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Background: Long-term data on COVID-19 vaccine safety, immunogenicity, and acceptance in adults with CHD are lacking. Methods: This is a prospective study including adults with CHD patients undergoing COVID-19 vaccination from January 2021 to June 2022. Data on adverse events, antispike IgG titre, previous or subsequent COVID-19 infection, booster doses, and patients’ attitude towards vaccination were collected. Results: Four hundred and ninety CHD patients (36 ± 13 years, 53% male, 94% with moderate/complex defects) were prospectively included: 433 (88%) received a Pfizer–BioNTech mRNA vaccine, 31 (6%) Moderna mRNA vaccine, 23 (5%) AstraZeneca–Oxford ChAdOx1 nCov-19 vaccine, and 3 (0.6%) Janssen Vaccine; 310 (63%) received a booster dose. Median follow-up after vaccination was 1.53 [1.41–1.58] years. No major adverse event was reported. Eighty-two fully vaccinated patients contracted COVID-19 during follow-up after a median of 5.4 [4.3–6.5] months from the last dose. One patient with Ebstein’s disease died from severe COVID-19. Symptoms’ duration in patients who tested positive after vaccination was significantly shorter than in the group tested positive before vaccination (5.5 [3–8] versus 9 [2.2–15] days, p = 0.04). Median antispike IgG titre measured in 280 individuals (57%) at a median of 1.4 [0.7–3.3] months from the last dose was 2381 [901–8307] BAU/ml. Sixty patients (12%) also showed positive antinucleocapsid antibodies, demonstrating previous SARS-COV2 exposure. Twenty-nine percent appeared to have concerns regarding vaccine safety and 42% reported fearing potential effects of the vaccine on their cardiac disease before discussing with their CHD cardiologist. Conclusion: COVID-19 vaccines appear safe in the mid-term follow-up in adults with CHD with satisfactory immunogenicity and reduction of symptoms’ duration in case of infection.

Background: Subcutaneous implantable cardioverter defibrillators (S-ICD) are widely accepted therapy in congenital heart disease (CHD) patients at risk of life-threatening ventricular arrhythmias or sudden cardiac death (SCD) when pacing is not required. Occasionally, pacemaker (PM) dependent CHD patients will subsequently develop an indication for a cardioverter defibrillator. The use of S-ICD in complex CHD who have had already PM devices implanted implies some specific considerations, as the safety for these patients in unknown and recommendations among physicians may vary widely. Methods: We review the data and studied the indications for S-ICD in complex CHD with previous PM and discuss its usefulness in clinical practice. Results: From a large cohort of 345 patients enrolled in the S-ICD “Monaldi care” registry, that encompass all the patients implanted in the Monaldi Hospital of Naples, we considered 11 consecutive complex CHD patients (10M/1F aged 40.4±18.4 years) who underwent S-ICD implant after a previous PM implant, from February 2015 to October 2022. Mean follow-up was 23.7±22.5 months. All the patients showed a good compliance to the device system with no complications (infections or skin erosions). Conclusions: In complex CHD with already implanted PM devices, S-ICD implant appears to be a safe alternative to PM upgrading to transvenous ICD system, avoiding abandoned leads or life-threatening lead extraction. However, there are important issues with regards to testing and programming that need to be addressed at the time of implantation.

Obstruction of the superior vena cava represents an under-recognized cause of chylothorax in the adult population. Our case report describes the successful conservative management of chylothorax due to bilateral superior vena cava obstruction in an adult patient with complex congenital heart disease. (Level of Difficulty: Beginner.), Central Illustration

Background: Implantable cardioverter defibrillators (ICD) are widely accepted therapy in children and adolescents who are survivors of cardiac arrest or for high-risk patients with inheritable channelopathies, cardiomyopathies, or congenital heart disease. Initial experience with subcutaneous ICD (S-ICD) systems has shown a high efficacy in adults. However, the use of S-ICD in children and adolescents implies some specific considerations, as the safety for these patients is unknown and recommendations among physicians may vary widely. Methods: We reviewed the data and studied the indications for S-ICD in children and adolescents and discuss the preliminary clinical experience. Results: From a cohort of 297 patients enrolled in the S-ICD “Monaldi care” registry that encompass all the patients implanted in the Monaldi Hospital of Naples, we considered 21 consecutive children and adolescents (mean age 13.9 years, range 8-18 years, mean body weight 59.3 kg, range 38-100 kg) who underwent S-ICD implant from April 2014 to June 2020. Mean follow-up was 41.9±21.9 months. Only one patient presented, 6 weeks after implantation, skin erosion at the inferior parasternal incision that resolved after antibiotic therapy, without the necessity of any system revision. Two patients experienced appropriate shocks and four inappropriate shocks, due to T wave oversensing or atrial arrhythmia. Only one patient, with arrhythmogenic right ventricular dysplasia, required a system revision after 36 months of the first implantation and then a reintervention with a replacement of the S-ICD by a conventional ICD system. Conclusions: Our experience suggests that the S-ICD device can be used in some children over the age of 8 as well as adults, with a similar rate of unwanted side effects, and early evidence of apparent efficacy.

Background Pulmonary valve (PV) endocarditis is a frequent complication during follow-up in patients with repaired right ventricular outflow tract (RVOT) obstruction and poses relevant diagnostic and treatment challenges. We aimed to describe in details the possible different clinical presentations of this rare condition and to highlight the role of both transthoracic and transoesophageal echocardiography which, in experienced hands, may provide comprehensive useful information for the clinicians. Case summary We below describe the clinical presentation and the echo findings of three cases of pulmonary valve endocarditis complicating disease course after different repair modalities of congenital right ventricular outflow tract obstruction. Discussion The present case series outlines the diagnostic challenges of this increasingly frequent complication during follow-up of patients with congenital RVOT dysfunction after both surgical and percutaneous repair. Despite the diffusion of multimodality imaging, echocardiography with PV-dedicated views play a pivotal role in diagnosing such condition and guiding clinical management. Furthermore, this case series highlight that the suspicion of infective endocarditis should be raised whenever a sudden increase in transvalvular gradient is found during follow-up.

Background:Adults with CHD are known to greatly benefit from a prompt access to continuous expert care. On the other hand, coronavirus disease 2019 pandemic has determined a dramatic worldwide reconfiguration of the healthcare systems, with rapid redeployment of resources towards this emergency. Italy was the first Western country affected by a large-scale spread of coronavirus disease 2019. The aim of our study is to analyse the impact of the coronavirus disease 2019 outbreak on in-hospital care of patients with CHD in an Italian tertiary centre.Methods and results:We retrospectively reviewed data on CHD hospital admissions in our centre since 1 March, 2020, when the adoption of a strict infection containment policy throughout the country resulted in limited access of patients to routine hospital care and resources reallocation to the care of infected patients. Comparison with data from the previous year was performed in order to identify any relevant differences attributable to the outbreak. Despite cancellation of all elective procedures, the overall number of urgent hospital admission remained stable throughout the period of study. Patients admitted during the pandemic had greater disease complexity (p = 0.001) with longer length of in-hospital stay (p = 0.01). No adverse events or positive swabs were reported among CHD patients who were admitted to hospital or medical personnel caring for these patients.Conclusion:Data from our early experience suggest that coronavirus disease 2019 pandemic did not impact significantly on the provision of urgent care to adult patients with CHD.

Implantable loop recorders (ILRs) are effective tools for detecting arrhythmias by long-term continuous heart rhythm monitoring. Benefits have been demonstrated even in pediatric patients. ILR with a long sensing vector has recently been designed to improve signal quality in terms of P wave visibility and R wave amplitude. However, there are no data on its use in pediatric patients. We considered a series of pediatric patients implanted with a long sensing vector ILR. Sensing performance, including R wave amplitude and P wave visibility, device-related complications, and diagnostic yield were collected. During follow-up, each patient guided by his/her parents/guardians was also asked to complete a brief questionnaire to assess patient acceptability of the device. Twenty-five consecutive pediatric patients (mean age 11.3 ± 3.5years, 72% male) were enrolled. The insertion success rate was 100% on the first attempt with no complications. The median amplitude of the R wave was 1.15mV (interquartile range, 1.01-1.42) with no significant differences between patients aged ≤ or > 10years (p = 0.726) and between female and male (p = 0.483). P wave was classified as 'always visible' in 24/25 patients (96%). ILR was generally well accepted and tolerated by all involved patients. During a median follow-up of 297days (117-317), we achieved in 5 patients a correlation between symptoms and rhythm disorders (20%)and ruled out significant arrhythmias in 6 symptomatic children (24%). Long sensing vector ILR showed to be well accepted, with good signal quality and an excellent safety profile even in pediatric patients.

Aims Wolff–Parkinson–White syndrome (WPW) is a clinical condition characterized by pre-excitation on electrocardiogram (ECG) and symptoms of arrhythmias. It has been described that premature ventricular activation induces septal wall motion abnormalities and ventricular dyssynchrony, causing detrimental effects on cardiac performance. The new speckle-tracking-based technique, blood speckle imaging (BSI), has been previously used to evaluate blood flow characteristics in normal and dysfunctional hearts in patients with normal atrio-ventricular (AV) conduction. We aimed to study the features of left ventricle blood vortices in patients with WPW and short AV conduction by using BSI. Methods and results Nineteen paediatric patients (age 7 ± 2.9 years) were included in the study: 13 patients with manifest WPW (WPW group) and 6 age and sex -matched controls with normal AV conduction (CTR group). A complete echocardiographic evaluation with 2D, color Doppler, and BSI was performed in all the included patients. BSI was recorded in apical 3-chamber view with a 6S-D probe. Vortices characteristics were analysed during the filling phase of the left ventricle. We focused on the anterior vortex generated by the mitral valve, which persisted longer during the cardiac cycle and is assumed to contribute to optimizing cardiac function. For each child in the WPW group, Arruda criteria were used to esteem accessory pathway localization from a 12-lead surface ECG. All patients in the WPW group manifested the accessory pathway in the septal region. All patients in the CTR group presented one major anterior vortex along the septal wall during the filling phase (Figure A), while in the WPW group, 10 patients out of 13 (P = 0.009) lacked this main anterior vortex, showing instead fragmented vortices (Figure B). Interestingly, the main differences in blood vortices pattern were showed in the last part of filling phase, when blood flow could be affected by premature activation of the septal wall. There were no differences in terms of left ventricle function (WPWg 59.8 ± 4.02% vs. CTRg 59.0 ± 2.5%, P = 0.6) and global longitudinal strain (WPWg −18.6 ± 1.0% vs. CTRg −19.6 ± 3.1%, P = 0.5) between the two groups. 136 Figure A and B Conclusions In our preliminary study, patients with WPW showed a fragmented pattern of diastolic blood vortices that adapted to septal dyssynchrony. We speculate this fragmentation may contribute to impair the performance of the left ventricle.

Aims Paediatric patients with a diagnosis of Wolff–Parkinson–White (WPW) Syndrome may develop a reduction of local myocardial deformation because of accessory pathway-related electrical dyssynchrony, which may lead to an impairment of left ventricular systolic function. The presence of ventricular dysfunction may be an indication for these patients to undergo radiofrequency catheter ablation (RFCA), even if asymptomatic. However, myocardial abnormalities are sometimes subtle and cannot be detected by standard echocardiographic evaluation. The purpose of this study was to assess the diagnostic value of non-invasive myocardial work in predicting subtle myocardial abnormalities in paediatric patients with WPW Syndrome. Methods and results Forty-four paediatric patients (age 8.2 ± 4.3 years) were included in this study: 12 cases with manifest WPW Syndrome and 32 age-, sex-, and arterial pressure-matched controls (CTR). Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were evaluated. Global myocardial work index (MWI) was measured as the area of the LV pressure-strain loops. From MWI, global constructive work (MCW), wasted work (MWW), and work efficiency (MWE) were estimated. Despite normal LV systolic function by standard echocardiographic parameters, paediatric patients with WPW Syndrome had lower MWI (1233.5 ± 281.6 mmHg% in WPW vs. 1624.0 ± 305.8 mmHg% in CTR, P = 0.0004), MCW (1833.4 ± 257.9 mmHg% in WPW vs. 2069.0 ± 319.9 mmHg% in CTR, P = 0.03), MWW (187.6 ± 117.7 mmHg% in WPW vs. 90.9 ± 58.9 mmHg% in CTR, P = 0.0008), and GWE (90.5 ± 4.8% in WPW vs. 95.2 ± 2.2% in CTR, P = 0.00006). There were no significant differences in GLS and LVEF between patients with WPW Syndrome and controls. Conclusions WPW Syndrome was found to be associated with a significant reduction of myocardial work indices in the paediatric population. The assessment of MWI may represent a sensitive measure to identify a subtle myocardial dysfunction in an early stage, even when LVEF and GLS are normal. It might be considered a further diagnostic parameter for referring little patients to RFCA.

This case report describes a procedure of retrieval of a leadless transcatheter pacemaker from the right pulmonary artery 3 days after device implantation. An 80-year-old man affected by ischemic cardiomyopathy and sinus node dysfunction was implanted with a leadless transcatheter pacemaker in the low septum of the right ventricle. Three days after the procedure, the leadless pacemaker migrated into a side branch of the right pulmonary artery. The device was successfully removed using two snares hooked to a tine via the proximal retrieval feature. This article is protected by copyright. All rights reserved.

Background Sacubitril/valsartan has been shown to reduce mortality and morbidity inpatients with heart failure and reduced systolic function. However, the effects of this novel association in patients with congenital heart disease and a systemic right ventricle (sRV) have not been investigated yet. Purpose We aimed to assess tolerability and efficacy of sacubitril/valsartan in patients with a sRV Methods From September 2020 to March 2021, 38 patients with congenitally corrected transposition of the great arteries or transposition of the great arteries after Senning or Mustard repair were prospectively enrolled. Inclusion criteria were: age ≥18 years, optimal medical therapy including ACEi/ARB for at least 6 months and EF of the sRV ≤40%. Patients with univentricular physiology, systolic blood pressure (SBP) 5.5mEq/L were excluded. RV systolic function was assessed on echocardiography using a multiparametric evaluation. The study protocol contemplates serial assessments at 1, 3, 6 and 12 months after treatment initiation. Results Up to March 31th, 23 patients completed 1-month and 15 completed 3-month assessment after treatment initiation. Baseline patients' characteristics are summarized in table 1. The medication dose was up-titrated to the highest tolerated dose during follow-up. During early follow-up, no major adverse events were reported. Treatment did not impact significantly on the values of serum potassium (basal K+ 4.4 [4.2–4.6] mEq/L, K+ at 3 months 4.4 [4.3–4.6] mEq/L, p=0.7) and GFR (basal GFR 113.9±35ml/min, GFR at 3 months 107.8±21 ml/min, p=0.7). Although SBP did not change significantly (114±12 vs 113.9±19 mmHg at 1-month and 117.3±12 mmHg at 3 months; p=0.9 for both), 2 (5%) patients ceased the treatment due to symptomatic hypotension during the first month of treatment. There was no significant change in the NYHA class. However, the 6-minute walking distance increased significantly after 3 months (365±120 vs 498.3±71 min; p=0.01). Furthermore, while traditional echocardiographic parameters of RV systolic function (TAPSE, s wave and FAC) did not change significantly, RV global longitudinal strain (GLS) and RV free wall GLS demonstrated subclinical improvement in right ventricular systolic function (table 2). Conclusions Our short-term results from an ongoing prospective study showed that sacubitril/valsartan is well tolerated in patients with a sRV with early evidence of improvement in exercise tolerance and sRV systolic function. Longer follow-up is warranted to confirm these data. Funding Acknowledgement Type of funding sources: None. Table 1Table 2

Background real-world data on COVID-19 vaccine safety, immunogenicity and acceptance in adults with congenital heart disease (ACHD) are lacking. Methods ACHD patients who were offered COVID-19 vaccination from January to June 2021 were included. Data on adverse events, on patients’ attitude towards vaccination and antispike IgG titre were retrospectively collected. A group of healthy individuals with similar age and sex undergoing vaccination was included for comparison. Results 208 patients followed in a single ACHD tertiary centre (33.3 [26–45]years,54%male) received COVID-19 vaccine, 65% vaccinated at our institution: 199 (96%)received Pfizer–BioNTech BNT162b2 vaccine, 4 (2%)Moderna-1273 and 5 (2%)AstraZeneca–ChAdOx1. Median follow-up after vaccination was 79 [57–96]days. No major adverse event was reported and there was no difference in the in adverse events incidence between ACHD patients and the control group. One patient was diagnosed with acute pericarditis. There were two unrelated deaths during follow-up. Three (1.5%)vaccinated patients tested positive for COVID-19. Antispike IgG titre, available in 159 (76%)patients, was 1334 [600–3401]BAU/ml, not significantly different from the control group (p = 0.2). One patient with Fontan failure was seronegative. Advanced physiological stage was related to lower antibody response, independently from previous viral exposure (p, Graphical abstract Image 1

Adults with congenital heart disease (ACHD) are frequently affected by thyroid diseases (TDs). However, the clinical relevance of TD in ACHD remains unknown. We aimed to describe the prevalence of TD in the ACHD population and to ascertain whether TD are associated with worse outcome. Patients with ACHD18 years attending our tertiary center for a day-case between 2014 and 2019 were included. Clinical data between patients' first visit and December 2020 were collected. Primary end point was a combination of death, hospitalization for heart failure (HF), and new-onset of arrhythmic events. Secondary end points were each part of the primary outcome as separate end points. A total of 495 patients with ACHD (32.2 [24.5 to 45.6] years; 54% women) were included. Median follow-up was 9.4 (4.5 to 13.1) years. The prevalence of TD was 30%. TD group showed worse clinical status, as demonstrated by N-terminal pro b-type natriuretic peptide values (243.5 [96.5 to 523] vs 94 [45 to 207] pg/ml, p0.001) and New York Heart Association class (27% vs 13% in class III to IV, p0.0001) with higher incident rate of adverse events at follow-up (4.45 [3.43 to 5.69] % vs 1.29[0.94 to 1.75] % per person-year, p0.001). TD were independently associated with higher risk of death (hazard ratio [HR] 4.1, p = 0.009), arrhythmic events (HR 3.8, p0.0001), and hospitalization for HF (HR 8.02, p0.0001). There was a fourfold increased risk of primary end point in the TD group even after propensity score matching for clinical variables including age, gender, disease complexity, physiological stage, previous palliative surgery, ventricular function, pulmonary arterial hypertension, cyanosis, and presence of systemic right ventricle (HR 4.47, p0.0001). In conclusion, TD are predictive of adverse outcome in the ACHD population. Routine screening of thyroid function during follow-up in this population may be helpful to identify those with higher risk of death, arrhythmias, and HF.

We report the case of a patient with recurrent episodes of postoperative intra-atrial reentrant tachycardia occurring after surgical patch closure of a sinus venosus atrial septal defect (SVASD). Arrhythmic episodes, as usually reported in scar-related arrhythmias, were resistant to antiarrhythmic therapy and worsened patient's quality of life. Therefore, we decided to perform an intracardiac electrophysiology study using a 3D-high definition mapping system to identify and treat the precise arrhythmic substrate with radiofrequency ablation. There is a growing evidence that this technique represents a valid therapeutic option in postoperative arrhythmias refractory to medical treatment in patients with repaired congenital heart disease.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

A 3-months-old infant was urgently admitted for drowsiness and lack of appetite started 24 h before. The ECG showed sinus rhythm with a prolonged AV interval (200 ms) and very large QRS complexes (280 ms) due to Flecainide overdosing following incorrectly administration for poor communication between parents resulted in both giving a dose to the infant. Flecainide serum level was 1.2μg/ml, confirming the diagnosis of an accidental drug intoxication. The patient started continue hydration with a close monitoring. Three hours later a significant narrowing of the QRS complex (150 ms) was observed, then over the following 24 h, the QRS almost completely normalized.

The purpose of this study was to evaluate the characteristics and outcome of patients undergoing ablation after electrical storm (ES).Clinical and procedural characteristics, ventricular tachycardia (VT) recurrence, and mortality rates from 1940 patients undergoing VT ablation were compared between patients with and without ES.The group of 677 patients with ES (34.9%) were older, were more frequently men, and had a lower ejection fraction, more advanced heart failure, and a higher prevalence of cardiovascular comorbidities as compared with those without ES (86.1% patients with ES had ≥2 comorbidities vs 71.4%; P.001). Patients with ES had more inducible VTs (2.5 ± 1.8 vs 1.9 ± 1.9; P.001), required longer procedures (296.1 ± 119.1 minutes vs 265.7 ± 110.3 minutes; P.001), and had a higher in-hospital mortality (42 deaths [6.2%] vs 18 deaths [1.4%]; P.001). At 1-year follow-up, patients with ES experienced a higher risk of VT recurrence and mortality (32.1% vs 22.6% and 20.1% vs 8.5%; long-rank, P.001 for both). Among patients with ES, those without any inducible VT after ablation had a higher survival rate (86.3%) than did those with nonclinical VTs only (72.9%), those with clinical VTs inducible at programmed electrical stimulation (51.2%), and not-tested patients (65.0%) (long-rank, P.001 for all). In multivariate analysis, ES remained an independent predictor of in-hospital mortality, VT recurrence, and 1-year mortality (P.001).Patients with ES have a high risk of VT recurrence and mortality. Patient and procedure characteristics are consistent with advanced cardiac disease and longer and more complex procedures. In patients with ES, acute procedural success is associated with a significant reduction in VT recurrence and improved 1-year survival.

Background The differential diagnosis between pre- and postcapillary pulmonary hypertension (PH) is of major therapeutic relevance and thus requires optimal clinical probability assessment with echocardiography. Methods We prospectively analyzed 152 consecutive patients referred to a PH center over a 1-year period undergoing quasi-simultaneous (within 1 hour) echocardiography and right heart catheterization. Echocardiography was performed as usually recommended for the assessment of PH and left heart conditions. PH was defined as a mean pulmonary artery pressure ≥ 25 mm Hg. Postcapillary PH was diagnosed on the basis of a pulmonary capillary wedge pressure >15 mm Hg. Results Ten of 152 patients (7%) had no PH, 81 of 152 (53%) had precapillary PH, and 61 of 152 (40%) had postcapillary PH. The following five echocardiographic variables were found to predict precapillary PH: right heart chamber larger than the left ( P = .0018), left ventricular eccentricity index > 1.2 ( P = .0039), dilated inferior vena cava without inspiratory collapse ( P = .0076), E/e′ ratio ≤10 ( P = .00001), and the right ventricle forming the heart apex ( P = .0144). Beta coefficients from multiple logistic regression were significant for dilated inferior vena cava without inspiratory collapse ( P = .0464) and E/e′ ratio ≤ 10 ( P = .0002). The score based on β coefficients, ranging from 3 to 34 points, resulted in optimal discrimination at >5, with a positive predictive value of 67.9% and a negative predictive value of 77.5% for precapillary PH. Conclusion Echocardiography enables a clinically satisfactory differential diagnosis between pre- and postcapillary PH.

Background Fluid challenge may help in the differential diagnosis between pre- and postcapillary pulmonary hypertension (PH). However, the test is still in need of standardization and better defined clinical relevance. Methods Two hundred twelve patients referred for PH underwent a right-sided heart catheterization with measurements before and after rapid infusion of 7mL/kg of saline. PH was defined as mean pulmonary artery pressure≥ 25mmHg, and postcapillary PH was defined as pulmonary artery wedge pressure (PAWP) > 15mmHg. An increase in PAWP≥ 18mmHg was considered diagnostic for postcapillary PH. At baseline, 66 patients received a diagnosis of no PH; 22, of postcapillary PH; and 124, of precapillary PH (mostly pulmonary arterial hypertension). Results After fluid challenge, five of 66 patients with no PH (8%) and eight of 124 with precapillary PH (6%) had the diagnosis reclassified as postcapillary PH. Fluid challenge was associated with an increase in PAWP by 7 ± 2mmHg in postcapillary PH and 3 ± 1mmHg in both precapillary PH and no-PH groups. Between-group differences were significant, but there was overlap. There were no adverse events related to fluid challenge. Prediction bands calculated from quadratic fits of the PAWP responses in pooled control subjects with no PH and patients with precapillary PH helped confirm 18mmHg as the cutoff for diagnosing postcapillary PH. Conclusions Fluid challenge with 7mL/kg saline increases PAWP, more in postcapillary than in precapillary PH or in control subjects with no PH. A cutoff value of 18mmHg allows reclassification of 6%to 8%of patients with precapillary PH or normal hemodynamic characteristics at baseline.

Background: Exercise-induced increase in pulmonary artery systolic pressure (PASP) as a possible measure of right ventricular (RV) contractile reserve has been shown to predict survival in severe pulmonary hypertension. However, RV contractile reserve can also be measured by changes in stroke volume (SV), tricuspid annular plane systolic excursion (TAPSE), or tricuspid annular systolic velocity (S'). The limits of normal values and the functional significance of these changes in healthy subjects are not well known. Methods: In this prospective study, 90 healthy subjects (45 male, mean age 39 ± 13years) underwent exercise stress echocardiography with measurement of TAPSE, S', TAPSE/PASP, SV, and PASP at rest and peak exercise. Maximum and minimum normal values were reported for all indices. Results: Normal values of exercise-induced changes (Δ) were 4 to 10mm for TAPSE, 6 to 14cm/s for S', 12 to 57mm Hg for PASP, 0 to 96mL for SV, and −1.2 to 0mm/mm Hg for TAPSE/PASP. At peak exercise, women showed lower ΔTAPSE/PASP, ΔPASP, ΔS', and ΔSV, but higher TAPSE/PASP than men. Aging was associated with decreased ΔTAPSE/PASP, ΔTAPSE, ΔS', ΔPASP, and ΔSV. In addition, ΔS', ΔTAPSE/PASP, ΔPASP, and ΔSV, but not ΔTAPSE, were directly correlated with maximum workload. Conclusions: Our results provide age- and sex-related limits of normal for RV contractile reserve as assessed by exercise stress echocardiography and demonstrate that RV systolic function indices (PASP, TAPSE, S', and TAPSE/PASP) correlate with maximum exercise capacity.

Background: Echocardiography is a valid tool for predicting the presence of pre- or post-capillary pulmonary hypertension (PH). A diastolic pulmonary gradient (DPG) equal or higher than 7 mmHg is a marker of pulmonary vascular disease also in patients with post-capillary PH. Aim: To detect if an echocardiographic score is able to allow a differential diagnosis between isolated post-capillary PH (Ipc-PH) and combined post- and pre-capillary PH (Cpc-PH). Methods: An echo-score, including right-to-left-heart chamber dimension >1 (2 points), dilation and no collapsibility of inferior vena cava (2 points), left ventricular eccentricity index ≥1.2 (1 point), E/e9 ratio ≤10 (1 point), and the right ventricle forming the heart apex (1 point), was applied to 230 consecutive patients referred for evaluation of PH and quasi-simultaneous right heart catheterization RHC (within 1 hour). Results: One-hundred-sixty/230 (70%) patients had pre-capillary PH and 70/230 (30%) had post-capillary PH. Within the 70 patients with post-capillary PH, 51/70 had Ipc-PH and 19/70 had Cpc-PH. There was a moderate linear correlation between Echo score and DPG (R 2 = 0.34). Echo score was higher in pre- vs post-capillary PH patients (4.0±2.0 vs 1.6±1.8, p The sensitivity and the specificity of Echo score ≥3 for pre-capillary PH were respectively 74% and 73%. Considering the 70 patients with post-capillary PH, the sensitivity and the specificity of Echo score ≥3 for Cpc-PH were respectively 68% and 88%. Conclusions: Echocardiography allows a satisfactory differential diagnosis not only between pre- and post-capillary PH, but also between Ipc-PH and Cpc-PH.

Objectives: Undifferentiated connective tissue disease at risk for Systemic Sclerosis (UCTD-risk-SSc) is a condition characterized by Raynaud9s phenomenon (RP) with SSc marker autoantibodies and/or typical capillaroscopic findings and unsatisfying classification criteria for the disease. UCTD-risk- SSc patients have been reported to show a preclinical vascular internal organ disease in about 40% of the patients. The present study is devoted to assess the prevalence of right (RV) or left ventricle (LV) systolic and/or diastolic dysfunction as assessed by tissue Doppler imaging (TDI). Methods: Fifty-three patients with UCTD-risk-SSc (46 female, aged 45±12 years, range 16-67) and 52 age- and sex-matched controls underwent cardiac assessment by standard echocardiography and TDI. Results: UCTD-risk-SSc patients and controls did not show any difference at standard echocardiographic evaluation. In particular, an inverted E/A ratio was pointed out in 14/53 patients and 12/52 controls (p=ns). TDI showed a mild impairment of LV and RV diastolic (E m 16±5 vs 19±5, p m 6.3±3.0 vs 4.9±1.4, p=0.005; E t 16±4 vs 18±3, p=0.03; E t /A t 1.1±0.4 vs 1.3±0.4, p m 11±3 vs 14±2 cm/sec, p t 14±3 vs 16±3 cm/sec, p=0.01) in UCTD- risk-SSc patients in comparison to controls. Estimated pulmonary artery systolic pressure (27±5 vs 25±4; p=0.07) and TAPSE (23±3 vs 23±4; p=0.20) were not significantly different between the 2 groups. Conclusions: Our study shows that UCTD-risk-SSc patients present a previously unrecognized, mild biventricular systolic and diastolic dysfunction as compared to controls.

Background: Right ventricular (RV) contractile reserve measured as exercise-induced increase in the pulmonary artery systolic pressure (PASP) has been shown to predict survival in severe pulmonary hypertension. However, RV contractile reserve can also be measured by changes in stroke volume (SV), tricuspid annular plane excursion (TAPSE) or tricuspid annulus systolic velocity (S). Aim: To explore the limits of normal and functional significance of these changes in healthy subjects, that is not exactly known so far. Methods and results: We measured PASP, TAPSE, SV, and S in 90 subjects aged 39 ± 13 yrs, 50% female, at rest and at maximum exercise, and estimated limits of normal as mean – 2SD to mean + 2SD. Normal values of exercise-induced changes (Δ) were 4 to 10 mm for TAPSE, 6 to 14 cm/s for S, 0 to 96 ml for SV, 12 to 57 mmHg for PASP and – 1.2 to 0 mm/mmHg for TAPSE/PASP. Limits of normal (shaded) and exercise-induced changes as a function of workload in TAPSE, S, SV, and PASP are shown in Figure 1. As compared to men (n=45), women had decreased ΔS, ΔTAPSE/PASP, ΔPASP and ΔSV, but increased TAPSE/PASP at peak exercise. Aging was associated with decreased ΔS, ΔTAPSE, ΔPASP, ΔSV and TAPSE/PASP. Changes in S, TAPSE/PASP, PASP and SV were directly correlated to workload. Conclusions: These results provide age- and sex-related limits of normal RV contractile reserve as assessed by stress echocardiographic PASP, TAPSE, S and TAPSE/PASP. Right ventricular contractile reserve, however measured, correlates with exercise capacity.

Background Pulmonary arterial hypertension (PAH) after shunt closure is associated with a poor prognosis. The aim of this study was to assess retrospectively the hemodynamics of patients developing PAH after shunt closure. Methods Hemodynamic data obtained by right heart catheterization (RHC) performed at baseline and after shunt closure were analyzed. Results Twenty-two patients, 13 with atrial septal defect (ASD), 6 with ventricular septal defect (VSD), 1 with patent ductus arteriosus, 1 with both ASD and VSD, and 1 with complete atrio-ventricular canal have been considered. The mean age at closure was 25.3±20.1years (range of 3months to 56.7years), and the mean age at PAH diagnosis was 37.0±20.8years (range of 5 to 61.2years). The time delay between shunt closure and PAH diagnosis was 140.2±100.2months. At baseline RHC, hemodynamic data were as follows: pulmonary vascular resistance (PVR) of 8.6±2.6Woodunits, PVR index (PVRi) of 10.1±2.7Woodunits∗m 2 , mean pulmonary arterial pressure of 43.7±9.7mmHg, PVR to systemic vascular resistance ratio (PVR/SVR) of 0.70±0.23, and Qp/Qs of 1.6±0.4. In particular, 18/22 (81%) had PVR≥5Woodunits, 21/22 (95%) PVRi≥6Woodunits∗m 2 , 21/22 (95%) PVR/SVR≥0.33, and 11/22 (50%) Qp/Qs≤1.5. During the follow-up, 5/22 (22%) patients died and one patient underwent successful double lung transplantation. Conclusions High baseline values of PVR (≥5Woodunits), PVRi (≥6Woodunits∗m 2 ) and PVR/SVR (≥0.33) are common findings in patients who develop PAH late after shunt closure. Large prospective clinical trials are needed to establish the safe limits for shunt closure.

Background Echocardiographic studies have contributed to progress in the understanding of the pathophysiology of the pulmonary circulation and have been shown to be useful for screening for and prognostication of pulmonary hypertension, but are considered unreliable for the diagnosis of pulmonary hypertension. We explored this apparent paradox with rigorous Bland and Altman analysis of the accuracy and the precision of measurements collected in a large patient population. Methods A total of 161 patients referred for a suspicion of pulmonary hypertension were prospectively evaluated by a Doppler echocardiography performed by dedicated cardiologists within 1h of an indicated right heart catheterization. Results Nine of the patients (6%) were excluded due to an insufficient signal quality. Of the remaining 152 patients, 10 (7%) had no pulmonary hypertension and most others had either pulmonary arterial hypertension (36%) or pulmonary venous hypertension (40%) of variable severities. Mean pulmonary artery pressure, left atrial pressure and cardiac output were nearly identical at echocardiography and catheterization, with no bias and tight confidence intervals, respectively ±3mm Hg, ±5mm Hg and ±0.3L/min. However, the ±2SD limits of agreement were respectively of +19 and −18mm Hg for mean pulmonary artery pressure, +8 and −12mm Hg for left atrial pressure and +1.8 and −1.7L/min for cardiac output. Conclusions Doppler echocardiography allows for accurate measurements of the pulmonary circulation, but with moderate precision, which explains why the procedure is valid for population studies but cannot be used for the individual diagnosis of pulmonary hypertension.

article i nfo Article history: Background: Oral bosentan is effective in pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). In patients with Down's syndrome, the effect of bosentan is largely unknown. Aim of the study was to evaluate the long-term effects of bosentan in adult patients with CHD-related PAH with and without Down's syndrome. Methods: WHO functional class, resting oxygen saturation, 6-minute walk test (6MWT) and hemodynamics were assessed at baseline and after 12 months of bosentan therapy in patients with CHD-related PAH with and without Down's syndrome. Results: Seventy-four consecutive patients were enrolled: 18 with and 56 without Down's syndrome. After 12 months of bosentan therapy, both with and without Down's syndrome patients showed an improvement in WHO functional class (Down: 2.5±0.5 vs 2.9±0.6, p=0.005; controls: 2.5±0.5 vs 2.9±0.5, p=0.000002), 6-minute walk distance (Down: 288±71 vs 239±74 m, p=0.0007; controls: 389±80 vs 343±86 m, p=0.00003), and hemodynamics (pulmonary flow, Down: 4.0±1.6 vs 3.5±1.4 l/m/m 2 ,p =0.006; controls: 3.5±1.4 vs 2.8±1.0 l/m/m 2 , p=0.0005; pulmonary to systemic flow ratio, Down: 1.4±0.7 vs 1.0±0.4, p=0.003; controls: 1.1±0.7 vs 0.9±0.3,p=0.012; pulmonary vascular resistanceindex, Down: 15±9 vs 20± 13 WU m 2 , p=0.007; controls: 20±10 vs 26±15 WU m 2 , p=0.002). No differences in the efficacy of therapy were observed between the two groups. Conclusions: Bosentan was safe and well tolerated in adult patients with CHD-related PAH with and without Down's syndrome during 12 months of treatment. Clinical status, exercise tolerance, and pulmonary hemodynamics improved, regardless of the presence of Down's syndrome.

Aim of the study was to explore the response to a fluid challenge test (FCT) in normal subjects and in patients with pulmonary hypertension (PH). 168 subjects underwent right heart catheterization in basal conditions and after FCT. At baseline, 50 subjects showed normal pressures (healthy controls

Ambrisentan, an oral endothelin-1-receptor antagonist (ERA) selective for the endothelin A, showed an improvement in WHO functional class, 6 minute walk distance, and time to clinical worsening relative to placebo in randomised, double-blind, placebo-controlled, multicenter, 12-week clinical trials (ARIES study 1 and 2, total n=394) [1]. At this time, the long-term effects of ambrisentan on haemodynamics have not been reported in a prospective study. The aim of this study was to evaluate prospectively the efficacy and safety of ambrisentan treatment in adult patients with pulmonary arterial hypertension by assessing its long term effects on clinical status, exercise capacity, and cardiopulmonary haemodynamics. This was a single-centre, open-label, single-arm, prospective study. All patients with PAH starting oral ambrisentan as first line therapy or combination therapy (based on recommendations of the current ESC/ERS guidelines on pulmonary hypertension) [2] were enrolled after obtaining the informed consent. Clinical status, resting transcutaneous oxygen saturation (SpO2), 6-minute walk distance, serology and right heart catheterization (RHC) were assessed at baseline (before starting ambrisentan therapy) and at 1 year follow-up. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [3]. Clinical status evaluation included medical history, assessment of WHO functional class, measurement of systemic arterial pressure, transcutaneous oxygen saturation (SpO2) and heart rate.

Purpose: To provide an easy and integrated echo-score for evaluating the pre-test probability of having a pre-capillary (pre-PH) rather than post-capillary (post-PH) Pulmonary Hypertension (PH). Methods: One-hundred-fifty-two consecutive patients referred to a tertiary PH center (June 2011 - May 2012) underwent standard Doppler Echocardiography (DE) within 1 hour of a clinically indicated Right Heart Catheterization (RHC). The DE was scored on the basis of features suggesting pre-PH: right atrium (RA) > left atrium (LA), right ventricle (RV) > left ventricle (LV), apex forming RV, LV eccentricity index (EI)