Axillary Artery Access for Mechanical Circulatory Support Devices in Patients With Prohibitive Peripheral Arterial Disease Presenting With Cardiogenic Shock.

In patients with severe peripheral vascular disease, the common femoral artery may be so diseased as to not allow for deployment of mechanical circulatory support (MCS) such as in the setting of cardiogenic shock (CS). We sought to study the feasibility of axillary artery as alternative access for MCS in CS patients with severe occlusive peripheral artery disease (PAD). Records of all patients who presented with CS requiring MCS through axillary artery access from January 2016 to October 2017 were examined. Demographics, clinical, procedural, and outcomes data were collected on all patients. A total of 17 patients (mean age 68 ± 14years, 95% men) were identified. This was due to severe PAD in the iliac and/or common femoral arteries prohibiting large bore sheath access in allcases. Of the 17 patients, 9 required percutaneous coronary intervention. Time from axillary access to activation of Impella was 14.8 ± 4 minutes. Three patients required concomitant Impella RP for right ventricular support due to biventricular CS. Twelve patients died before Impella was explanted due to multiorgan failure, stroke, and infection. None of the patients who died had vascular complications related to axillary access. All 5 patients who survived to Impella explant were discharged from the hospital without major complication. Axillary artery is a safe and feasible alternative access for large bore devices in patients with prohibitive PAD. The meticulous technique described assures a very low rate of access related complications.

Mechanical Circulatory Support for High-Risk Pulmonary Embolism.

Temporary mechanical circulatory support (MCS) devices have a role in treating high-risk patients with pulmonary embolism with cardiogenic shock. Mechanical circulatory device selection should be made based on center experience and device-specific features. All current devices are effective in decreasing right arterial pressure and providing circulatory support of 4 to 5 L/min. The pulmonary artery pulsatility index may prove to be an unreliable method to assess right ventricular function. Careful clinical evaluation on an individual patient basis should determine the need for MCS.

Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation.

Pompe disease is due to a deficiency in acid-α-glucosidase (GAA) and results in debilitating skeletal muscle wasting, characterized by the accumulation of glycogen and autophagic vesicles. Given the role of lysosomes as a platform for mTORC1 activation, we examined mTORC1 activity in models of Pompe disease. GAA-knockdown C2C12 myoblasts and GAA-deficient human skin fibroblasts of infantile Pompe patients were found to have decreased mTORC1 activation. Treatment with the cell-permeable leucine analog L-leucyl-L-leucine methyl ester restored mTORC1 activation. In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine-treated Pompe mice showed increased spontaneous activity and running capacity, with reduced muscle protein breakdown and glycogen accumulation. Together, these data demonstrate that GAA deficiency results in reduced mTORC1 activation that is partly responsible for the skeletal muscle wasting phenotype. Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model.

The antidepressant trans-2-phenylcyclopropylamine protects mice from high-fat-diet-induced obesity.

Mice treated with the antidepressant trans-2-phenylcyclopropylamine (2-PCPA) were protected against diet-induced-obesity, and adiposity was reversed in pre-established diet-induced obese mice. Contrary to a recent report that inhibition of lysine-specific demethylase-1 by 2-PCPA results in increased energy expenditure, long-term 2-PCPA treatment had no such effect but its protection against obesity was associated with increased spontaneous locomotor activity, Moreover, pair feeding to assure equal caloric intake in wild type mice as well as in genetic hyperphagic mice (ob/ob) also resulted in weight reduction in 2-PCPA treated mice that correlated with increased activity but no change in energy expenditure. Similarly, short-term intraperitoneal injections of 2-PCPA did not affect food intake but caused a substantial increase in locomotor activity in the light cycle that correlated with increased energy expenditure, whereas activity and energy expenditure were unchanged in the dark cycle. Lastly, 2-PCPA was also effective in reducing obesity in genetic UCP1 null mice. These data suggest that 2-PCPA can reduce obesity by decreasing food intake in the long term while increasing activity in the short-term. However, the protective and weight loss effects of 2-PCPA are independent of UCP1-regulated thermogenesis or basal energy expenditure.

Selective translocation of Ca2+/calmodulin protein kinase IIalpha (CaMKIIalpha) to inhibitory synapses.

Ca(2+)/calmodulin protein kinase IIα (CaMKIIα) has a central role in regulating neuronal excitability. It is well established that CaMKIIα translocates to excitatory synapses following strong glutamatergic stimuli that induce NMDA-receptor (NMDAR)-dependent long-term potentiation in CA1 hippocampal neurons. We now show that CaMKIIα translocates to inhibitory but not excitatory synapses in response to more moderate NMDAR-activating stimuli that trigger GABA(A)-receptor (GABA(A)R) insertion and enhance inhibitory transmission. Such moderate NMDAR activation causes Thr286 autophosphorylation of CaMKIIα, which our results demonstrate is necessary and sufficient, under basal conditions, to localize CaMKIIα at inhibitory synapses and enhance surface GABA(A)R expression. Although stronger glutamatergic stimulation coupled to AMPA receptor insertion also elicits Thr286 autophosphorylation, accumulation of CaMKIIα at inhibitory synapses is prevented under these conditions by the phosphatase calcineurin. This preferential targeting of CaMKIIα to glutamatergic or GABAergic synapses provides neurons with a mechanism whereby activity can selectively potentiate excitation or inhibition through a single kinase mediator.