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Transcatheter Aortic Valve Implantation (TAVI) or Replacement (TAVR) is a promising treatment for aortic valve stenosis, consisting of a procedure to replace a damaged native aortic valve by a bioprosthetic one. This replacement valve control the flow of blood using leaflets that are similar to the ones of a native aortic valve. Commonly manufactured using bovine or porcine pericardium, it is a tissue histologically composed of collagen fibers embedded into a nearly-isotropic matrix, where their distribution makes the pericardium behave as an anisotropic hyperelastic material. Because of such complicated behavior, bioprosthetic pericardium valves are, as expected, sensitive to the distribution and orientation of these fibers in such device. Therefore, the objective of this work is a thorough systematic study on the influence of these fibers' distribution. First, a Finite Element model of a bioprosthetic valve is generated; then, a material routine to accurately describe the behavior of pericardium is implemented in a commercial software package; in addition, a dedicated algorithm to specify the direction of fibers is developed. Finally, a systematic study on the influence that fiber orientations have on the overall behavior of the TAV is performed. As a result of this study, two extreme behaviors are highlighted depending on the preferential orientation of collagen fibers; namely, one with fibers in circumferential direction and the opposite with fibers in an axial orientation. Then, it is concluded that the behavior of fibers in circumferential direction is very sensitive to small variations of the orientation angle, whereas such orientation is not as determining when the aim is to achieve a behavior near to the one corresponding with axial orientation.

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Alcohol use disorder is a significant global burden. Stress has been identified as an etiological factor in the initiation and continuation of ethanol consumption. Understanding adaptations within stress circuitry is an important step toward novel treatment strategies. The effects of protracted abstinence following long-term ethanol self-administration on the central nucleus of the amygdala (CeA) and the hypothalamic paraventricular nucleus (PVN) were evaluated in male rhesus monkeys. Using whole-cell patch-clamp electrophysiology, inhibitory GABAergic transmission in the CeA and excitatory glutamatergic transmission in the PVN were measured. CeA neurons from abstinent drinkers displayed an elevated baseline spontaneous inhibitory postsynaptic current (sIPSC) frequency compared with controls, indicating increased presynaptic GABA release. Application of acute ethanol significantly increased the frequency of sIPSCs in controls, but not in abstinent drinkers, suggesting a tolerance to ethanol-enhanced GABA release in abstinent rhesus monkeys with a history of chronic ethanol self-administration and repeated abstinence. In the PVN, the frequency of spontaneous excitatory postsynaptic currents (sEPSC) was elevated in abstinent drinkers compared with controls, indicating increased presynaptic glutamate release. Notably, acute ethanol decreased presynaptic glutamate release onto parvocellular PVN neurons in both controls and abstinent drinkers, suggesting a lack of tolerance to acute ethanol among PVN neurons. These results are the first to demonstrate distinct synaptic adaptations and ethanol sensitivity in both the extrahypothalamic and hypothalamic stress circuits in abstinent rhesus males. Importantly, our findings describe adaptations in stress circuitry present in the brain at a state during abstinence, just prior to relapse to ethanol drinking.

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Aldosterone regulates electrolyte and fluid homeostasis through binding to the mineralocorticoid receptors (MRs). Previous work provides evidence for a role of aldosterone in alcohol use disorders (AUDs). We tested the hypothesis that high functional activity of the mineralocorticoid endocrine pathway contributes to vulnerability for AUDs. In Study 1, we investigated the relationship between plasma aldosterone levels, ethanol self-administration and the expression of CYP11B2 and MR (NR3C2) genes in the prefrontal cortex area (PFC) and central nucleus of the amygdala (CeA) in monkeys. Aldosterone significantly increased after 6- and 12-month ethanol self-administration. NR3C2 expression in the CeA was negatively correlated to average ethanol intake during the 12 months. In Study 2, we measured Nr3c2 mRNA levels in the PFC and CeA of dependent and nondependent rats and the correlates with ethanol drinking during acute withdrawal. Low Nr3c2 expression levels in the CeA were significantly associated with increased anxiety-like behavior and compulsive-like drinking in dependent rats. In Study 3, the relationship between plasma aldosterone levels, alcohol drinking and craving was investigated in alcohol-dependent patients. Non-abstinent patients had significantly higher aldosterone levels than abstinent patients. Aldosterone levels positively correlated with the number of drinks consumed, craving and anxiety scores. These findings support a relationship between ethanol drinking and the aldosterone/MR pathway in three different species.

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