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.

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.

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.

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.

Safety of catheter ablation of atrial fibrillation in cancer survivors.

PURPOSE: In patients with cancer, the safety of catheter ablation for non-valvular atrial fibrillation (AF) has not been evaluated, yet. The aim of this study was to assess the safety of AF ablation in cancer survivors. METHODS: Consecutively recruited patients undergoing catheter ablation of non-valvular AF at our center between March 2015 and March 2017 were evaluated. The primary outcome of the study was clinically relevant bleedings occurred within 30 ± 5 days after the procedure. Patients with cancer were propensity matched to patients without cancer in a 1:3 and 1:6 ratio after stratification by baseline clinical features. RESULTS: Overall, 184 patients were included in the study. Of them, 21 (11%) were cancer survivors. Cancer site was more frequently gastrointestinal (36%), breast (23%), and genitourinary (18%). At 30 ± 5 days, clinically relevant bleedings occurred in 14 patients. Crude odds ratio (OR) for clinically relevant bleedings was 3.60 (95% CI 1.02-12.7) higher in cancer than in non-cancer patients. This trend remained after propensity score-matched population (OR 3.48, 95% CI 0.76-15.90 for matched 1:3, OR 4.95, 95% CI 1.2-20.2 for matched 1:6). Type of anticoagulation was not associated with bleedings. CONCLUSIONS: Preliminary results suggest that clinically relevant bleeding after catheter ablation for AF is more frequent in cancer survivors than in patients without cancer. Further studies are required to confirm the present data.

Nearly fatal ventricular arrhythmia following pacemaker implantation in a young female with complete heart block.

This case concerns a 24-year-old female who developed malignant ventricular tachyarrhythmia a few weeks after pacemaker implantation for complete heart block. Apparently, right ventricular pacing caused significant repolarization abnormalities in both native and paced rhythms with marked QT prolongation and substantial electrical instability. This case highlights other intriguing phenomena in the puzzle of cardiac repolarization and how pacing therapy may alter this complex process providing arrhythmic substrate in vulnerable subjects. Though such arrhythmic events are clinically rare, vulnerable patients or with suspected myocardial disease that may cause QT prolongation should be carefully followed in the course of pacing therapy.

Short and long-term changes in platelet and inflammatory biomarkers after cryoballoon and radiofrequency ablation.

BACKGROUND: Cryoballoon (CB) versus radiofrequency (RF) ablation response on prothrombotic biomarkers obtained different results at short-term, while long-term is still unknown in atrial fibrillation (AF) treatment. We evaluated short and long-term changes in platelet and inflammatory biomarkers after CB and RF ablation. METHODS: Fifty-eight paroxysmal AF patients were randomized for pulmonary vein (PV) isolation using either CB (n = 29) or RF (n = 29) ablation. Biomarkers of platelet activation [P-selectin (CD62P), CD40 ligand (CD40L), platelet factor-4 (PF-4), mean platelet volume (MPV), platelet-leukocyte ratio (P-LCR), and platelet distribution width (PDW)]; and inflammatory [high sensitivity CRP (hs-CRP) and interleukin-6 (IL-6)] were measured at baseline, 18-24 h and 6-Months postablation. RESULTS: Twenty-four (86.2%) and twenty-six (89.7%) patients remained in sinus rhythm at 6-Months in CB and RF group respectively (p = 0.500). After 18-24 h postablation, CD62P, CD40L, PF-4, hs-CRP, and IL-6 levels were significantly activated in both groups (p < 0.001). However, CD62P was significantly lower in CB than RF (p = 0.017). At 6-Month postablation in CB group, all platelet biomarkers CD62P (p = 0.021), CD40L (p < 0.001), PF-4 (p < 0.001), MPV (p = 0.010), PDW (p = 0.004), and P-LCR (p = 0.033) were significantly decreased compared to baseline levels. However in RF group, CD40L and PF-4 (p < 0.001) significant decreased, CD62P (p = 0.022) increased, and no change in MPV and P-LCR (p > 0.05) compared to baseline levels. hs-CRP and IL-6 levels were comparable between baseline and 6-Months in both groups (p > 0.05). CONCLUSIONS: CB ablation might influence the risk of thromboembolism due to less platelet activation after PV isolation and decreased platelet activation at long-term in maintained sinus rhythm patients compared to RF.

Left atrial thrombus resolution in non-valvular atrial fibrillation or flutter: biomarker substudy results from a prospective study with rivaroxaban (X-TRA).

BACKGROUND: Non-vitamin K antagonist oral anticoagulants including rivaroxaban are widely used for stroke prevention in patients with atrial fibrillation (AF). We investigated the relationship between plasma biomarkers (indicative of thrombogenesis, fibrinolysis and inflammation) and left atrial thrombus resolution after rivaroxaban treatment. METHODS: This was an ancillary analysis of the X-TRA study, which was a prospective interventional study evaluating the use of rivaroxaban for left atrial/left atrial appendage (LA/LAA) thrombus resolution in AF patients. We assessed various biomarkers of thrombogenesis/fibrinolysis [D-dimer, plasminogen activator inhibitor-1 (PAI-1), prothrombin fragment 1 + 2 (F1,2), thrombin-antithrombin (TAT) complexes, von Willebrand factor (vWF)] and inflammation [high-sensitivity interleukin-6 (hsIL-6), and high-sensitivity C-reactive protein (hsCRP)], measured at baseline and after 6 weeks' of rivaroxaban treatment. RESULTS: There was a significant decrease in the mean levels of hsCRP, D-dimer, vWF, and TAT from baseline to end of treatment with rivaroxaban. Although none of the thrombogenesis/fibrinolysis biomarkers showed a significant relationship with thrombus resolution, high inflammatory biomarkers at baseline were significantly associated with an increased chance of the thrombus being completely resolved (hsIL-6) or reduced/resolved (hsCRP). CONCLUSIONS: Biomarkers of inflammation are significantly associated with LA/LAA thrombus outcomes in AF patients prospectively treated with rivaroxaban.

Clinical and electrocardiographic features of complete heart block after blunt cardiac injury: A systematic review of the literature.

The underlying mechanisms and temporal course of complete heart block (CHB) after blunt cardiac injuries (BCIs) are poorly understood, and a systematic analysis of available data is lacking. In this systematic review, PubMed was searched for publications of reported cases of CHB-BCI analyzing clinical findings, electrocardiographic features, temporal course, and outcomes. Case reports on CHB-BCI were available for 50 patients, mainly secondary to traffic or sport accidents. A fatal outcome occurred in 10 of 50 (20%) of patients, while a structural damage of the atrioventricular (AV) conductive system was evident in 4 of 8 (50%) of necropsy studies. Clinical manifestation of CHB-BCI occurred within 72 hours of injury in 38 of 47 (∼80%) of patients, and 1:1 AV conduction was restored within 7-10 days in about half of early survivors. Permanent pacemaker implantation was indicated in 22 of 42 (∼50%) of early survivors because of recurrent or permanent CHB. Cardiac troponins, when analyzed, were elevated in 12 of 13 (∼90%) of patients, and electrocardiographic features of aberrancy were present in 29 of 40 (>70%) of patients. In conclusion, CHB secondary to BCI is associated with 20% mortality mainly occurring in the early posttraumatic period and most of the deaths are due to or triggered by this malignant arrhythmia. Recurrent or permanent CHB requiring pacemaker implantation occurs in ∼50% of survivors. A structural damage of the AV conductive system can be found in 50% of necropsy studies.

Exploring unmet needs in venous and arterial thromboembolism with rivaroxaban.

The vast clinical research programme for the direct, oral factor Xa inhibitor rivaroxaban has generated a wealth of data since the first rivaroxaban approval in 2008 for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery. While rivaroxaban is widely used across a spectrum of seven indications, there is continuous commitment to investigating its wider benefits in new indications and attempts to refine current evidence. Key data from recently completed randomised controlled trials (RCTs) have shown that rivaroxaban is a feasible anticoagulation option for patients with non-valvular atrial fibrillation (NVAF) undergoing cardioversion or catheter ablation. Now, a number of Phase II and III RCTs are underway that seek to uncover further roles for rivaroxaban in patients at risk of thrombosis and aim to improve quality of life. This article will introduce and provide context for these RCTs in the contemporary management of arterial and venous thromboembolism in the following underserved areas: Patients with both NVAF and acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI); patients with embolic stroke of undetermined source (ESUS); patients who require transcatheter aortic valve replacement (TAVR); patients with acute or chronic coronary artery disease (CAD; including those with heart failure [HF]); those at risk of or suffering from cancer-associated thrombosis (CAT) and those requiring long-term anticoagulation. It is hoped that this collection of studies provides clarity around the use of rivaroxaban as a fundamental component of antithrombotic therapy in an array of clinical situations.

Adenosine and Preexcitation Variants: Reappraisal of Electrocardiographic Changes.

Intravenous adenosine is a short-acting blocker of the atrioventricular node that has been used to unmask subtle or latent preexcitation, and also to enable catheter ablation in selected patients with absent or intermittent preexcitation. Depending on the accessory pathway characteristics, intravenous adenosine may produce specific electrocardiographic changes highly suggestive of the preexcitation variant. Herein, we view different ECG responses to this pharmacological test in various preexcitation patterns that were confirmed by electrophysiological studies. Careful analysis of electrocardiographic changes during adenosine test, with emphasis on P-delta interval, preexcitation degree, and atrioventricular block, can be helpful to diagnose the preexcitation variant/pattern.

Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.

AIMS: VENTURE-AF is the first prospective randomized trial of uninterrupted rivaroxaban and vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) undergoing catheter ablation (CA). METHODS AND RESULTS: Trial size was administratively set at 250, the protocol-specified target. Events were independently and blindly adjudicated. We randomly assigned 248 NVAF patients to uninterrupted rivaroxaban (20 mg once-daily) or to an uninterrupted VKA prior to CA and for 4 weeks afterwards. The primary endpoint was major bleeding events after CA. Secondary endpoints included thromboembolic events (composite of stroke, systemic embolism, myocardial infarction, and vascular death) and other bleeding or procedure-attributable events. Patients were 59.5 ± 10 years of age, 71% male, 74% paroxysmal AF, and had a CHA2DS2-VASc score of 1.6. The average total heparin dose used to manage activated clotting time (ACT) was slightly higher (13 871 vs. 10 964 units; P < 0.001) and the mean ACT level attained slightly lower (302 vs. 332 s; P < 0.001) in rivaroxaban and VKA arms, respectively. The incidence of major bleeding was low (0.4%; 1 major bleeding event). Similarly, thromboembolic events were low (0.8%; 1 ischemic stroke and 1 vascular death). All events occurred in the VKA arm and all after CA. The number of any adjudicated events (26 vs. 25), any bleeding events (21 vs. 18), and any other procedure-attributable events (5 vs. 5) were similar. CONCLUSION: In patients undergoing CA for AF, the use of uninterrupted oral rivaroxaban was feasible and event rates were similar to those for uninterrupted VKA therapy. NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov trial registration number is NCT01729871.

An unusual WPW syndrome: What is the preexcitation variant?

A 15-year-old female with WPW syndrome and normal heart underwent an electrophysiology study for paroxysmal palpitations and syncope. Intravenous adenosine produced an unexpected response of QRS changes and advanced AV block. During isoproteronol infusion, short-lasting and poorly tolerated wide QRS tachycardia was inducible, but pacing maneuvers were not feasible during tachycardia to determine its definitive mechanism. However, various electrophysiologic phenomena including adenosine response, junctional beats pattern, and multisite atrial pacing were helpful to overcome the diagnosis challenges. Finally, careful evaluation of tachycardia features and the comprehensive electrophysiology study were crucial to establish presence of unusual preexcitation variants, and thus to guide successful catheter ablation of the arrhythmic substrate.