VINYL: Variant prIoritizatioN bY survivaL analysis

Motivation: Clinical applications of genome re\uadsequencing technologies typically generate large amounts of data that need to be carefully annotated and interpreted to identify genetic variants associated with pathological conditions. In this context, accurate and reproducible methods for the functional annotation and prioritization of genetic variants are of fundamental importance, especially when large volumes of data \uad like those produced by modern sequencing technologies \uad are involved. Results: In this paper, we present VINYL, a highly accurate and fully automated system for the functional annotation and prioritization of genetic variants in large scale clinical studies. Extensive analyses of both real and simulated datasets suggest that VINYL show higher accuracy and sensitivity when compared to equivalent state of the art methods, allowing the rapid and systematic identification of potentially pathogenic variants in different experimental settings

Functional study of a KCNH2 mutant: Novel insights on the pathogenesis of the LQT2 syndrome

The K+ voltage-gated channel subfamily H member 2 (KCNH2) transports the rapid component of the cardiac delayed rectifying K+ current. The aim of this study was to characterize the biophysical properties of a C-terminus-truncated KCNH2 channel, G1006fs/49 causing long QT syndrome type II in heterozygous members of an Italian family. Mutant carriers underwent clinical workup, including 12-lead electrocardiogram, transthoracic echocardiography and 24-hour ECG recording. Electrophysiological experiments compared the biophysical properties of G1006fs/49 with those of KCNH2 both expressed either as homotetramers or as heterotetramers in HEK293 cells. Major findings of this work are as follows: (a) G1006fs/49 is functional at the plasma membrane even when co-expressed with KCNH2, (b) G1006fs/49 exerts a dominant-negative effect on KCNH2 conferring specific biophysical properties to the heterotetrameric channel such as a significant delay in the voltage-sensitive transition to the open state, faster kinetics of both inactivation and recovery from the inactivation and (c) the activation kinetics of the G1006fs/49 heterotetrameric channels is partially restored by a specific KCNH2 activator. The functional characterization of G1006fs/49 homo/heterotetramers provided crucial findings about the pathogenesis of LQTS type II in the mutant carriers, thus providing a new and potential pharmacological strategy

Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and cancer a meta-analysis

Background: Direct oral anticoagulants (DOACs) are recommended as first-line anticoagulants in patients with atrial fibrillation (AF). However, in patients with cancer and AF the efficacy and safety of DOACs are not well established. Objective: We performed a meta-analysis comparing available data regarding the efficacy and safety of DOACs vs vitamin K antagonists (VKAs) in cancer patients with non-valvular AF. Methods: An online search of Pubmed and EMBASE libraries (from inception to May, 1 2020) was performed, in addition to manual screening. Nine studies were considered eligible for the meta-analysis involving 46,424 DOACs users and 182,797 VKA users. Results: The use of DOACs was associated with reduced risks of systemic embolism or any stroke (RR 0.65; 95% CI 0.52–0.81; p 0.001), ischemic stroke (RR 0.84; 95% CI 0.74–0.95; p 0.007) and hemorrhagic stroke (RR 0.61; 95% CI 0.52–0.71; p 0.00001) as compared to VKA group. DOAC use was associated with significantly reduced risks of major bleeding (RR 0.68; 95% CI 0.50–0.92; p 0.01) and intracranial or gastrointestinal bleeding (RR 0.64; 95% CI 0.47–0.88; p 0.006). Compared to VKA, DOACs provided a non-statistically significant risk reduction of the outcomes major bleeding or non-major clinically relevant bleeding (RR 0.94; 95% CI 0.78–1.13; p 0.50) and any bleeding (RR 0.91; 95% CI 0.78–1.06; p 0.24). Conclusions: In comparison to VKA, DOACs were associated with a significant reduction of the rates of thromboembolic events and major bleeding complications in patients with AF and cancer. Further studies are needed to confirm our results

Is Less Always More? A Prospective Two-Centre Study Addressing Clinical Outcomes in Leadless versus Transvenous Single-Chamber Pacemaker Recipients

(1) Background: Leadless (LL) stimulation is perceived to lower surgical, vascular, and lead-related complications compared to transvenous (TV) pacemakers, yet controlled studies are lacking and real-life experience is non-conclusive. (2) Aim: To prospectively analyse survival and complication rates in leadless versus transvenous VVIR pacemakers. (3) Methods: Prospective analysis of mortality and complications in 344 consecutive VVIR TV and LL pacemaker recipients between June 2015 and May 2021. Indications for VVIR pacing were “slow” AF, atrio-ventricular block in AF or in sinus rhythm in bedridden cognitively impaired patients. LL indication was based on individualised clinical judgement. (4) Results: 72 patients received LL and 272 TV VVIR pacemakers. LL pacemaker indications included ongoing/expected chronic haemodialysis, superior venous access issues, active lifestyle with low pacing percentage expected, frailty causing high bleeding/infectious risk, previous valvular endocarditis, or device infection requiring extraction. No significant difference in the overall acute and long-term complication rate was observed between LL and TV cohorts, with greater mortality occurring in TV due to selection of older patients. (5) Conclusions: Given the low complication rate and life expectancy in this contemporary VVIR cohort, extending LL indications to all VVIR candidates is unlikely to provide clear-cut benefits. Considering the higher costs of LL technology, careful patient selection is mandatory for LL PMs to become advantageous, i.e., in the presence of vascular access issues, high bleeding/infectious risk, and long life expectancy, rendering lead-related issues and repeated surgery relevant in the long-term perspective

Pro-inflammatory cytokines as emerging molecular determinants in cardiolaminopathies

Mutations in Lamin A/C gene (lmna) cause a wide spectrum of cardiolaminopathies strictly associated with significant deterioration of the electrical and contractile function of the heart. Despite the continuous flow of biomedical evidence, linking cardiac inflammation to heart remodelling in patients harbouring lmna mutations is puzzling. Therefore, we profiled 30 serum cytokines/chemokines in patients belonging to four different families carrying pathogenic lmna mutations segregating with cardiac phenotypes at different stages of severity (n = 19) and in healthy subjects (n = 11). Regardless lmna mutation subtype, high levels of circulating granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6) were found in all affected patients’ sera. In addition, elevated levels of Interleukins (IL) IL-1Ra, IL-1β IL-4, IL-5 and IL-8 and the granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured in a large subset of patients associated with more aggressive clinical manifestations. Finally, the expression of the pro-inflammatory 70 kDa heat shock protein (Hsp70) was significantly increased in serum exosomes of patients harbouring the lmna mutation associated with the more severe phenotype. Overall, the identification of patient subsets with overactive or dysregulated myocardial inflammatory responses could represent an innovative diagnostic, prognostic and therapeutic tool against Lamin A/C cardiomyopathies

The practice of deep sedation in electrophysiology and cardiac pacing laboratories: Results of an italian survey promoted by the aiac (italian association of arrhythmology and cardiac pacing)

The aim of this survey, which was open to all Italian cardiologists involved in arrhythmia, was to assess common practice regarding sedation and analgesia in interventional electrophysiology procedures in Italy. The survey consisted of 28 questions regarding the approach to sedation used for elective direct-current cardioversion (DCC), subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation, atrial fibrillation (AF) ablation, ventricular tachycardia (VT) ablation, and transvenous lead extraction procedures. A total of 105 cardiologists from 92 Italian centres took part in the survey. The rate of centres where DCC, S-ICD implantation, AF ablation, VT ablation and lead extraction procedures were performed without anaesthesiologic assistance was 60.9%, 23.6%, 51.2%, 37.3%, and 66.7%, respectively. When these procedures were performed without anaesthesiologic assistance, the drugs (in addition to local anaesthetics) commonly administered were benzodiazepines (from 64.3% to 79.6%), opioids (from 74.4% to 88.1%), and general anaesthetics (from 7.1% to 30.4%). Twenty-three (21.9%) of the 105 cardiologists declared that they routinely administered propofol, without the supervision of an anaesthesiologist, in at least one of the above-mentioned procedures. In current Italian clinical practice, there is a lack of uniformity in the sedation/analgesia approach used in interventional electrophysiology procedures

Electrocardiographic features, mapping and ablation of idiopathic outflow tract ventricular arrhythmias

Idiopathic outflow tract ventricular arrhythmias are ventricular tachycardias or premature ventricular contractions presumably not related to myocardial scar or disorders of ion channels. These arrhythmias have focal origin and display characteristic electrocardiographic features. The purpose of this article is to review the state of the art of diagnosis and treatment of idiopathic outflow tract ventricular arrhythmias

Monitoring Atrial Fibrillation After Catheter Ablation

Although catheter ablation is an effective treatment for recurrent atrial fibrillation (AF), there is no consensus on the definition of success or follow-up strategies. Symptoms are the major motivation for undergoing catheter ablation in patients with AF, however it is well known that reliance on perception of AF by patients after AF ablation results in an underestimation of recurrence of the arrhythmia. Because symptoms of AF occurrence may be misleading, a reliable assessment of rhythm outcome is essential for the definition of success in both clinical care and research trials. Continuous rhythm monitoring over long periods of time is superior to intermittent recording using external monitors to detect the presence of AF episodes and to quantify the AF burden. Today, new devices implanted subcutaneously using a minimally invasive technique have been developed for continuous AF monitoring. Implantable devices keep detailed information about arrhythmia recurrences and might allow identification of very brief episodes of AF, the significance of which is still uncertain. In particular, it is not known whether there is any critical value of daily AF burden that has a prognostic significance. This issue remains an area of active discussion, debate and investigation. Further investigation is required to determine if continuous AF monitoring with implantable devices is effective in reducing stroke risk and facilitating maintenance of sinus rhythm after AF ablation

Antecedent administration of angiotensin-converting enzyme inhibitors or angiotensin ii receptor antagonists and survival after hospitalization for COVID-19 syndrome

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes the angiotensin-converting enzyme-2 (ACE-2) receptor to enter human cells. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) are associated with ACE-2 upregulation. We hypothesized that antecedent use of ACEI/ARB may be associated with mortality in coronavirus disease 2019 (COVID-19). Methods and Results We used the Coracle registry, which contains data of patients hospitalized with COVID-19 in 4 regions of Italy, and restricted analyses to those ≥50 years of age. The primary outcome was in-hospital mortality. Among these 781 patients, 133 (17.0%) used an ARB and 171 (21.9%) used an ACEI. While neither sex nor smoking status differed by user groups, patients on ACEI/ARB were older and more likely to have hypertension, diabetes mellitus, and congestive heart failure. The overall mortality rate was 15.1% (118/781) and increased with age (PTrend<0.0001). The crude odds ratios (ORs) for death for ACEI users and ARB users were 0.98, 95% CI, 0.60-1.60, P=0.9333, and 1.13, 95% CI, 0.67-1.91, P=0.6385, respectively. After adjusting for age, hypertension, diabetes mellitus, and congestive heart failure, antecedent ACEI administration was associated with reduced mortality (OR, 0.55; 95% CI, 0.31-0.98, P=0.0436); a similar, but weaker trend was observed for ARB administration (OR, 0.58; 95% CI, 0.32-1.07, P=0.0796). Conclusions In those aged ≥50 years hospitalized with COVID-19, antecedent use of ACEI was independently associated with reduced risk of inpatient death. Our findings suggest a protective role of renin-angiotensin-aldosterone system inhibition in patients with high cardiovascular risk affected by COVID-19