Comparative Analysis of Response to Cardiac Resynchronisation Therapy Upgrades in Patients with Implantable Cardioverter-Defibrillators and Pacemakers.

Introduction: The efficacy of de novo cardiac resynchronisation therapy (CRT) in patients with heart failure (HF), left ventricular systolic dysfunction (LVSD), and a broad QRS morphology is well established. However, the optimal stage for upgrading patients with existing pacemakers (PPMs) or implantable cardioverter-defibrillators (ICDs) and HF with high-burden right ventricular (RV) pacing remains uncertain. Thus, this multicentre retrospective analysis compared patients with pre-existing PPMs or ICDs who underwent CRT upgrades to investigate the appropriate stage for CRT implantation in these patients and to assess the validity of treating both PPM and ICD recipients under the same recommendation level in the current guidelines. Materials and Methods: A total of 151 participants underwent analysis in this study, comprising 93 upgrades to cardiac resynchronisation therapy with pacemaker (CRT-P) and 58 upgrades to cardiac resynchronisation therapy with defibrillator (CRT-D) across three centres in the UK. The aim of the study was to investigate the safety and efficacy of upgrading to CRT from an existing conventional pacemaker or an ICD in the context of high-burden RV pacing. The analysis was conducted separately for each group, assessing changes in echocardiographic parameters, functional New York Heart Association (NYHA) class, and procedure-related complications. Results: The PPM group had a higher percentage RVP burden compared to the ICD group. Post-upgrade, NYHA functional class and EF and LV volumes improved in both groups; however, the response to an upgrade from a pacemaker was greater compared to an upgrade from an ICD. Post-procedural complication risks were similar across the two subgroups but significantly higher compared to de novo implantation. Conclusions: Within the CRT-P subgroup, participants exhibited better responses than their CRT-D counterparts, evident both in echocardiographic improvements and clinical outcomes. Furthermore, patients with non-ischemic cardiomyopathy (NICM) were better responders than those with ischaemic cardiomyopathy. These findings suggest that international guidelines should consider approaching each subgroup separately in the future.

Cryothermal energy demonstrates shorter ablation time and lower complication rates compared with radiofrequency in surgical hybrid ablation for recurrent ventricular tachycardia.

BACKGROUND: Recurrent ventricular tachycardia (VT) after prior endocardial catheter ablation(s) presents challenges in the setting of prior cardiac surgery where percutaneous epicardial access may not be feasible. OBJECTIVE: The purpose of this study was to compare the outcomes of cryothermal vs radiofrequency ablation in direct surgical epicardial access procedures. METHODS: We performed a retrospective study of consecutive surgical epicardial VT ablation cases. Surgical cases using cryothermal vs radiofrequency ablation were analyzed and outcomes were compared. RESULTS: Between 2009 and 2022, 43 patients underwent either a cryothermal (n = 17) or a radiofrequency (n = 26) hybrid epicardial ablation procedure with direct surgical access. Both groups were similarly matched for age, sex, etiology of VT, and comorbidities with a high burden of refractory VT despite previous endocardial and/or percutaneous epicardial ablation procedures. The surgical access site was lateral thoracotomy (76.5%) in the cryothermal ablation group compared with lateral thoracotomy (42.3%) and subxiphoid approach (38.5%) in the radiofrequency group, with the remainder in both groups performed via median sternotomy. The ablation time was significantly shorter in those undergoing cryothermal ablation vs radiofrequency ablation (11.54 ± 15.5 minutes vs 48.48 ± 23.6 minutes; P < .001). There were no complications in the cryothermal ablation group compared with 6 patients with complications in the radiofrequency group. Recurrent VT episodes and all-cause mortality were similar in both groups. CONCLUSION: Hybrid surgical VT ablation with cryothermal or radiofrequency energy demonstrated similar efficacy outcomes. Cryothermal ablation was more efficient and safer than radiofrequency in a surgical setting and should be considered when surgical access is required.

Contact force and catheter stability are predictive metrics of successful pulmonary vein isolation with high-power short duration ablation in atrial fibrillation.

INTRODUCTION: Preliminary data suggest that high power short duration (HPSD) ablation for pulmonary vein isolation (PVI) are safe. Limited data are available on its effectiveness. Aim was to evaluate HPSD ablation in atrial fibrillation ablation using a novel Qdot Micro catheter. METHODS AND RESULTS: Prospective multicenter study evaluating safety and efficacy of PVI with HPSD ablation. First pass isolation (FPI) and sustained PVI was assessed. If FPI was not achieved additional ablation index (AI)-guided ablation with 45 W was performed and metrics predictive of this were determined. Sixty-five patients and 260 veins were treated. Procedural and LA dwell time was 93.9 ± 30.4 and 60.5 ± 23.1 min, respectively. FPI was achieved in 47 (72.3%) patients and 231 veins (88.8%) with an ablation duration of 4.6 ± 1.0 min. Twenty-nine veins required additional AI-guided ablation to achieve initial PVI with 24 anatomical sites ablated with the right posterior carina being the most common site (37.5%). A contact force of ≥8 g (area under the curve [AUC]: 0.81; p < 0.001) and catheter position variation of ≤1.2 mm (AUC: 0.79; p < 0.001) with HPSD were strongly predictive of not requiring additional AI-guided ablation. Out of the 260 veins, only 5 (1.9%) veins showed acute reconnection. HPSD ablation was associated with shorter procedure times (93.9 vs. 159.4 min; p < 0.001), ablation times (6.1 vs. 27.7 min; p < 0.001), and lower rates of PV reconnection (9.2% vs. 30.8%; p = 0.004) compared to moderate power cohort. CONCLUSIONS: HPSD ablation is an effective ablation modality which results in effective PVI whilst maintaining a safety profile. Its superiority needs to be evaluated in randomized controlled trials.

Non-invasive imaging in cardiology for the generalist.

In contrast to invasive techniques, the goal of non-invasive cardiac imaging is to identify or exclude heart disease in response to a patient's clinical history of cardiac localizing symptoms. Imaging also aims to establish the risk of an individual developing future heart disease with a view to preventing major cardiovascular events such as myocardial infarction. As well as a role in risk stratification, non-invasive cardiac imaging also helps with decision making for future medical and procedural interventions. This review outlines the non-invasive imaging modalities available to physicians to identify and risk stratify cardiovascular disease. It discusses the strengths of each imaging technique, in which circumstances it is most useful and its diagnostic accuracy.

Non-invasive phenotyping and drug testing in single cardiomyocytes or beta-cells by calcium imaging and optogenetics.

Identification of drug induced electrical instability of the heart curtails development, and introduction, of potentially proarrhythmic drugs. This problem usually requires complimentary contact based approaches such as patch-clamp electrophysiology combined with field stimulation electrodes to observe and control the cell. This produces data with high signal to noise but requires direct physical contact generally preventing high-throughput, or prolonged, phenotyping of single cells or tissues. Combining genetically encoded optogenetic control and spectrally compatible calcium indicator tools into a single adenoviral vector allows the analogous capability for cell control with simultaneous cellular phenotyping without the need for contact. This combination can be applied to single rodent primary adult cardiomyocytes, and human stem cell derived cardiomyocytes, enabling contactless small molecule evaluation for inhibitors of sodium, potassium and calcium channels suggesting it may be useful for early toxicity work. In pancreatic beta-cells it reveals the effects of glucose and the KATP inhibitor gliclazide.

An unusual haemoperitoneum--secondary abdominal pregnancy.

A 36-year-old amenorrhoeic patient presented with vague abdominal discomfort, and haemodynamic instability, a large haemoperitoneum was identified on transvaginal ultrasound. Ruptured tubal ectopic pregnancy was suspected. At laparotomy ruptured primary tubal ectopic pregnancy was identified, with 12-14 week secondary abdominal pregnancy implanted onto the omentum, confirmed by histopathology. Salpingo-oophrectomy with peritoneal washout was performed, and three units blood transfusion was required. The patient had an uneventful recovery to health.

Neuroserpin polymers activate NF-kappaB by a calcium signaling pathway that is independent of the unfolded protein response.

The autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies is characterized by the accumulation of ordered polymers of mutant neuroserpin within the endoplasmic reticulum of neurones. We show here that intracellular neuroserpin polymers activate NF-kappaB by a pathway that is independent of the IRE1, ATF6, and PERK limbs of the canonical unfolded protein response but is dependent on intracellular calcium. This pathway provides a mechanism for cells to sense and react to the accumulation of folded structures of mutant serpins within the endoplasmic reticulum. Our results provide strong support for the endoplasmic reticulum overload response being independent of the unfolded protein response.

The molecular aetiology of the serpinopathies.

Members of the serine proteinase inhibitor or serpin superfamily inhibit their target proteinases by a conformational transition that involves the enzyme being translocated from the upper to the lower pole of the protein. This sophisticated mechanism is subverted by point mutations to form ordered polymers that are retained within the endoplasmic reticulum of the cell of synthesis. These polymers activate NF-kappaB and cause cytotoxicity by a pathway that is independent of the unfolded protein response. As diverse conditions can be explained the same mechanism of polymerisation we have grouped them together as a new class of disease, the serpinopathies. We review here the structural basis of the serpinopathies and discuss how the ordered accumulation of polymers causes cell death.

The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB.

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant dementia that is characterized by the retention of polymers of neuroserpin as inclusions within the endoplasmic reticulum (ER) of neurons. We have developed monoclonal antibodies that detect polymerized neuroserpin and have used COS-7 cells, stably transfected PC12 cell lines and transgenic Drosophila melanogaster to characterize the cellular handling of all four mutant forms of neuroserpin that cause FENIB. We show a direct correlation between the severity of the disease-causing mutation and the accumulation of neuroserpin polymers in cell and fly models of the disease. Moreover, mutant neuroserpin causes locomotor deficits in the fly allowing us to demonstrate a direct link between polymer accumulation and neuronal toxicity.

Expression of the serine protease inhibitor neuroserpin in cells of the human myeloid lineage.

Myeloid progenitors in the bone marrow differentiate into most of the major cell types of the immune system, including macrophages and dendritic cells. These cells play important roles in both innate and adaptive immunity. They express a number of proteases and protease inhibitors including members of the serine proteinase inhibitor or serpin superfamily. In this study we report the differential expression of neuroserpin in cells of the human myeloid lineage. Neuroserpin was highly expressed and secreted following the differentiation of monocytes to macrophages and dendritic cells. Activation of dendritic cells with lipopolysaccharide resulted in increased neuroserpin mRNA levels but no neuroserpin secretion. Confocal immunofluorescence microscopy showed neuroserpin was differentially localised in human myeloid cells. In macrophages and dendritic cells it was concentrated in vesicles located in close proximity to the plasma membrane. The majority of activated dendritic cells also exhibited an intracellular focal concentration of neuroserpin which co-localised with the lysosomal/late endosomal marker LAMP-1. As neuroserpin inhibits tissue plasminogen activator, a comparative analysis of tPA and plasminogen activator inhibitor-1 (PAI-1) expression was undertaken. This analysis revealed differential expression of PAI-1 and neuroserpin suggesting they may have different functions in human immune cells.