Metabolic disorders affecting the liver and heart: Therapeutic efficacy of miRNA-based therapies?

Liver and heart disease are major causes of death worldwide. It is known that metabolic alteration causing type 2 diabetes (T2D) and Nonalcoholic fatty liver (NAFLD) coupled with a derangement in lipid homeostasis, may exacerbate hepatic and cardiovascular diseases. Some pharmacological treatments can mitigate organ dysfunctions but the important side effects limit their efficacy leading often to deterioration of the tissues. It needs to develop new personalized treatment approaches and recent progresses of engineered RNA molecules are becoming increasingly viable as alternative treatments. This review outlines the current use of antisense oligonucleotides (ASOs), RNA interference (RNAi) and RNA genome editing as treatment for rare metabolic disorders. However, the potential for small non-coding RNAs to serve as therapeutic agents for liver and heart diseases is yet to be fully explored. Although miRNAs are recognized as biomarkers for many diseases, they are also capable of serving as drugs for medical intervention; several clinical trials are testing miRNAs as therapeutics for type 2 diabetes, nonalcoholic fatty liver as well as cardiac diseases. Recent advances in RNA-based therapeutics may potentially facilitate a novel application of miRNAs as agents and as druggable targets. In this work, we sought to summarize the advancement and advantages of miRNA selective therapy when compared to conventional drugs. In particular, we sought to emphasise druggable miRNAs, over ASOs or other RNA therapeutics or conventional drugs. Finally, we sought to address research questions related to efficacy, side-effects, and range of use of RNA therapeutics. Additionally, we covered hurdles and examined recent advances in the use of miRNA-based RNA therapy in metabolic disorders such as diabetes, liver, and heart diseases.

Regional differences in outcomes with ablation versus drug therapy for atrial fibrillation: Results from the CABANA trial.

BACKGROUND: The finding of unexpected variations in treatment benefits by geographic region in international clinical trials raises complex questions about the interpretation and generalizability of trial findings. We observed such geographical variations in outcome and in the effectiveness of atrial fibrillation (AF) ablation versus drug therapy in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. This paper describes these differences and investigates potential causes. METHODS: The examination of treatment effects by geographic region was a prespecified analysis. CABANA enrolled patients from 10 countries, with 1,285 patients at 85 North American (NA) sites and 919 at 41 non-NA sites. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Death and first atrial fibrillation recurrence were secondary endpoints. RESULTS: At least 1 primary endpoint event occurred in 157 patients (12.2%) from NA and 33 (3.6%) from non-NA sites over a median 54.9 and 40.5 months of follow-up, respectively (NA/non-NA adjusted hazard ratio (HR) 2.18, 95% confidence interval (CI) 1.48-3.21, P < .001). In NA patients, 78 events occurred in the ablation and 79 in the drug arm, (HR 0.91, 95% CI 0.66, 1.24) while 11 and 22 events occurred in non-NA patients (HR 0.51, 95% CI 0.25,1.05, interaction P = .154). Death occurred in 53 ablation and 51 drug therapy patients in the NA group (HR 0.96, 95% CI 0.65,1.42) and in 5 ablation and 16 drug therapy patients in the non-NA group (HR 0.32, 95% CI 0.12,0.86, interaction P = .044). Adjusting for baseline regional differences or prognostic risk variables did not account for the regional differences in treatment effects. Atrial fibrillation recurrence was reduced by ablation in both regions (NA: HR 0.54, 95% CI 0.46, 0.63; non-NA: HR 0.44, 95% CI 0.30, 0.64, interaction P = .322). CONCLUSIONS: In CABANA, primary outcome events occurred significantly more often in the NA group but assignment to ablation significantly reduced all-cause mortality in the non-NA group only. These differences were not explained by regional variations in procedure effectiveness, safety, or patient characteristics. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0091150; https://clinicaltrials.gov/study/NCT00911508.

Ten years of subcutaneous defibrillator therapy: Consolidated clinical evidence and future perspectives.

The subcutaneous implantable cardioverter defibrillator (S-ICD) was developed as an alternative to the traditional transvenous implantable cardioverter defibrillator (TV-ICD), aiming to provide easier implantation, simplified detection algorithm of malignant ventricular arrhythmias and prevention from placing components in the cardiovascular system. The S-ICD is implanted subcutaneously or intramuscularly with the generator placed in the left midaxillary line and the lead tunneled subcutaneously in the left para-sternal region. Preimplant electrocardiogram screening is recommended to prevent implantation in patients at high risk of T wave over-sensing. Currently, the S-ICD is unsuitable for patients requiring pacing or cardiac resynchronization. Since the beginning, the S-ICD underwent extensive preclinical investigation until the first prospective multicentre trial demonstrating high efficacy and safety led to market release. While earlier studies focused on younger patients with higher ejection fraction, more recent studies showed favorable outcomes even in patients with comorbidities similar to those typically observed in patients receiving TV-ICD. The development of second and third generation devices has contributed to reduce inappropriate shocks and overcome previous limitations. The aim of this paper is to review the evidence in the literature over the past decade supporting S-ICD as a valid alternative to TV-ICD in terms of safety and efficacy, highlighting the improvements in technology, as well as outcomes.

Irregular Rhythm in a Middle-Aged Man Presenting With New-Onset Heart Failure.

A man in his 50s with recurrent palpitations, fatigue, and progressive exertion dyspnea had irregular narrow-QRS tachycardia in an incessant, repetitive fashion with heart rates up to 180 beats per minute and occasional short runs of wide-QRS tachycardia on Holter monitoring and 12-lead electrocardiogram. What would you do next?

Lessons derived from post authorisation safety studies (ETNA-AF and XANTUS) on once daily direct oral anticoagulants for atrial fibrillation.

BACKGROUND: Phase III trials should be integrated by post authorisation safety studies (PASS) to confirm their conclusions in real life. In this setting, comorbidities are commonly more prevalent, decisions about drugs and regimens are left to the attending physicians and therapy monitoring is not usually as strict as in pivotal trials. AIMS AND METHODS: To evaluate real life safety and effectiveness of edoxaban and rivaroxaban, ETNA-AF Europe (ETNA-AF-Eu) and XANTUS studies were reviewed and compared. A further comparison between data collected in these studies and in the pivotal studies ENGAGE AF-TIMI 48 and ROCKET-AF was also performed. RESULTS: ETNA-AF-Eu and XANTUS showed lower bleeding, stroke, cardiovascular- and all-cause mortality rates as compared to those observed in Phase 3 trials, even when including subgroups with lower comorbidities. Patients in ETNA-AF-Eu were older, with a larger proportion of octogenarians (≥85 years in 10.5%) and patients with impaired renal function as compared to patients in XANTUS (CrCl <50 ml/min in 18.2% vs 12.2%) and in ENGAGE AF-TIMI 48 and ROCKET-AF, without paying any excess tribute in terms of safety. Therapy persistence was very high in the two real life studies (91.9% in ETNA-AF-Eu and 79.9% in XANTUS), thus showing that edoxaban and rivaroxaban are well tolerated in real life. CONCLUSION: The ETNA-AF-Eu and XANTUS confirmed the safety and effectiveness of edoxaban and rivaroxaban in real life.

Practical Considerations for Cardiac Electronic Devices Reimplantation Following Transvenous Lead Extraction Due to Related Endocarditis.

Despite progress in implantation technology and prophylactic measures, infection complications related to cardiac implantable electronic devices (CIED) are still a major concern with negative impacts on patient outcomes and the health system's resources. Infective endocarditis (IE) represents one of the most threatening CIED-related infections associated with high mortality rates and requires prompt diagnosis and management. Transvenous lead extraction (TLE), combined with prolonged antibiotic therapy, has been validated as an effective approach to treat patients with CIED-related IE. Though early complete removal is undoubtedly recommended for CIED-related IE or systemic infection, device reimplantation still represents a clinical challenge in these patients at high risk of reinfection, with many gaps in the current knowledge and international guidelines. Based on the available literature data and authors' experience, this review aims to address the practical and clinical considerations regarding CIED reimplantation following lead extraction for related IE, focusing on the reassessment of CIED indication, procedure timing, and the reimplanted CIED type and site. A tailored, multidisciplinary approach involving clinical cardiologists, electrophysiologists, cardiac imaging experts, cardiac surgeons, and infectious disease specialists is crucial to optimize these patients' management and clinical outcomes.

Catheter-induced right bundle branch block: Practical implications for the cardiac electrophysiologist.

The right bundle branch (RBB), due to its endocardial course, is susceptible to traumatic block caused by "bumping" during right-heart catheterization. In the era of cardiac electrophysiology, catheter-induced RBB block (CI-RBBB) has become a common phenomenon observed during electrophysiological studies and catheter ablation procedures. While typically transient, it may persist for the entire procedure time. Compared to pre-existing RBBB, the transient nature of CI-RBBB allows for comparative analysis relative to the baseline rhythm. Furthermore, unlike functional RBBB, it occurs at similar heart rates, making the comparison of conduction intervals more reliable. While CI-RBBB can provide valuable diagnostic information in various conditions, it is often overlooked by cardiac electrophysiologists. Though it is usually a benign and self-limiting conduction defect, it may occasionally lead to diagnostic difficulties, pitfalls, or undesired consequences. Avoidance of CI-RBBB is advised in the presence of baseline complete left bundle branch block and when approaching arrhythmic substrates linked to the right His-Purkinje-System, such as fasciculo-ventricular pathways, bundle branch reentry, and right-Purkinje focal ventricular arrhythmias. This article aims to provide a comprehensive practical review of the electrophysiological phenomena related to CI-RBBB and its impact on the intrinsic conduction system and various arrhythmic substrates.

How much does the presentation pattern of atrial fibrillation affect thrombo-embolic risk and mortality?

Atrial fibrillation (AF) is associated with a substantial increase in mortality and morbidity. Systemic thrombo-embolism is the most serious complication associated with this arrhythmia. The use of anticoagulant drugs is the cornerstone of therapy for the prophylaxis of stroke and peripheral ischaemia in these patients. The current guidelines recommend the use of anticoagulant drugs based on the thrombo-embolic risk profile of each individual patient calculated by SCORE based on the presence or absence of clinical risk factors and regardless of the presentation pattern of AF. A review of literature data investigating the effect of AF presentation pattern on thrombo-embolic risk and mortality showed an increased risk of both thrombo-embolic events and death in patients with non-paroxysmal AF compared to patients with paroxysmal AF. Most of these studies, however, consist of post-hoc analyses of large trials or observational studies and meta-analyses derived from these, resulting in an important limitation in the interpretation of data derived from such studies. At the same time, these data suggest the need for both new therapies to prevent AF progression and for further studies to explore the integration of AF presentation pattern into models of thrombo-embolic risk.

Outcomes of cavotricuspid isthmus-dependent flutter ablation: randomized study comparing single vs. multiple catheter procedures-the SIMPLE study.

BACKGROUND: Catheter ablation is recommended as first-line therapy for patients with symptomatic typical AFl. Although the conventional multi-catheter approach is the standard of care for cavotricuspid isthmus (CTI) ablation, a single-catheter approach was recently described as a feasible alternative. The present study sought to compare safety, efficacy, and efficiency of single vs. multi-catheter approach for atrial flutter (AFl) ablation. METHODS: In this randomized multi-center study, consecutive patients referred for AFl ablation (n = 253) were enrolled and randomized to multiple vs. single-catheter approach for CTI ablation. In the single-catheter arm, PR interval (PRI) on the surface ECG was used to prove CTI block. Procedural and follow-up data were collected and compared between the two arms. RESULTS: 128 and 125 patients were assigned to the single-catheter and to the multi-catheter arms, respectively. In the single-catheter arm, procedure time was significantly shorter (37 ± 25 vs. 48 ± 27 minutes, p = 0.002) and required less fluoroscopy time (430 ± 461 vs. 712 ± 628 seconds, p < 0.001) and less radiofrequency time (428 ± 316 vs. 643 ± 519 seconds, p < 0.001), achieving a higher first-pass CTI block rate (55 (45%) vs. 37 (31%), p = 0.044), compared with the multi-catheter arm. After a median follow-up of 12 months, 11 (4%) patients experienced AFl recurrences (5 (4%) in the single-catheter arm and 6 (5%) in the multi-catheter arm, p = 0.99). No differences were found in arrhythmia-free survival between arms (log-rank = 0.71). CONCLUSIONS: The single-catheter approach for typical AFl ablation is not inferior to the conventional multiple-catheter approach, reducing procedure, fluoroscopy, and radiofrequency time.

Catheter ablation of left atrial tachycardia adjacent to a septal closure device: A multifaceted challenge?

Catheter ablation (CA) of left atrial tachycardia adjacent to implanted septal closure devices represents a multifaceted challenge. We describe the case of a 57-year-old patient with remote percutaneous closure of atrial septal defect who underwent successful CA of left atrial tachycardia adjacent to the septal device using a transaortic approach and RF energy. Besides the technical difficulties and associated risks, interference between the device and applied RF parameters may limit ablation efficiency. Further research is required to evaluate the safety, efficacy, and optimal energy type/parameters when ablating arrhythmias adjacent to these devices.

A hybrid clinical and electrocardiographic score to predict the origin of outflow tract ventricular arrhythmias.

BACKGROUND: To predict the outflow tract ventricular arrhythmias (OTVA) site of origin (SOO) before the ablation procedure has important practical implications. The present study sought to prospectively evaluate the accuracy of a clinical and electrocardiographic hybrid algorithm (HA) for the prediction of OTVAs-SOO, and at the same time to develop and to prospectively validate a new score with improved discriminatory capacity. METHODS: In this multicenter study, we prospectively enrolled consecutive patients referred for OTVA ablation (N = 202), and we divided them in a derivation sample and a validation cohort. Surface ECGs during OTVA were analyzed to compare previous published ECG-only criteria and to develop a new score. RESULTS: In the derivation sample (N = 105), the correct prediction rate of HA and ECG-only criteria ranged from 74 to 89%. R-wave amplitude in V3 was the best ECG parameter for discriminating LVOT origin in V3 precordial transition (V3PT) patients, and was incorporated to the novel weighted hybrid score (WHS). WHS correctly classified 99 (94.2%) patients, presenting 90% sensitivity and 96% specificity (AUC 0.97) in the entire population; WHS mantained a 87% sensitivity and 91% specificity (AUC 0.95) in patients with V3PT subgroup. The high discriminatory capacity was confirmed in the validation sample (N = 97): the WHS exhibited an AUC (0.93), and a WHS ≥ 2 allowed a correct prediction of LVOT origin in 87 (90.0%) cases, yielding a sensitivity of 87% and specificity of 90%; moreover, the V3PT subgroup showed an AUC of 0.92, and a punctuation ≥ 2 predicted an LVOT origin with a sensitivity of 94% and specificity of 78%. CONCLUSIONS: The novel hybrid score has proved to accurately anticipate the OTVA's origin, even in those with a V3 precordial transition. A Weighted hybrid score. B Typical examples of the use of the weighted hybrid score. C ROC analysis of WHS and previous ECG criteria for prediction of LVOT origin in the derivation cohort. D ROC analysis of WHS and previous ECG criteria for prediction of LVOT origin in the V3 precordial transition OTVA subgroup.

A Single-lead ECG algorithm to differentiate right from left manifest accessory pathways: A reappraisal of the P-Delta interval.

INTRODUCTION: Despite numerous ECG algorithms being developed to localize the site of manifest accessory pathways (AP), they often require stepwise multiple-lead analysis with variable accuracy, limitations, and reproducibility. The study aimed to develop a single-lead ECG algorithm incorporating the P-Delta interval (PDI) as an adjunct criterion to discriminate between right and left manifest AP. METHODS: Consecutive WPW patients undergoing electrophysiological study (EPS) were retrospectively recruited and split into a derivation and validation group (1:1 ratio). Sinus rhythm ECG analysis in lead V1 was performed by three independent investigators blinded to the EPS results. Conventional ECG parameters and PDI were assessed through the global cohort. RESULTS: A total of 140 WPW patients were included (70 for each group). A score-based, single-lead ECG algorithm was developed through derivation analysis incorporating the PDI, R/S ratio, and QRS onset polarity in lead V1. The validation group analysis confirmed the proposed algorithm's high accuracy (95%), which was superior to the previous ones in predicting the AP side (p < 0.05). A score of ≤+1 was 96.5% accurate in predicting right AP while a score of ≥+2 was 92.5% accurate in predicting left AP. The new algorithm maintained optimal performance in specific subgroups of the global cohort showing an accuracy rate of 90%, 92%, and 96% in minimal pre-excitation, posteroseptal AP, and pediatric patients, respectively. CONCLUSIONS: A novel single-lead ECG algorithm incorporating the PDI interval with previous conventional criteria showed high accuracy in differentiating right from left manifest AP comprising pediatric and minimal pre-excitation subgroups in the current study.

Chiari network for the interventional cardiologist: A hidden enemy at the heart gate - A systematic review of the literature.

BACKGROUND: This study aimed to collect and analyze the literature data regarding Chiari network (CN) and other right atrium (RA) remnants comprising the Eustachian and Thebesian valves (EV, ThV) as a potential entrapment site during different percutaneous cardiac procedures (PCP). METHODS AND RESULTS: A systematic search was conducted using Pubmed and Embase databases following the PRISMA guidelines to obtain available data concerning PCP associated with entrapment of inserted materials within CN-EV-ThV. The final analysis included 41 patients who underwent PCP with reported material entrapment within these RA remnants. The PCP was atrial septal defect (ASD)/patent foramen ovale (PFO) closure, catheter ablation, and pacemaker/defibrillator implantation in 44%, 22%, and 17% of patients, respectively. The entrapped materials were ASD/PFO devices, multipolar electrophysiology catheters, passive-fixation pacing leads, and J-guidewires in about 30%, 20%, 15%, and 10% of patients, respectively. Intraprocedural transthoracic, transoesophageal and intracardiac echocardiography showed sensitivity to reveal these structures of 20%, ∼95%, and 100%, respectively. A percutaneous approach successfully managed 70% of patients, while cardiovascular surgery was required in 20% and three patients died (7.3%). CONCLUSIONS: CN and other RA remnants may cause entrapment of various devices or catheters during PCP requiring right heart access. The percutaneous approach, guided by intraprocedural imaging, appears safe and effective in managing most patients. Prevention includes recognizing these anatomical structures at baseline cardiac imaging and intraprocedural precautions. Further studies are needed to analyze the actual incidence of this condition, its clinical impact and appropriate management.

Oral mexiletine for ventricular tachyarrhythmias treatment in implantable cardioverter-defibrillator patients: a systematic review of the literature.

INTRODUCTION: To evaluate the clinical outcomes of oral mexiletine (oMXT) to treat ventricular tachyarrhythmias (VTAs) in the era of implantable cardioverter-defibrillator (ICD) technology. EVIDENCE ACQUISITION: A systematic search was conducted using PubMed, Embase and Cochrane databases following the PRISMA guidelines to collect literature data reporting oMXT efficacy and safety outcomes in treating VTAs in ICD recipients. EVIDENCE SYNTHESIS: Final analysis included four studies accounting for a total of 91 patients with recurrent VTAs treated with oMXT. Amiodarone therapy was initially attempted in most patients (91.2%), while catheter ablation was performed in one-third of patients. VTA recurrences were observed in 55/91 patients (60.4%) during oMXT treatment compared to 91/91 (100%) before treatment (P<0.001). Appropriate therapies occurred in 55/88 ICD patients (62.5%) during oMXT treatment compared to 80/88 (90.9%) before treatment (P<0.001). After oMXT introduction, there was a significant reduction of the individual burden of VTA episodes and appropriate ICD therapies per patient, showing Hedges'g values of -1.103 (P=0.002) and -1.474 (P=0.008), respectively. Safety analysis showed a sample-weighted overall side-effect rate of 30%, while 21% of patients required drug reduction or discontinuation. Aggregated meta-regression analysis of the included studies and remote literature revealed a linear correlation between oMXT dosage and the overall side effects rate (r2 = 0.48; P=0.014). CONCLUSIONS: Oral mexiletine provides an adjunctive treatment to manage VTAs and reduces appropriate therapies in ICD patients with moderate efficacy and acceptable safety profiles. These observations await confirmation through randomised clinical trials.

The many NOs to the use of Class IC antiarrhythmics: weren't the guidelines too strict?

Class IC antiarrhythmic drugs (AADs) currently represent a cornerstone in the therapy of atrial fibrillation, both for the restoration of sinus rhythm and for the prophylaxis of long-term relapses. They also play an important role in the treatment of idiopathic ventricular arrhythmias. Following the results of the Cardiac Arrhythmia Suppression Trial study, flecainide and by extension the other Class IC AADs were contraindicated in patients with ischaemic and structural heart disease, due to their pro-arrhythmic effect and the consequent increase in mortality observed in the study. Recent studies carried out on patients with chronic coronary heart disease without previous heart attacks and/or residual ischaemia have shown a good safety profile for this class of drugs. In addition, other studies have shown excellent efficacy in the absence of pro-arrhythmic effects of Class IC AADs in patients with structural heart disease such as arrhythmogenic right ventricular cardiomyopathy (ARVC) and tachy-cardiomyopathy. The purpose of this review is to evaluate the appropriate use of Class IC AADs in the different patient subgroups, in the light of the evidence and new diagnostic and therapeutic tools available.