heart transplant haemodynamics

OBJECTIVES This study aimed to investigate the characteristics of a reduced right ventricular distensibility after heart transplant. METHODS This study enrolled 64 adult patients who underwent heart transplant at our institution. The degree of right ventricular distensibility was quantified by calculating the difference between right atrial pressures (RAPs) of X descent and Y descent (X–Y) from the RAP waveform in right heart catheterization. Histologically, the ratio of the interstitial tissue in myocardial biopsy samples was calculated. RESULTS Of the 64 patients, 35 (55%) had a reduced right ventricular distensibility at 1 week after heart transplant (X–Y > 1 mmHg, RD group), and 29 (45%) had a normal right ventricular distensibility (X–Y ≤ 1 mmHg, ND group). The mean RAP and mean pulmonary capillary wedge pressure 1 week after heart transplant in the RD group were significantly higher than that in the ND group. The mean RAP and mean pulmonary capillary wedge pressure in the RD group gradually normalized 12 weeks postoperation. The ratio of the interstitial tissue of biopsy samples significantly correlated with the X–Y value. The number of patients who required inotropic support >14 days was higher in the RD group than in the ND group. CONCLUSIONS Reduced donor heart distensibility was a common impairment early after heart transplant. It might result from interstitial oedema in the myocardial tissue of the donor heart. Reduced donor heart distensibility after heart transplant might be associated with early clinical outcomes; however, further investigation is required.

Abstract 149: Zoniporide Combined with α-Methylnorepinephrine Promotes Greater Hemodynamic Stability than Either Agent Alone During Chest Compression in Rats

Background: We have reported in animal models of cardiac arrest that sodium hydrogen exchanger-1 (NHE-1) inhibition - by attenuating reperfusion injury - helps preserve left ventricular distensibility yielding higher forward blood flows during chest compression. Others have reported that α-methylnorepinephrine (α-MNE) - a selective peripheral α2-adrenoreceptor agonist - is superior to epinephrine given its lack of β-agonist effect that intensifies myocardial ischemia. We examined in a rat model of VF the effects of combining the NHE-1 inhibitor zoniporide (ZNP) with α-MNE during CPR, expecting to elicit a vasopressor effect (α-MNE) that is better maintained over time because of ZNP. Methods: VF was electrically induced in 32 male retired breeder Sprague-Dawley rats and left untreated for 8 minutes. Chest compression was then initiated, gradually increasing the depth of compression (maximum 17 mm) to attain an aortic diastolic pressure of 28 mmHg by the end of minute 2, maintaining such level for the remaining 6 minutes of chest compression, time at which defibrillation was attempted. The rats were randomized 1:1:1:1 to receive a 3 mg/kg bolus of ZNP or 0.9% NaCl before starting chest compression and a 100 μg/kg bolus of α-MNE or its vehicle at minute 2 of chest compression with the investigators blind to the assignment. Results: The ratio between the aortic diastolic pressure and depth of compression (Figure) was higher - as expected - in rats that received α-MNE(+) given its vasopressor effect. The effect, however, was not maintained and declined over time; but to a significantly lesser degree in rats that also received ZNP; i.e., α-MNE(+)/ZNP(+) group. Conclusions: The findings support a favorable interaction between α-MNE and ZNP; the first prompting needed peripheral vasoconstriction - likely with less concomitant myocardial injury - and the latter preserving left ventricular distensibility, which combined enhance the hemodynamic efficacy of chest compression.