Aim In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodelling in cardiac diseases is associated with downregulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signalling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes. Methods and results Rat ventricular myocytes kept in culture for 4 days showed extensive T-tubule remodelling with impaired JPH2 localization and relocation of the scaffolding protein Caveolin3 (Cav3) from the T-tubules to the outer membrane. Overexpression of JPH2 restored T-tubule structure and Cav3 relocation. Depletion of membrane cholesterol by chronic treatment with methyl-β-cyclodextrin (MβCD) countered the stabilizing effect of JPH2 overexpression on T-tubules and Cav3. Super-resolution scanning patch-clamp showed that JPH2 overexpression greatly increased the number of functional LTCCs at the plasma membrane. Treatment with MβCD reduced LTCC open probability and activity. Proximity ligation assays showed that MβCD did not affect JPH2 interaction with RyR and the pore-forming LTCC subunit Cav1.2, but strongly impaired JPH2 association with Cav3 and the accessory LTCC subunit Cavβ2. Conclusions JPH2 promotes T-tubule structural stability and recruits functional LTCCs to the membrane, most likely by directly binding to the channel. Cholesterol is involved in the binding of JPH2 to T-tubules as well as in the modulation of LTCC activity. We propose a model where cholesterol and Cav3 support the assembly of lipid rafts which provide an anchor for JPH2 to form JMCs and a platform for signalling complexes to regulate LTCC activity.

Objectives This study aims to investigate the prognostic significance of late gadolinium enhancement (LGE) in patients without coronary artery disease and with normal range left ventricular (LV) volumes and ejection fraction. Background Nonischemic patterns of LGE with normal LV volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance, but their prognostic significance, and consequently management, is uncertain. Methods Patients with midwall/subepicardial LGE and normal LV volumes, wall thickness, and ejection fraction on cardiovascular magnetic resonance were enrolled and compared to a control group without LGE. The primary outcome was actual or aborted sudden cardiac death (SCD). Results Of 748 patients enrolled, 401 had LGE and 347 did not. The median age was 50 years (interquartile range: 38-61 years), LV ejection fraction 66% (interquartile range: 62%-70%), and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). No patient experienced SCD and only 1 LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3 years, 30 patients (4.0%) died. All-cause mortality was similar for LGE+/- patients (3.7% vs 4.3%; P = 0.71) and was associated with age (HR: 2.04 per 10 years; 95% CI: 1.46-2.79; P < 0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned cardiovascular hospital admission (HR: 7.22; 95% CI: 4.26-21.17; P < 0.0001). Conclusions There was a low SCD risk during long-term follow-up in patients with LGE but otherwise normal LV volumes and ejection fraction. Mortality was driven by age and not LGE presence, location, or extent, although the latter was associated with greater cardiovascular hospitalization for suspected myocarditis and symptomatic ventricular tachycardia.

Objectives We sought to identify baseline demographics and procedural factors that might independently predict in‐hospital stroke following transcatheter aortic valve implantation (TAVI). Background Stroke is a recognized, albeit infrequent, complication of TAVI. Established predictors of procedure‐related in‐hospital stroke; however, remain poorly defined. Methods We conducted an observational cohort analysis of the multicenter UK TAVI registry. The primary outcome measure was the incidence of in‐hospital stroke. Results A total of 8,652 TAVI procedures were performed from 2007 to 2015. There were 205 in‐hospital strokes reported by participating centers equivalent to an overall stroke incidence of 2.4%. Univariate analysis showed that the implantation of balloon‐expandable valves caused significantly fewer strokes (balloon‐expandable 96/4,613 [2.08%] vs. self‐expandable 95/3,272 [2.90%]; p = .020). After multivariable analysis, prior cerebrovascular disease (CVD) (odds ratio [OR] 1.51, 95% confidence interval [CI 1.05–2.17]; p = .03), advanced age at time of operation (OR 1.02 [0.10–1.04]; p = .05), bailout coronary stenting (OR 5.94 [2.03–17.39]; p = .008), and earlier year of procedure (OR 0.93 [0.87–1.00]; p = .04) were associated with an increased in‐hospital stroke risk. There was a reduced stroke risk in those who had prior cardiac surgery (OR 0.62 [0.41–0.93]; p = .01) and a first‐generation balloon‐expandable valve implanted (OR 0.72 [0.53–0.97]; p = .03). In‐hospital stroke significantly increased 30‐day (OR 5.22 [3.49–7.81]; p < .001) and 1‐year mortality (OR 3.21 [2.15–4.78]; p < .001). Conclusions In‐hospital stroke after TAVI is associated with substantially increased early and late mortality. Factors independently associated with in‐hospital stroke were previous CVD, advanced age, no prior cardiac surgery, and deployment of a predominantly first‐generation self‐expandable transcatheter heart valve.

Objectives: To determine whether a permanent pacemaker (PPM) in situ can enhance survival after transcatheter aortic valve implantation (TAVI), in a predominantly inoperable or high risk cohort.Background: New conduction disturbances are the most frequent complication of TAVI, often necessitating PPM implantation before hospital discharge.Methods: We performed an observational cohort analysis of the UK TAVI registry (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015). Primary and secondary endpoints were 30-day post-discharge allcause mortality and long-term survival, respectively.