The role of early cardiac resynchronization therapy implantation in dilated cardiomyopathy patients with narrow QRS carrying lamin A/C mutation.

BACKGROUND: Dilated cardiomyopathy (DCM) caused by Lamin A/C gene (LMNA) mutation is complicated with atrioventricular conduction disturbances, malignant ventricular arrhythmias and progressive severe heart failure. OBJECTIVE: We hypothesized that early cardiac resynchronization therapy (CRT) implantation in LMNA mutation carriers with an established indication for pacemaker or implantable cardioverter defibrillator (ICD), may preserve ejection fraction, and delay disease progression to end stage heart failure. METHODS: We compared the primary outcomes: time to heart transplantation, death due to end stage heart failure or ventricular tachycardia (VT) ablation and secondary outcomes: change in left ventricular ejection fraction (EF) and ventricular arrhythmia burden between LMNA DCM patients in the early CRT and non-CRT groups. RESULTS: Of ten LMNA DCM patients (age 51±10 years, QRS 96±14 msec, EF 55±7%) with indication for pacemaker or ICD implantation, five underwent early CRT-D implantation. After 7.2±4 years, three patients (60%) in the non-CRT group reached the primary outcome, compared to no patients in the CRT group (P=0.046). Four patients in non-CRT group (80%) experienced sustained ventricular tachycardia or received appropriate ICD shock compared to 1 patient (20%) in the CRT group (P=0.058). LMNA patients without early CRT had a higher burden of VPC/24 h in 12-lead holter (median 2352 vs 185, P=0.09). Echocardiography showed statistically lower LVEF in the non-CRT group compared to CRT group [(32±15)% vs (61±4)%, 95% CI: 32.97-61.03, P=0.016]. CONCLUSION: Early CRT implantation in LMNA cardiomyopathy patients, with an indication for pacemaker or ICD, may reduce heart failure deterioration and life-threatening heart failure complications.

Clinical management of conduction abnormalities following transcatheter aortic valve replacement: prospective evaluation of a standardized management pathway.

PURPOSE: Limited evidence guides management of conduction abnormalities following TAVR. Standardized clinical pathways may reduce variability in care while minimizing bradyarrhythmic morbidity, length of stay (LOS), and pacemaker (PPM) implantation rates. METHODS: A multidisciplinary consensus pathway to standardize post-TAVR management was developed. We evaluated (1) pathway adherence; (2) LOS; (3) PPM implantation rates; (4) 1-month survival, and (5) late heart block. Exploratory analyses evaluated factors associated with PPM implantation. RESULTS: A total of 181 consecutive patients without prior PPM who underwent TAVR between February 2020 and February 2021 (mean age 77.9 ± 9.1, 38% women) were included. Average LOS was 3.0 days (± 2.7), and no deaths related to syncope/bradyarrhythmia were reported by 1 month. Overall, 93% of the 181 patients were managed by pathway; deviations were due to failure of discharge with a heart monitor when it was clinically indicated for either pre-existing RBBB or new PR prolongation/new LBBB. PPM implantation occurred in 19 patients by discharge, and 21 by 1-month (13%). In our exploratory analysis, pre-existing RBBB, transient peri-procedural heart block, and LOTUS valves were associated with pacemaker implantation: OR (CI) of 8.16 (3.06-21.78), 6.83 (1.94-24.03), and 8.32 (1.11-62.49), respectively. CONCLUSIONS: This report illustrates that a standardized protocol for the management of conduction abnormalities after TAVR can be implemented with high compliance, safe management of conduction disturbance, and relatively short LOS with discharge supported by ambulatory monitoring.

[SYNCOPE CAUSED BY INTRA-OCULAR TIMOLOL].

INTRODUCTION: Timolol eye-drops are commonly used for the treatment of glaucoma. Despite being topically applied, some systemic absorption occurs with the resulting adverse reactions related to its beta-adrenoreceptor blocking activity CASE PRESENTATION: We report the case of a 68 years old healthy male who was admitted to our department for further workup following two episodes of syncope. Medical history taking revealed that the episodes of syncope occurred soon after beginning treatment with intra-ocular timolol for glaucoma. An electrocardiogram demonstrated a sinus bradycardia rhythm and a prolonged PR interval, consistent with the negative effects of a beta adrenergic receptor antagonist on the heart's electrical generation and conduction system. DISCUSSION: This case demonstrates the potential for dangerous systemic side effects of a topically-applied medication. It also highlights the importance of thorough medical history taking in the evaluation of syncope, including inquiry regarding the use of all, especially new, medications. CONCLUSION: Detailed medical history taking can help in avoiding the performance of an expensive and unnecessary workup.

From hypomagnesaemia to Zollinger-Ellison syndrome: an adverse effect of a proton pump inhibitor.

We describe the case of a 53-year-old man who presented with abdominal pain, diarrhoea and hypomagnesaemia. The hypomagnesaemia proved to be due to gastrointestinal loss as urinary fractional excretion was very low, suggesting non-renal loss. Common causes were discarded and the hypomagnesaemia was attributed to chronic use of the proton pump inhibitor, omeprazole. As such, omeprazole was discontinued and an H2 blocker was given. Several days later the patient presented with upper gastrointestinal bleeding. CT scan demonstrated marked enlargement of the duodenum and proximal jejunum, and abnormal thickening and enhancement of the bowel wall. Urgent oesophagogastroduodenoscopy revealed coffee-ground and bloody contents in the distal oesophagus and stomach, and numerous ulcers along the duodenum and jejunum. A positron emission tomography-CT scan using GA 68-DOTANOC demonstrated increased uptake in the gastroduodenum junction, suggesting a neuroendocrine tumour. Pancreaticoduodenectomy was performed and tumour cells stained positive for gastrin, confirming the tentative diagnosis of Zollinger-Ellison syndrome.

Pre-operative systolic anterior motion of the mitral valve in a patient undergoing mitral valve repair.

A patient with myxomatous mitral valve prolapse underwent mitral mitral valve repair due to severe symptomatic mitral regurgitation. Preoperative echocardiography demonstrated systolic anterior motion of the mitral valve. This finding disappeared once spontaneous chordal rupture occurred, resulting in a flail posterior mitral leaflet. As the patient was considered at high risk of developing post-repair SAM, he was operated on using surgical techniques aimed at lowering the risk of this complication. Despite this, post-repair SAM did develop and could only be eliminated by a surgical edge-to-edge (Alfieri) repair.

Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates alpha-synuclein monoubiquitylation and inclusion formation.

Parkinson disease (PD) is characterized by the presence of ubiquitylated inclusions and the death of dopaminergic neurons. Seven in absentia homolog (SIAH) is a ubiquitin-ligase that ubiquitylates alpha-synuclein and synphilin-1 and is present in Lewy bodies of PD patients. Understanding the mechanisms that regulate the ubiquitylation of PD-related proteins might shed light on the events involved in the formation of Lewy bodies and death of neurons. We show in this study that the recently described synphilin-1 isoform, synphilin-1A, interacts in vitro and in vivo with the ubiquitin-protein isopeptide ligase SIAH and regulates its activity toward alpha-synuclein and synphilin-1. SIAH promotes limited ubiquitylation of synphilin-1A that does not lead to its degradation by the proteasome. SIAH also increases the formation of synphilin-1A inclusions in the presence of proteasome inhibitors, supporting the participation of ubiquitylated synphilin-1A in the formation of Lewy body-like inclusions. Synphilin-1A/SIAH inclusions recruit PD-related proteins, such as alpha-synuclein, synphilin-1, Parkin, PINK1, and UCH-L1. We found that synphilin-1A robustly increases the steady-state levels of SIAH by decreasing its auto-ubiquitylation and degradation. In addition, synphilin-1A blocks the ubiquitylation and degradation of the SIAH substrates synphilin-1 and deleted in colon cancer protein. Furthermore, synphilin-1A strongly decreases the monoubiquitylation of alpha-synuclein by SIAH and the formation of alpha-synuclein inclusions, supporting a role for monoubiquitylation in alpha-synuclein inclusion formation. Our results suggest a novel function for synphilin-1A as a regulator of SIAH activity and formation of Lewy body-like inclusions.

Synphilin isoforms and the search for a cellular model of lewy body formation in Parkinson's disease.

A common finding in many neurodegenerative diseases is the presence of inclusion bodies made of aggregated proteins in neurons of affected brain regions. In Parkinson's disease, the inclusion bodies are referred to as Lewy bodies and their main component is alpha-synuclein. Although many studies have suggested that inclusion bodies may be cell protective, it is still not clear whether Lewy bodies promote or inhibit dopaminergic cell death in Parkinson's disease. Synphilin-1 interacts with alpha-synuclein and is present in Lewy bodies. Accumulation of ubiquitylated synphilin-1 leads to massive formation of inclusion bodies, which resemble Lewy bodies by their ability to recruit alpha-synuclein. We have recently isolated an isoform of synphilin-1, synphilin-1A, that spontaneously aggregates in cells, and is present in detergent-insoluble fractions of brain protein samples from alpha-synucleinopathy patients. Synphilin-1A displays marked neuronal toxicity and, upon proteasome inhibition, accumulates into ubiquitylated inclusions with concomitant reduction of its intrinsic toxicity. The fact that alpha-synuclein interacts with synphilin-1A, and is recruited to synphilin-1A inclusion bodies in neurons together with synphilin-1, further indicates that synphilin-1A cell model is relevant for research on Parkinson's disease. Synphilin-1A cell model may help provide important insights regarding the role of inclusion bodies in Parkinson's disease and other neurodegenerative disorders.

Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes neuronal death and is present in aggregates from alpha-synucleinopathy patients.

alpha-Synucleinopathies are a group of neurological disorders characterized by the presence of intracellular inclusion bodies containing alpha-synuclein. We previously demonstrated that synphilin-1 interacts with alpha-synuclein, implying a role in Parkinson's disease. We now report the identification and characterization of synphilin-1A, an isoform of synphilin-1, which has enhanced aggregatory properties and causes neurotoxicity. The two transcripts encoding synphilin-1A and synphilin-1 originate from the SNCAIP gene but differ in both their exon organization and initial reading frames used for translation. Synphilin-1A binds to alpha-synuclein and induces the formation of intracellular aggregates in human embryonic kidney 293 cells, primary neuronal cultures, and human dopaminergic cells. Overexpression of synphilin-1A in neurons results in striking cellular toxicity that is attenuated by the formation of synphilin-1A inclusions, which recruit alpha-synuclein. Synphilin-1A is present in Lewy bodies of patients with Parkinson's disease and Diffuse Lewy Body disease, and is observed in detergent-insoluble fractions of brain protein samples obtained from Diffuse Lewy Body disease patients. These findings suggest that synphilin-1A may contribute to neuronal degeneration in alpha-synucleinopathies and also provide important insights into the role of inclusion bodies in neurodegenerative disorders.

Glycogen synthase kinase 3beta modulates synphilin-1 ubiquitylation and cellular inclusion formation by SIAH: implications for proteasomal function and Lewy body formation.

alpha-Synuclein is known to play a major role in the pathogenesis of Parkinson disease. We previously identified synphilin-1 as an alpha-synuclein-interacting protein and more recently found that synphilin-1 also interacts with the E3 ubiquitin ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system. Inability of the proteasome to degrade synphilin-1 promotes the formation of ubiquitylated inclusion bodies. We now show that synphilin-1 is phosphorylated by GSK3beta within amino acids 550-659 and that this phosphorylation is significantly decreased by pharmacological inhibition of GSK3beta and suppression of GSK3beta expression by small interfering RNA duplex. Mutation analysis showed that Ser556 is a major GSK3beta phosphorylation site in synphilin-1. GSK3beta co-immunoprecipitated with synphilin-1, and protein 14-3-3, an activator of GSK3beta activity, increased synphilin-1 phosphorylation. GSK3beta decreased the in vitro and in vivo ubiquitylation of synphilin-1 as well as its degradation promoted by SIAH. Pharmacological inhibition and small interfering RNA suppression of GSK3beta greatly increased ubiquitylation and inclusion body formation by SIAH. Additionally, synphilin-1 S556A mutant, which is less phosphorylated by GSK3beta, formed more inclusion bodies than wild type synphilin-1. Inhibition of GSK3beta in primary neuronal cultures decreased the levels of endogenous synphilin-1, indicating that synphilin-1 is a physiologic substrate of GSK3beta. Using GFPu as a reporter to measure proteasome function in vivo, we found that synphilin-1 S556A is more efficient in inhibiting the proteasome than wild type synphilin-1, raising the possibility that the degree of synphilin-1 phosphorylation may regulate the proteasome function. Activation of GSK3beta during endoplasmic reticulum stress and the specific phosphorylation of synphilin-1 by GSK3beta place synphilin-1 as a possible mediator of endoplasmic reticulum stress and proteasomal dysfunction observed in Parkinson disease.

Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by Lewy body formation and death of dopaminergic neurons. Mutations in alpha-synuclein and parkin cause familial forms of PD. Synphilin-1 was shown to interact with alpha-synuclein and to promote the formation of cytosolic inclusions. We now report that synphilin-1 interacts with the E3 ubiquitin-ligases SIAH-1 and SIAH-2. SIAH proteins ubiquitylate synphilin-1 both in vitro and in vivo, promoting its degradation by the ubiquitin-proteasome system. Inability of the proteasome to degrade synphilin-1/SIAH complex leads to a robust formation of ubiquitylated cytosolic inclusions. Ubiquitylation is required for inclusion formation, because a catalytically inactive mutant of SIAH-1, which still binds to synphilin-1, fails to promote inclusions. Like synphilin-1, alpha-synuclein associates with SIAH in intact cells, but the interaction with SIAH-2 was much stronger that with SIAH-1. In vitro experiments show that SIAH-2 monoubiquitylates alpha-synuclein. Further evidence that SIAH proteins may play a role in inclusion formation comes from the demonstration of SIAH immunoreactivity in Lewy bodies of PD patients.