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Cardiac arrhythmias are commonly encountered perioperatively, and these can be associated with increased perioperative risk. The causes of the conduction abnormalities and rhythm abnormalities can be reversible. Their etiologies can be classified into several broad categories, including bradyarrhythmias, supraventricular arrhythmias, ventricular arrhythmias, and inherited disorders. Inherited disorders include prolonged QT syndrome and Brugada syndrome. This chapter discusses the details of these conduction abnormalities, including perioperative considerations, medical and surgical management, and management with pacemakers and automated implanted cardioverter/defibrillators (AICDs). Diagnosis includes an electrocardiogram at minimum. Also, the management of pacemakers and AICDs are reviewed, including their indications, types and possible settings, and reprogramming perioperatively.

Physiologic adaptations mediate normal responses to short-term and long-term stresses to ensure organ function. Organ failure results if adaptive responses fail to resolve persistent stresses or maladaptive reactions develop. The retinal neurovascular unit likewise undergoes adaptive responses to diabetes resulting in a retinal sensory neuropathy analogous to other sensory neuropathies. Vision-threatening diabetic retinal neuropathy results from unremitting metabolic and inflammatory stresses, leading to macular edema and proliferative diabetic retinopathy, states of "retinal failure." Current regulatory strategies focus primarily on the retinal failure stages, but new diagnostic modalities and understanding of the pathophysiology of diabetic retinopathy may facilitate earlier treatment to maintain vision in persons with diabetes.

A large and diverse array of small hydrophobic molecules induce general anesthesia. Their efficacy as anesthetics has been shown to correlate both with their affinity for a hydrophobic environment and with their potency in inhibiting certain ligand gated ion channels. Here we explore the effects that n-alcohols and other liquid anesthetics have on the two-dimensional miscibility critical point observed in cell derived giant plasma membrane vesicles (GPMVs). We show that anesthetics depress the critical temperature (Tc) of these GPMVs without strongly altering the ratio of the two liquid phases found below Tc. The magnitude of this affect is consistent across n-alcohols when their concentration is rescaled by the median anesthetic concentration (AC50) for tadpole anesthesia, but not when plotted against the overall concentration in solution. At AC50 we see a 4{\deg}C downward shift in Tc, much larger than is typically seen in the main chain transition at these anesthetic concentrations. GPMV miscibility critical temperatures are also lowered to a similar extent by propofol, phenylethanol, and isopropanol when added at anesthetic concentrations, but not by tetradecanol or 2,6 diterbutylphenol, two structural analogs of general anesthetics that are hydrophobic but have no anesthetic potency. We propose that liquid general anesthetics provide an experimental tool for lowering critical temperatures in plasma membranes of intact cells, which we predict will reduce lipid-mediated heterogeneity in a way that is complimentary to increasing or decreasing cholesterol. Also, several possible implications of our results are discussed in the context of current models of anesthetic action on ligand gated ion channels., Comment: 16 pages, 6 figures

There is a long-standing debate on whether general anesthetics act through a non-specific perturbation of bilayer physical properties or through binding to specific sites within ion channels, particularly the GABA-A receptor. In this study, we demonstrate that a series of liquid n-alcohol general anesthetics lower phase transition temperatures in giant plasma membrane vesicles, which have previously been shown to sit close to a miscibility critical point. All n-alcohols depress critical temperatures (Tc) by 4±1°C when added to vesicles at their anesthetic dose. Current work is investigating if transition temperatures are also depressed when n-alcohols are added to synthetic vesicles with critical lipid compositions. We also performed simulations of simplified receptors embedded in a nearly-critical membrane. In this model, receptor channels can be in two distinct internal states (conducting or non-conducting), and the occupancy of these states is allosterically regulated by their local lipid environment as well as the availability of ligand. We show that model channels with dimensions comparable to that of GABA-A could have their conductance increased by 50% when Tc is lowered by 4°C in the limit of low ligand concentration. This is in good agreement with experimental observations of GABA-A channels in the presence of general anesthetics (compare to Figure 2b in [1]). Taken together, these findings suggest that general anesthetics can have dramatic effects on the internal states of membrane bound proteins without requiring that they directly bind to specific sites. Instead, we propose that anesthetics may act by lowering the critical temperature of the membrane which in turn allosterically regulates ion channel function.1. N. Franks and W. Lieb, Molecular and cellular mechanisms of general anesthesia. Nature, 367, 607 (1994).

There is a long standing debate whether general anesthetics act through non-specific perturbation of bilayer physical properties or through binding to specific sites within ion channels. In this study, we investigate how a series of liquid general anesthetics impact phase transition temperatures in giant plasma membrane vesicles (GPMVs) isolated from RBL-2H3 mast cells. We have chosen to use a series of alcohol general anesthetics with a range of chain lengths that have well characterized membrane partitioning properties and anesthetic potency. We find that all alcohols investigated lower critical temperatures in GPMVs. When alcohol concentrations are scaled by anesthetic potency, the magnitude of depression is equivalent within error. All compounds depress critical temperatures by 4±1°C when added to vesicles at their anesthetic dose. This is larger than depressions previously measured for the gel-liquid transition in vesicles. Since the functional effects of general anesthetic treated cells are well characterized in the ion channel context, we have chosen to investigate the effects of alcohols on another signaling pathway thought to be sensitive to membrane physical properties. RBL cells undergo immune signaling when IgE antibodies bound to FceRI receptors are cross-linked with a multivalent antigen, and early signaling steps are sensitive to plasma membrane lipids. We find that treatment with alcohols general anesthetics disrupts signaling as assayed by measuring de-granulation, a functional output downstream of receptor activation. Current work is investigating functional outputs at earlier signaling steps including calcium responses and receptor phosphorylation. We are investigating receptor mobility and signaling responses in cells treated with alcohol general anesthetics using super-resolution localization microscopy. By correlating the critical temperature lowering effects of alcohol with cell signaling events, we hope to better understand how membrane physical properties influence signaling processes.

Diverse molecules induce general anesthesia with potency strongly correlated with both their hydrophobicity and their effects on certain ion channels. We recently observed that several n-alcohol anesthetics inhibit heterogeneity in plasma-membrane-derived vesicles by lowering the critical temperature (Tc) for phase separation. Here, we exploit conditions that stabilize membrane heterogeneity to further test the correlation between the anesthetic potency of n-alcohols and effects on Tc. First, we show that hexadecanol acts oppositely to n-alcohol anesthetics on membrane mixing and antagonizes ethanol-induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described “intoxication reversers” raise Tc and counter ethanol’s effects in vesicles, mimicking the findings of previous electrophysiological and behavioral measurements. Third, we find that elevated hydrostatic pressure, long known to reverse anesthesia, also raises Tc in vesicles with a magnitude that counters the effect of butanol at relevant concentrations and pressures. Taken together, these results demonstrate that ΔTc predicts anesthetic potency for n-alcohols better than hydrophobicity in a range of contexts, supporting a mechanistic role for membrane heterogeneity in general anesthesia.

Many small molecules induce general anesthesia in animals ranging from insects to mammals. Although their mechanism of action remains controversial, it is known that a compound's efficacy as an anesthetic is strongly predicted by both its hydrophobicity and its potency in inhibiting certain ligand gated ion channels. We recently published experiments showing that n-alcohol anesthetics (n≤10) take plasma membrane derived vesicles away from a biologically tuned, two dimensional (2D) liquid-liquid critical point [1]. Here, we present one line of investigation into our working hypothesis that anesthetics exert at least some of their effects by interfering with native regulation by the nearly critical plasma membrane. While most compounds, including the n≤10-alcohol anesthetics, lower critical temperatures in membranes, certain compounds raise critical temperatures counteracting the effects of anesthetics on membrane criticality. These compounds should specifically reverse effects mediated through membrane criticality. We demonstrate that hexadecanol (n=16) is such a compound, raising critical temperatures in cell-derived vesicles in a dose-dependent manner. We also present evidence that hexadecanol reverses ethanol's anesthetic effects on the tadpole righting response, in a manner quantitatively predicted by its effects on membrane criticality.1. Gray, E.; Karslake, J.; Machta, B.B.; Veatch, S.L.; Biophys. J. 105(12): 2751-9 (2013).