Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell–cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.

The relative analgesic efficacy and side-effect profile of peripheral nerve blockade (PNB) techniques compared with lumbar epidural analgesia for major knee surgery is unclear. We undertook a systematic review and meta-analysis of all randomized trials comparing epidural analgesia with PNB for major knee surgery. Eight studies were identified that had enrolled a total of 510 patients of whom 464 (91%) had undergone total knee joint replacement. All were small trials and none was blinded (Jadad score 1-3). PNB technique was variable: in addition to a femoral catheter (n=5), femoral single shot (n=2), or lumbar plexus catheter (n=1) techniques, sciatic blockade was performed in three trials. There was no significant difference in pain scores between epidural and PNB at 0-12 or 12-24 h, WMD 0.22 (95% CI: -0.36, 0.81), 0.05 (-1.01, 0.91), respectively, and no clinically significant difference at 24-48 h, WMD -0.35 (-0.64, -0.02). There was also no difference in morphine consumption (mg) at 0-24 h, WMD -6.25 (-18.35, 5.86). Hypotension occurred more frequently among patients who received epidurals [OR 0.19 (0.08, 0.45)], but there was no difference in the incidence of nausea and vomiting. Two studies reported a higher incidence of urinary retention in the epidural group. Patient satisfaction was higher with PNB in two of three studies which measured this, although rehabilitation indices were similar. PNB with a femoral nerve block provides postoperative analgesia which is comparable with that obtained with an epidural technique but with an improved side-effect profile and is less likely to cause a severe neuraxial complication.

Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Na1.5 and N-Cadherin clusters at junctional sites. This suggests that Na1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Na1.5 dysfunction causes cardiomyopathy.

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The use of CPAP is associated with significant reduction in recurrence of AF in patients with OSA. This effect remains consistent and similar across patient populations irrespective of whether they undergo PVI.