Raffaele Calabrò

A 41-year-old asymptomatic Italian male underwent cardiologic screening before blood donation. A transthoracic echocardiogram showed a huge right coronary artery (RCA) aneurysm continuing into a very twisted, worm-like channel, apparently draining into the right atrium (RA), suggesting the diagnosis of RCA–RA coronary fistula. Multidetector computed tomography showed a mild dilatation of the proximal RCA that gave rise to a giant ‘snake-like’ aneurysm (6.6 × 7 cm) followed by a long, tortuous and circumvolved channel spreading all over the right atrium and right ventricular free wall and finally draining into the coronary sinus.

Congenital long QT syndrome (LQTS) is associated with high genetic and allelic heterogeneity. In some cases, more than one genetic variant is identified in the same (compound heterozygosity) or different (digenic heterozygosity) genes, and subjects with multiple pathogenic mutations may have a more severe disease. Standard-of-care clinical genetic testing for this and other arrhythmia susceptibility syndromes improves the identification of complex genotypes. Therefore, it is important to distinguish between pathogenic mutations and benign rare variants. We identified four genetic variants (KCNQ1-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-p.G38S could be LQTS modifiers.

Point mutations are the most common cause of inherited diseases. Bioinformatics tools can help to predict the pathogenicity of mutations found during genetic screening, but they may work less well in determining the effect of point mutations in non-coding regions. In silico analysis of intronic variants can reveal their impact on the splicing process, but the consequence of a given substitution is generally not predictable. The aim of this study was to functionally test five intronic variants (MYBPC3-c.506-2A>C, MYBPC3-c.906-7G>T, MYBPC3-c.2308+3G>C, SCN5A-c.393-5C>A, and ACTC1-c.617-7T>C) found in five patients affected by inherited cardiomyopathies in the attempt to verify their pathogenic role. Analysis of the MYBPC3-c.506-2A>C mutation in mRNA from the peripheral blood of one of the patients affected by hypertrophic cardiac myopathy revealed the loss of the canonical splice site and the use of an alternative splicing site, which caused the loss of the first seven nucleotides of exon 5 (MYBPC3-G169AfsX14). In the other four patients, we generated minigene constructs and transfected them in HEK-293 cells. This minigene approach showed that MYBPC3-c.2308+3G>C and SCN5A-c.393-5C>A altered pre-mRNA processing, thus resulting in the skipping of one exon. No alterations were found in either MYBPC3-c.906-7G>T or ACTC1-c.617-7T>C. In conclusion, functional in vitro analysis of the effects of potential splicing mutations can confirm or otherwise the putative pathogenicity of non-coding mutations, and thus help to guide the patient's clinical management and improve genetic counseling in affected families.

Aims: To elucidate right ventricular (RV) function in patients with idiopathic pulmonary fibrosis (IPF) with and without pulmonary hypertension (PH) and its relation to other features of the disease.Methods and Results: Clinical evaluation, standard Doppler echo, Doppler myocardial imaging (DMI), and 2D strain echocardiography (STE) of RV septal and lateral walls were performed in 52 IPF patients (66.5 ± 8.5 years; 27 males) and in 45 age‐ and sex‐comparable controls using a commercial US system (MyLab Alpha, Esaote). Pulmonary artery mean pressure (mPAP) was estimated by standard echo Doppler. RV global longitudinal strain (RV GLS) was calculated by averaging RV local strains. The IPF patients were divided into 2 groups by noninvasive assessment of PH: no PH (mPAP<25 mmHg; 36 pts) and PH (mPAP ≥25 mmHg; 16 pts). Left ventricular diameters and ejection fraction were comparable between controls and IPF, while GLS was impaired in IPF (P < 0.01). RV end‐diastolic diameters, wall thickness andmPAP were increased in IPF patients with PH. In addition, pulsed DMI detected in PH IPF impaired myocardial RV early diastolic (Em) peak velocity. Also peak systolic RV strain was reduced in basal and middle RV lateral free walls in IPF, as well as RV GLS (P < 0.0001). The impairment in RV wall strain was more evident when comparing controls with the no PH group than comparing the no PH group with the PH group. By multivariate analysis, independent association of RV strain with both six‐minute walking test distance (P < 0.001), mPAP (P < 0.0001), as well as with forced vital capacity (FVC) % (P < 0.005) in IPF patients were observed.Conclusions: Impaired RV diastolic and systolic myocardial function were present even in IPF patients without PH, which indicates an early impact on RV function and structure in patients with IPF.

Paroxysmal supraventricular arrhythmias (SVAs) frequently occur in patients with atrial septal aneurysm (ASA). The aim of the current study was to evaluate the electrocardiographic (P-wave duration and dispersion) and echocardiographic (atrial electromechanical delay, AEMD) noninvasive indicators of atrial conduction heterogeneity in healthy ASA subjects without interatrial shunt and to assess the AEMD role in predicting the SVAs onset in this population. One hundered ASA patients (41 males, mean age of 32.5 ± 8 years) and 100 healthy subjects used as controls, matched for age and gender, were studied for the occurrence of SVAs during a 4-year follow-up, through 30-day external loop recorder (ELR) monitoring performed every 3 months. ASAs were diagnosed by transthoracic echocardiography based on the criteria of a minimal aneurismal base of ≥15 mm and an excursion of ≥10 mm. Intra-AEMD and inter-AEMD of both atria were measured through tissue Doppler echocardiography. P-wave dispersion (PD) was carefully measured using 12-lead electrocardiogram (ECG). Compared to the healthy control group, the ASA group showed a statistically significant increase in inter-AEMD, intra-left AEMD, maximum P-wave duration, and PD. Dividing the ASA group into 2 subgroups (patients with or without SVAs), the inter-AEMD, intra-left AEMD, P max, and PD were significantly higher in the subgroup with SVAs compared to the subgroup without SVAs. There were significant good correlations of intra-left AEMD and inter-AEMD with PD. A cutoff value of 40.1 msec for intra-left AEMD had a sensitivity of 82% and a specificity of 83% in identifying ASA patients at risk for SVA. Our results showed that the echocardiographic AEMD indices (intra-left and inter-AEMD) and the PD were significantly increased in healthy ASA subjects without interatrial shunt. PD and AEMD represent noninvasive, inexpensive, useful, and simple parameters to assess the SVAs' risk in ASA patients.

Bicuspid aortic valve (BAV) cannot be considered an innocent finding, but it is not necessarily a life-threatening condition. Athletes with BAV should undergo a thorough staging of the valve anatomy, taking into consideration hemodynamic factors, as well as aortic diameters and looking for other associated significant cardiovascular anomalies by use of a multimodality cardiac imaging approach. Furthermore an accurate follow-up is mandatory with serial cardiological controls in those allowed to continue sports.

P-wave dispersion is a non invasive indicator of intra-atrial conduction heterogeneity producing substrate for reentry, which is a pathophysiological mechanism of atrial fibrillation. The relationship between P-wave dispersion (PD) and atrial fibrillation (AF) in Myotonic dystrophy type 1 (DM1) patients is still unclear. Atrial Preference Pacing (APP) is an efficient algorithm to prevent paroxysmal AF in patients implanted with dual-chamber pacemaker. Aim of our study was to evaluate the possible correlation between atrial preference pacing algorithm, P-wave dispersion and AF burden in DM1 patients with normal cardiac function underwent permanent dual-chamber pacemaker implantation.

Mitral regurgitation (MR) is the second most common heart valve disease worldwide. Currently, the management of MR is based on medical therapy (including biventricular pacing), surgery (mitral valve replacement or repair) and percutaneous therapy. However, in spite of guideline recommendations, 50% of individuals assessed in the Euro Heart Survey were not referred to surgical intervention due to comorbidities or real or perceived high risks for cardiac surgery; thus, in recent years, the focus of research has shifted to the development of percutaneous approaches to treat severe MR in order to restore valve function in a minimally invasive fashion. Among these techniques, the percutaneous mitral valve repair procedure using the MitraClip(®) system (Abbott Vascular, IL, USA) is one of the most promising. Usually, patient selection for MitraClip implantation is based on careful echocardiographic assessment of valve disease; however, although definitive data are lacking, evidence is mounting for a multiparametric approach including the evaluation of the functional status of patients.