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Background and Objective: Balance between benefit and burden of implantable cardioverter-defibrillator (ICD) therapy is more debatable in older patients, compared to younger patients. Of around 6000 yearly implanted ICDs in the Netherlands, 1:4 is received by patients ≥75 years. We aimed to evaluate the current clinical practice in the Netherlands for ICD implants and generator replacements, with a special focus on the older ICD patients., Research Design and Methods: Cardiologists from all Dutch ICD implanting centres (n = 28) were interviewed. Questions aimed to evaluate outpatient care, pre-operative patient assessment, end-of-life-care counselling, evaluation of social and cognitive wellbeing, clinical evaluation of all patients prior to ICD replacement, and the consideration of the option to downgrade or not replace a device., Results: Implanting cardiologists from all 28 implanting centres were approached for an interview. Response rate was 86%. Management appeared diverse. An age ≥80 years was consistently reported as incentive for more extensive patient evaluation. Patients were invited for counselling prior to device replacements in only the minority (46%) of hospitals. Downgrade or non-replacement was performed in rare cases. End-of-life care discussions were not standard procedure in 67% of the hospitals. Evaluation of social and cognitive wellbeing of patients was based solely on the general clinical impression of the physician in 83%, or not at all assessed in 8% of the centres., Discussion and Implication: A structured framework for care and evaluation of cognitive and/or physical limitations is currently absent in most hospitals. At time of ICD (re-)evaluation, several factors may be considered before deciding on (continuation of) ICD therapy: patient preferences and comorbidity, the need for pacemaker therapy, primary vs. secondary prevention, procedural risks, and patient preferences., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Aims: The Leiden Convention coronary coding system structures the large variety of coronary anatomical patterns; isolated and in congenital heart disease. It is widely used by surgeons but not by cardiologists as the system uses a surgeons' cranial view. Since thoracic surgeons and cardiologists work closely together, a coronary coding system practical for both disciplines is mandatory. To this purpose, the 'surgical' coronary coding system was adapted to an 'imaging' system, extending its applicability to different cardiac imaging techniques., Methods and Results: The physician takes place in the non-facing sinus of the aortic valve, oriented with the back towards the pulmonary valve, looking outward from the sinus. From this position, the right-hand sinus is sinus 1, and the left-hand sinus is sinus 2. Next, a clockwise rotation is adopted starting at sinus 1 and the encountered coronary branches described. Annotation of the normal anatomical pattern is 1R-2LCx, corresponding to the 'surgical' coding system. The 'imaging' coding system was made applicable for Computed Tomography (CT), Magnetic Resonance Imaging (MRI), echocardiography, and coronary angiography, thus facilitating interdisciplinary use. To assess applicability in daily clinical practice, images from different imaging modalities were annotated by cardiologists and cardiology residents and results scored. The average score upon evaluation was 87.5%, with the highest scores for CT and MRI images (average 90%)., Conclusion: The imaging Leiden Convention is a coronary coding system that unifies the annotation of coronary anatomy for thoracic surgeons, cardiologists, and radiologists. Validation of the coding system shows it can be easily and reliably applied in clinical practice., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Non-acute chest pain is a common complaint and can be caused by various conditions. With the rising healthcare expenditures of today, it is necessary to use our healthcare resources effectively. This study aims to give insight into the diagnostic effort and costs for patients with non-acute chest pain., Methods and Results: Financial data of patients without a cardiac history from four hospitals (January 2012-October 2018), who were registered with the national diagnostic code 'no cardiac pathology' (ICD-10 Z13.6), 'chest wall syndrome' (ICD-10 R07.4), or 'stable angina pectoris' (ICD-10 I20.9) were extracted. In total, 74 091 patients were included for analysis and divided into the following final diagnosis groups: no cardiac pathology: N = 19 688 (age 53 ± 18), 46% male; chest wall syndrome: N = 40 858 (age 56 ± 15), 45% male; and stable angina pectoris (AP): N = 13 545 (age 67 ± 11), 61% male. A total of approximately €142.7 million was spent during diagnostic work-up. The total expenditure during diagnostic effort was €1.97, €8.13, and €10.7 million, respectively for no cardiac pathology, chest wall syndrome, and stable AP per year. After 8 years of follow-up, ≥95% of the patients diagnosed with no cardiac pathology or chest wall syndrome had an (cardiac) ischaemic-free survival., Conclusion: The diagnostic expenditure and clinical effort to ascertain non-cardiac chest pain are high. We should define what we as society find acceptable as 'assurance costs' with an increasing pressure on the healthcare system and costs., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: In patients with post-myocardial infarction (post-MI) ventricular tachycardia (VT), the presence of myocardial calcification (MC) may prevent heating of a subepicardial VT substrate contributing to endocardial ablation failure. The aims of this study were to assess the prevalence of MC in patients with post-MI VT and evaluate the impact of MC on outcome after endocardial ablation., Methods and Results: In 158 patients, the presence of MC was retrospectively assessed on fluoroscopy recordings in seven standard projections obtained during pre-procedural coronary angiograms. Myocardial calcification, defined as a distinct radiopaque area that moved synchronously with the cardiac contraction, was detected in 30 patients (19%). After endocardial ablation, only 6 patients (20%) with MC were rendered non-inducible compared with 56 (44%) without MC (P = 0.033) and of importance, 8 (27%) remained inducible for the clinical VT [compared with 9 (6%) patients without MC; P = 0.003] requiring therapy escalation. After a median follow-up of 31 months, 61 patients (39%) had VT recurrence and 47 (30%) died. Patients with MC had a lower survival free from the composite endpoint of VT recurrence or therapy escalation at 24-month follow-up (26% vs. 59%; P = 0.003). Presence of MC (HR 1.69; P = 0.046), a lower LV ejection fraction (HR 1.03 per 1% decrease; P = 0.017), and non-complete procedural success (HR 2.42; P = 0.002) were independently associated with a higher incidence of VT recurrence or therapy escalation., Conclusion: Myocardial calcification was present in 19% of post-MI patients referred for VT ablation and was associated with a high incidence of endocardial ablation failure., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: Statin treatment is one of the hallmarks of secondary prevention after myocardial infarction. Adherence to statins tends to be difficult and can be improved by patient education. Novel technologies such as mixed reality (MR) expand the possibilities to support this process. To assess if an MR medication-application supports patient education focused on function of statins after myocardial infarction., Methods and Results: A human-centred design-approach was used to develop an MR statin tool for Microsoft HoloLens™. Twenty-two myocardial infarction patients were enrolled; 12 tested the application, 10 patients were controls. Clinical, demographic, and qualitative data were obtained. All patients performed a test on statin knowledge. To test if patients with a higher tendency to become involved in virtual environments affected test outcome in the intervention group, validated Presence- and Immersive Tendency Questionnaires (PQ and ITQ) were used. Twenty-two myocardial infarction patients (ST-elevation myocardial infarction, 18/22, 82%) completed the study. Ten out of 12 (83%) patients in the intervention group improved their statin knowledge by using the MR application (median 8 points, IQR 8). Test improvement was mainly the result of increased understanding of statin mechanisms in the body and secondary preventive effects. A high tendency to get involved and focused in virtual environments was moderately positive correlated with better test improvement ( r  = 0.57, P  < 0.05). The median post-test score in the control group was poor (median 6 points, IQR 4)., Conclusions: An MR statin education application can be applied effectively in myocardial infarction patients to explain statin function and importance., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Patients with a systemic right ventricle (sRV) in the context of transposition of the great arteries (TGA) after atrial switch or congenitally corrected TGA are prone to heart failure and arrhythmias. This study evaluated feasibility, patient adherence, and satisfaction of a smart technology-based care pathway for heart failure treatment optimization in these patients., Methods and Results: Patients with symptomatic sRV failure eligible for initiation of sacubitril/valsartan were provided with four smartphone compatible devices (blood pressure monitor, weight scale, step counter, and rhythm monitor) and were managed according to a smart technology-based care pathway. Biweekly sacubitril/valsartan titration visits were replaced by electronical visits, patients were advised to continue measurements at least weekly after titration. Data of 24 consecutive sRV patients (median age 47 years, 50% female) who participated in the smart technology-based care pathway were analysed. Median home-hospital distance was 65 km (maximum 227 km). Most patients (20, 83.3%) submitted weekly measurements; 100% submitted prior to electronical visits. Titration conventionally occurs during a hospital visit. By implementing eHealth smart technology, 68 such trips to hospital were replaced by virtual visits facilitated by remote monitoring. An eHealth questionnaire was completed by 22 patients (92%), and 96% expressed satisfaction. After titration, 30 instances of remote adjustment of heart failure medication in addition to scheduled outpatient clinic visits occurred, one (4%) heart failure admission followed, despite ambulant adjustments. Five patients (21%) sent in rhythm registrations ( n  = 17), of these 77% showed sinus rhythm, whereas supraventricular tachycardia was detected in the remaining four registrations., Conclusion: These data suggest that implementation of a smart technology-based care pathway for optimization of medical treatment sRV failure is feasible with high measurement adherence and patient satisfaction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Cerebral amyloid angiopathy (CAA) is an important cause of cognitive impairment and spontaneous lobar intracerebral haemorrhage in older individuals. When necessary, anticoagulant treatment in these patients comes with two dilemmas; significant intracerebral bleeding risk with treatment vs. high risk of embolic stroke with no treatment., Case Summary: A 66-year-old female patient presented to the emergency clinic with a ST-elevation myocardial infarction. Her past medical history revealed cognitive problems associated with lobar cerebral microbleeds on magnetic resonance imaging suspect for probable CAA. A primary percutaneous coronary intervention of the left anterior descending artery with implantation of drug eluting stent was performed. Dual antiplatelet treatment was started initially. During hospitalization, an impaired left ventricular (LV) function was observed with an apical aneurysm. Six months after the initial event, LV function remained stable however a LV thrombus was observed. Apixaban 5 mg twice daily was started based on multidisciplinary consensus and on its efficacy and safety profile in patients with atrial fibrillation. Despite treatment, patient suffered a new ischaemic stroke probably from the LV thrombus, for which vitamin K antagonist treatment was initiated and Apixaban discontinued., Discussion: Evidence for LV thrombus treatment with direct oral anticoagulants in CAA patients is scarce, however feasible based on its efficacy and safety profile. For CAA patients, the cardinal role of both clinical and radiological characteristics in determining the risk-benefit ratio for anticoagulant initiation in this specific subset of patients, is crucial. The clinical course described highlights the therapeutical dilemma of coexisting CAA and the clinical challenge it creates., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Left ventricular (LV) mechanical dispersion (MD) may result from heterogeneous electrical conduction and is associated with adverse events. The present study investigated (i) the association between LV MD and the extent of LV scar as assessed with contrast-enhanced cardiac magnetic resonance (CMR) and (ii) the prognostic implications of LV MD in patients after ST-segment elevation myocardial infarction., Methods and Results: LV MD was calculated by echocardiography and myocardial scar was analysed on CMR data retrospectively. Infarct core and border zone were defined as ≥50% and 35-50% of maximal signal intensity, respectively. Patients were followed for the occurrence of the combined endpoint (all-cause mortality and appropriate implantable cardioverter-defibrillator therapy). In total, 96 patients (87% male, 57 ± 10 years) were included. Median LV MD was 53.5 ms [interquartile range (IQR) 43.4-62.8]. On CMR, total scar burden was 11.4% (IQR 3.8-17.1%), infarct core tissue 6.2% (IQR 2.0-12.7%), and border zone was 3.5% (IQR 1.5-5.7%). Correlations were observed between LV MD and infarct core (r = 0.517, P < 0.001), total scar burden (r = 0.497, P < 0.001), and border zone (r = 0.298, P = 0.003). In total, 14 patients (15%) reached the combined endpoint. Patients with LV MD >53.5 ms showed higher event rates as compared to their counterparts. Finally, LV MD showed the highest area under the curve for the prediction of the combined endpoint., Conclusion: LV MD is correlated with LV scar burden. In addition, patients with prolonged LV MD showed higher event rates. Finally, LV MD provided the highest predictive value for the combined endpoint when compared with other parameters., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: We aimed to evaluate the associations of body fat distribution with cardiovascular function and geometry in the middle-aged general population., Methods and Results: Four thousand five hundred and ninety participants of the UK Biobank (54% female, mean age 61.1 ± 7.2 years) underwent cardiac magnetic resonance for assessment of left ventricular (LV) parameters [end-diastolic volume (EDV), ejection fraction (EF), cardiac output (CO), and index (CI)] and magnetic resonance imaging for body composition analysis [subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT)]. Body fat percentage (BF%) was assessed by bioelectrical impedance. Linear regressions were performed to assess the impact of visceral (VAT) and general (SAT and BF%) obesity on cardiac function and geometry. Visceral obesity was associated with a smaller EDV [VAT: β -1.74 (-1.15 to -2.33)], lower EF [VAT: β -0.24 (-0.12 to -0.35), SAT: β 0.02 (-0.04 to 0.08), and BF%: β 0.02 (-0.02 to 0.06)] and the strongest negative association with CI [VAT: β -0.05 (-0.06 to -0.04), SAT: β -0.02 (-0.03 to -0.01), and BF% β -0.01 (-0.013 to -0.007)]. In contrast, general obesity was associated with a larger EDV [SAT: β 1.01 (0.72-1.30), BF%: β 0.37 (0.23-0.51)] and a higher CO [SAT: β 0.06 (0.05-0.07), BF%: β 0.02 (0.01-0.03)]. In the gender-specific analysis, only men had a significant association between VAT and EF [β -0.35 (-0.19 to -0.51)]., Conclusion: Visceral obesity was associated with a smaller LV EDV and subclinical lower LV systolic function in men, suggesting that visceral obesity might play a more important role compared to general obesity in LV remodelling., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Restrictive mitral annuloplasty (RMA) can provide a durable solution for functional mitral regurgitation (MR), but might result in obstruction to antegrade mitral flow. Aim of this study was to assess the magnitude of change in mitral valve area (MVA) during exercise after RMA, to relate the change in MVA to left ventricular (LV) geometry and function, and to assess its haemodynamic and clinical impact., Methods and Results: Bicycle exercise echocardiography was performed in 32 patients after RMA. Echocardiographic data at rest and during exercise were compared with preoperative echocardiographic data. Clinical endpoints were collected following the study visit. MVA increased during exercise in 25 patients (1.6 ± 0.4 cm2 to 2.0 ± 0.6 cm2, P < 0.001), whereas MVA decreased in 7 patients (1.8 ± 0.5 cm2 to 1.5 ± 0.4 cm2, P = 0.020). Patients with an increased MVA showed a significant reduction in LV volumes at rest compared to preoperatively, and an increase in stroke volume and cardiac output (CO) during exercise. In patients with decreased MVA, LV reverse remodelling was absent and myocardial flow reserve limited. Patients with decreased exercise MVA had a higher increase in mean pulmonary artery pressure (PAP) with respect to CO and worse survival 36 months after the study visit (69±19% vs. 92±5%, P = 0.005)., Conclusions: Both increased and decreased MVA were observed during exercise echocardiography after RMA for functional MR. Change in MVA was related to the extent of LV geometrical and functional changes. A decreased MVA during exercise was associated with a higher increase in mean PAP with respect to CO, and worse survival., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Initial studies have suggested the familial clustering of mitral valve prolapse, but most of them were either community based among unselected individuals or applied non-specific diagnostic criteria. Therefore little is known about the familial distribution of mitral regurgitation in a referral-type population with a more severe mitral valve prolapse phenotype. The objective of this study was to evaluate the presence of familial mitral regurgitation in patients undergoing surgery for mitral valve prolapse, differentiating patients with Barlow's disease, Barlow forme fruste and fibro-elastic deficiency., Methods: A total of 385 patients (62 ± 12 years, 63% men) who underwent surgery for mitral valve prolapse were contacted to assess cardiac family history systematically. Only the documented presence of mitral regurgitation was considered to define 'familial mitral regurgitation'. In the probands, the aetiology of mitral valve prolapse was defined by surgical observations., Results: A total of 107 (28%) probands were classified as having Barlow's disease, 85 (22%) as Barlow forme fruste and 193 (50%) patients as fibro-elastic deficiency. In total, 51 patients (13%) reported a clear family history for mitral regurgitation; these patients were significantly younger, more often diagnosed with Barlow's disease and also reported more sudden death in their family as compared with 'sporadic mitral regurgitation'. In particular, 'familial mitral regurgitation' was reported in 28 patients with Barlow's disease (26%), 15 patients (8%) with fibro-elastic deficiency and eight (9%) with Barlow forme fruste ( P  < 0.001)., Conclusions: In a large cohort of patients operated for mitral valve prolapse, the self-reported prevalence of familial mitral regurgitation was 26% in patients with Barlow's disease and still 8% in patients with fibro-elastic deficiency, highlighting the importance of familial anamnesis and echocardiographic screening in all mitral valve prolapse patients.

Aims: Quantitative flow ratio (QFR) is a recently developed technique to calculate fractional flow reserve (FFR) based on 3D quantitative coronary angiography and computational fluid dynamics, obviating the need for a pressure-wire and hyperaemia induction. QFR might be used to guide patient selection for FFR and subsequent percutaneous coronary intervention (PCI) referral in hospitals not capable to perform FFR and PCI. We aimed to investigate the feasibility to use QFR to appropriately select patients for FFR referral., Methods and Results: Patients who underwent invasive coronary angiography in a hospital where FFR and PCI could not be performed and were referred to our hospital for invasive FFR measurement, were included. Angiogram images from the referring hospitals were retrospectively collected for QFR analysis. Based on QFR cut-off values of 0.77 and 0.86, our patient cohort was reclassified to 'no referral' (QFR ≥0.86), referral for 'FFR' (QFR 0.78-0.85), or 'direct PCI' (QFR ≤0.77). In total, 290 patients were included. Overall accuracy of QFR to detect an invasive FFR of ≤0.80 was 86%. Based on a QFR cut-off value of 0.86, a 50% reduction in patient referral for FFR could be obtained, while only 5% of these patients had an invasive FFR of ≤0.80 (thus, these patients were incorrectly reclassified to the 'no referral' group). Furthermore, 22% of the patients that still need to be referred could undergo direct PCI, based on a QFR cut-off value of 0.77., Conclusion: QFR is feasible to use for the selection of patients for FFR referral., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Objectives: In repaired tetralogy of Fallot, surgical pulmonary valve replacement (PVR) is in certain cases required. Our institution reported earlier about 26 patients who received a pulmonary homograft via PVR. To date, we have data from more than 17 years of follow-up. The aim of this retrospective study was to evaluate the late haemodynamic and clinical outcomes in this predefined patient group., Methods: Between 1993 and 2001, 26 patients underwent PVR for pulmonary regurgitation (58% men; 30.4 ± 8.9 years). The rates of mortality and of complications (re-PVR, ablation and cardioverter defibrillator implants) were analysed. Other main study outcomes were haemodynamic parameters determined from cardiovascular magnetic resonance imaging: pulmonary regurgitation; right ventricular (RV) end-diastolic volume; RV ejection fraction; left ventricular (LV) end-diastolic volume; LV ejection fraction; New York Heart Association functional class at the latest follow-up visit; and echocardiographic parameters of the right ventricle., Results: The median follow-up time was 17 ± 1.1 years. Overall freedom from complications was 61.5% (95% confidence interval 47.5-78.6%). One patient died 18 months after surgery of unknown causes. Two patients needed replacement of the homograft at 24 and 39 months after PVR. The indication in both patients was recurrence of severe homograft regurgitation with important RV dilatation. Six patients received an implantable cardioverter defibrillator at a median age of 41 years (interquartile range 36-47); 12 patients experienced supra- and/or ventricular arrhythmias and 6 of these needed ablation. There was no significant deterioration of haemodynamic function or functional class., Conclusions: The patients who underwent PVR exhibited long-term follow-up stabilization of RV function and impressive functional durability of the graft. After a follow-up of 17 years, 23 out of 26 patients (89%) were alive without redo PVR. Event-free survival was good (61.5%).

Aims: Functional tricuspid regurgitation (TR) associated with atrial septal defects (ASDs) is frequently present due to right-sided volume-overload. Tricuspid valve (TV) repair is often considered in candidates for surgical ASD closure, and percutaneous TV repair is currently under clinical investigation. In this study, we develop a prediction model to identify patients with residual moderate/severe TR after percutaneous ASD closure., Methods and Results: In this observational study, 172 adult patients (26% male, age 49 ± 17 years) with successful percutaneous ASD closure had pre- and post-procedural echocardiography. Right heart dimensions/function were measured. TR was assessed semi-quantitatively. A prediction model for 6-month post-procedural moderate/severe TR was derived from uni-and multi-variable logistic regression. Clinical follow-up (FU) was updated and adverse events were defined as cardiovascular death or hospitalization for heart failure. Pre-procedural TR was present in 130 (76%) patients (moderate/severe: n = 64) of which 72 (55%) had ≥1 grade reduction post-closure. Independent predictors of post-procedural moderate/severe TR (n = 36) were age ≥60 years [odds ratio (OR) 2.57; P = 0.095], right atrial end-diastolic area ≥10cm2/m2 (OR 3.36; P = 0.032), right ventricular systolic pressure ≥44 mmHg (OR 6.44; P = 0.001), and tricuspid annular plane systolic excursion ≤2.3 cm (OR 3.29; P = 0.037), producing a model with optimism-corrected C-index = 0.82 (P < 0.001). Sensitivity analysis excluding baseline none/mild TR yielded similar results. Patients with moderate/severe TR at 6-month FU had higher adverse event rates [hazard ratio = 6.2 (95% confidence interval 1.5-26); log-rank P = 0.004] across a median of 45 (30-76) months clinical FU., Conclusion: This study shows that parallel to reduction of volume-overload and reverse remodelling after percutaneous ASD closure, TR improved substantially despite significant TR at baseline. Our proposed risk model helps identify ASD patients in whom TR regression is unlikely after successful percutaneous closure.

Aims: The aim of this study was to determine the long-term prognostic value of infarct size and myocardial ischaemia on single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI)., Methods and Results: In total, 1092 STEMI patients who underwent primary PCI and SPECT MPI within 1-6 months were included (median follow-up time of 6.9 years). In the entire cohort, SPECT infarct size was independently associated with the composite of cardiac death or reinfarction [hazard ratio (HR) per 10% increase in summed rest score 1.33; 95% confidence interval (95% CI) 1.12-1.58; P = 0.001], whereas myocardial ischaemia was not (HR per 5% increase in summed difference score 1.18; 95% CI 0.94-1.48; P = 0.16). Addition of SPECT infarct size to a model including the clinical variables provided significant incremental prognostic value for the prediction of cardiac death or reinfarction (global χ2 13.8 vs. 24.2; P = 0.002), whereas addition of SPECT ischaemia did not add significantly (global χ2 24.2 vs. 25.6; P = 0.24). In the subgroup of patients with left ventricular ejection fraction (LVEF) ≤ 45%, SPECT infarct size was independently associated with cardiac death or reinfarction (HR 1.59; 95% CI 1.15-2.22; P = 0.006), whereas in patients with LVEF > 45%, only SPECT ischaemia was independently associated with cardiac death or reinfarction (HR 1.28; 95% CI 1.00-1.63; P = 0.050)., Conclusion: In patients with first STEMI and primary PCI, SPECT infarct size was independently associated with cardiac death and/or reinfarction, whereas myocardial ischaemia was not. In patients with LVEF ≤ 45%, SPECT infarct size was independently associated with cardiac death or reinfarction, whereas myocardial ischaemia was not. Conversely, in patients with LVEF > 45%, only SPECT ischaemia was independently associated with cardiac death or reinfarction.

Objectives: Surgical ventricular reconstruction (SVR) is an effective treatment to improve left ventricular (LV) function in patients with ischaemic heart failure and an LV anterior-apical aneurysm. Ventricular arrhythmia (VA) is an important cause for morbidity and mortality in these patients. Therefore, encircling cryoablation targeting the VA substrate may be required. Programmed electrical stimulation (PES) can identify patients at risk for VA. The objective of this study was to evaluate the incidence and type of VA during long-term follow-up after PES-guided encircling cryoablation concomitant to SVR for primary prevention of VA., Methods: Thirty-eight patients without spontaneous VA referred for SVR who underwent preoperative PES were included (PES group); 27 (71%) patients inducible for aneurysm-related VA received cryoablation. A historical cohort of 39 patients without spontaneous VA, preoperative PES and antiarrhythmic surgery served as the control group. Patients were discharged with an implantable cardioverter defibrillator (ICD)., Results: During 74 ± 35 months of follow-up, no arrhythmic deaths occurred. Five-year survival for the total study population was 78%. Twenty-eight (36%) patients experienced ≥1 VA. There were no differences in the number and type of ICD therapies between groups: shocks, P = 0.699 and antitachypacing, P = 0.403. Five-year VA-free survival was 61% for the PES group and 65% for the control group (hazard ratio 1.67, P = 0.290)., Conclusions: The majority of the patients referred for SVR without previously documented VA was inducible for aneurysm-related VA. During the follow-up, more than one-third of the patients experienced sustained VA and 25% received appropriate ICD therapy. No difference in VA occurrence or ICD therapy was observed between groups.

Objectives: The aim of this study was to provide predictive data on the performance of the Freestyle stentless bioprosthesis that can be used to support and improve the shared decision-making process of prosthetic valve choice for aortic valve replacement., Methods: Between 1993 and 2014, 604 patients received the Freestyle stentless bioprosthesis (143 subcoronary, 58 root inclusion and 403 full-root replacement). Perioperative data were collected retrospectively, and follow-up data were collected prospectively from 2015. Follow-up was 96% complete (median 4.3 years), with 114 (19%) patients having a follow-up period exceeding 10 years. A competing risks regression model was developed to predict the probability of mortality, structural valve deterioration (SVD) and reoperation for other causes than SVD., Results: The median age of patients was 64 years, 91 (15%) patients had undergone previous aortic valve replacement and 351 (58%) underwent concomitant procedures. The 15-year probability of SVD, reoperation for other causes and death were 16.9%, 8.1% and 47.7%, respectively. Linearized occurrence rates for prosthesis endocarditis, thromboembolic events and bleeding were 0.5%, 0.9% and 0.1% per patient-year, respectively. The constructed predictive model, including age, renal function and implantation technique as significant covariates, had good to fair predictive performance up to 19 years., Conclusions: The Freestyle stentless bioprosthesis is an efficient prosthesis for aortic valve replacement or root replacement, with low incidences of SVD and valve-related events at long-term follow-up. The predictive model designed in this study can be used to fully inform patients about their expected individual trajectory after implantation of this prosthesis. This improves the shared decision-making process between patients and clinicians.

Aims: To assess mitral annulus dynamics in primary and secondary mitral regurgitation (MR) with 3-dimensional transesophageal echocardiography (3D TEE) and the impact on MR quantification., Methods and Results: One hundred and twenty-three patients with moderate and severe MR (63 ± 11 years, 78 males) and 29 controls (59 ± 15 years, 19 males) were evaluated. Functional MR (FMR) was present in 31 patients, fibroelastic deficiency (FED) in 52 and Barlow's disease (BD) in 40. Annular geometry was assessed with 3D TEE. The annulus height to commissural width ratio (AHCWR) was calculated to characterize the saddle shape of the mitral annulus. MR was graded as holo- or late-systolic. Effective regurgitant orifice area (EROA) and regurgitant volume (Rvol) were measured with 2D and 3D TEE. FMR, FED, and BD patients had larger mitral annular dimensions than controls. BD patients showed the largest dimensions whereas FMR and FED were similar. Early-systolic saddle shape was flatter in FMR whereas, in FED and BD, it was more pronounced. Annular dynamics were reduced in FMR but increased in FED and BD, compared with controls. In BD patients, 3D EROA and Rvol were larger compared with 2D TEE. In BD patients with late systolic MR (48%), 3D Rvol was larger than 2D Rvol. Univariate regression analyses showed significant correlations between relative change of annulus height (β = 0.43, P = 0.011) and AHCWR (β = 0.40, P = 0.024) with 3D Rvol in FED and BD., Conclusion: The mitral annulus is enlarged and stiff in FMR patients, whereas in FED and BD it is characterized by excessive dynamicity during systole. Enhanced annular dynamics leads to significant changes in grade of MR measured by 3D TEE particularly in those with late onset MR., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Background Following myocardial infarction, medication is, besides lifestyle interventions, the cornerstone treatment to improve survival and minimize the occurrence of new cardiovascular events. Still, data on nationwide medication adherence are scarce. This study assesses medical adherence during one year following myocardial infarction, stratifying per type of infarct, age and gender. Design Retrospective cohort study. Methods In The Netherlands, all inhabitants are by law obliged to have health insurance and all claims data are centrally registered. In 2012 and 2013, all national diagnosis-codings of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI) were acquired. Furthermore, information on retrieved medication was extracted from the Dutch Pharmacy Information System. Twelve months after discharge, the retrieved medication at the pharmacy of each pharmacological therapy (aspirin-species, P2Y12-inhibitor, statin, beta-blocker, angiotensin-converting enzyme-/angiotensin 2-inhibitor, vitamin-K antagonists or novel oral anticoagulant) were analysed. Results In total, 59,534 patients (67 ± 13 years, 39,545 (66%) male, 57% NSTEMI) were included, of whom 52,672 (88%) patients were analysed for one-year medical adherence. STEMI patients more often achieved optimal medical adherence than NSTEMI patients (60% vs. 40%, p ≤ 0.001). In both STEMI and NSTEMI, use of all five indicated drugs was higher in male patients compared with female (STEMI male 61% vs. female 57%, p ≤ 0.001; NSTEMI male 43% vs. female 37%, p ≤ 0.001. With increasing age, a gradual decrease was observed in the use of aspirin, P2Y12-inhibitors and statins. Conclusion Age and gender differences existed in medical adherence after myocardial infarction. Medical adherence was lower in women, young patients and elderly patients, specifically in NSTEMI patients.

Objectives: Surgical left ventricular (LV) restoration (SVR) induces changes in LV systolic and diastolic function that may affect postoperative right ventricular (RV) function. This study aimed to evaluate the long-term effect of SVR on RV function, with specific focus on determinants and prognostic implications of RV dysfunction., Methods: Eighty-six patients (age 60 ± 10 years, 73% male) with clinical and echocardiographic follow-up 2 years after SVR were included. RV dysfunction was defined as RV fractional area change <35%. The association between RV dysfunction at follow-up and clinical and echocardiographic characteristics and outcome was investigated., Results: RV dysfunction at follow-up was present in 40% of patients and was associated with worse preoperative RV fractional area change (39 ± 9 vs 46 ± 7%, P < 0.01), pulmonary hypertension (18 vs 4%, P = 0.03) and higher follow-up LV filling pressures (E/E' ratio 23 ± 8 vs 15 ± 8, P = 0.02). At follow-up, patients with RV dysfunction were more frequently in New York Heart Association Class III or IV (30 vs 12%, P = 0.04) and 5-year mortality, heart transplantation and LV assist device implantation rate was increased (49 vs 17%, P < 0.01) as compared to patients with normal RV function., Conclusions: RV dysfunction after SVR was observed in 40% of patients and was associated with preoperative RV dysfunction, presence of pulmonary hypertension and an increase in LV filling pressures at follow-up. Patients with RV dysfunction after SVR had worse clinical functioning and outcome as compared to patients with normal RV function., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: It has been hypothesized that in response to dilation of the aortic root, the aortic valve cusps may remodel to prevent aortic regurgitation (AR). The aim of the present study was to evaluate the association between aortic cusp dimensions and aortic root geometry., Methods and Results: Three-dimensional transoesophageal echocardiography was performed in 40 patients with aortic root dilation (mean age 57 ± 12 years, 75% men, 35% bicuspid aortic valve) and 20 controls with a normal aortic root (mean age 61 ± 13 years, 65% men). Aortic valve geometry was measured, and the ratio between closed cusp area and sinotubular junction (STJ) area as a measure of the aortic cusp remodelling relative to the aortic root dilation was assessed. Patients with aortic root dilation with tricuspid aortic valve (n = 26) showed significant increase in aortic cusp size. However, the closed cusp area to STJ area ratio was smaller in dilated aortic roots [0.88 (95% confidence interval: 0.78-0.98)] compared with normal aortic roots [1.22 (95% confidence interval: 1.02-1.41); P = 0.002]. In addition, in patients with central AR, there was insufficient cusp tissue, as suggested by a closed cusp area to STJ area ratio of 0.75 (95% confidence interval: 0.67-0.82), compared with relative excess of cusp tissue in eccentric AR with a ratio of 1.14 (95% confidence interval: 1.01-1.27; P < 0.001)., Conclusion: Aortic root dilation was associated with significant increase in aortic valve cusp size. However, this increase seemed insufficient to match aortic root size, particularly in central AR, whereas in eccentric AR, there was relative abundance of cusp tissue resulting in relative cusp prolapse., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: The prevalence of atrial fibrillation (AF) in end-stage renal disease (ESRD) patients is relatively high. The present study evaluated the association between left atrial (LA) remodelling, including an increased size and myocardial fibrosis, and slow LA conduction and the occurrence of AF., Methods: In 171 ESRD patients enrolled in the Implantable Cardioverter Defibrillators in Dialysis patients (ICD2) trial, the LA dimensions, LA conduction delay [as reflected by the time difference between P-wave onset on surface electrocardiogram and A'-wave on tissue Doppler imaging (PA-TDI)] and LA function were compared between patients who exhibited AF versus patients without AF. Based on ICD remote monitoring or clinical records, the occurrence of AF was detected., Results: Of 171 patients, 47 (27%) patients experienced AF. Despite comparable left ventricular ejection fraction and prevalence of significant mitral regurgitation, patients with AF had significantly larger LA volume index (mean ± standard deviation) (29 ± 11 versus 23 ± 10 mL/m2, P = 0.001), longer PA-TDI duration (144 ± 30 versus 131 ± 27 ms, P = 0.010) and reduced late diastolic mitral annular velocity (A') (7.1 ± 2.8 versus 8.2 ± 2.4 cm/s, P = 0.012) compared with patients without AF. On multivariable analysis, larger LA volume index [odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.08, P = 0.017], longer PA-TDI duration (OR 1.02, 95% CI 1.00-1.03, P = 0.025) and reduced A' (OR 0.84, 95% CI 0.72-0.98, P = 0.025) were independently associated with AF after adjusting for age and left ventricle diastolic relaxation., Conclusion: ESRD patients with AF show more advanced changes in the LA substrate than ESRD patients without AF., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Aims: Current treatments of ventricular arrhythmias rely on modulation of cardiac electrical function through drugs, ablation or electroshocks, which are all non-biological and rather unspecific, irreversible or traumatizing interventions. Optogenetics, however, is a novel, biological technique allowing electrical modulation in a specific, reversible and trauma-free manner using light-gated ion channels. The aim of our study was to investigate optogenetic termination of ventricular arrhythmias in the whole heart., Methods and Results: Systemic delivery of cardiotropic adeno-associated virus vectors, encoding the light-gated depolarizing ion channel red-activatable channelrhodopsin (ReaChR), resulted in global cardiomyocyte-restricted transgene expression in adult Wistar rat hearts allowing ReaChR-mediated depolarization and pacing. Next, ventricular tachyarrhythmias (VTs) were induced in the optogenetically modified hearts by burst pacing in a Langendorff setup, followed by programmed, local epicardial illumination. A single 470-nm light pulse (1000 ms, 2.97 mW/mm2) terminated 97% of monomorphic and 57% of polymorphic VTs vs. 0% without illumination, as assessed by electrocardiogram recordings. Optical mapping showed significant prolongation of voltage signals just before arrhythmia termination. Pharmacological action potential duration (APD) shortening almost fully inhibited light-induced arrhythmia termination indicating an important role for APD in this process., Conclusion: Brief local epicardial illumination of the optogenetically modified adult rat heart allows contact- and shock-free termination of ventricular arrhythmias in an effective and repetitive manner after optogenetic modification. These findings could lay the basis for the development of fundamentally new and biological options for cardiac arrhythmia management., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Limited left atrial (LA) surgical ablation with bipolar radiofrequency is considered to be an effective procedure for treatment of atrial fibrillation (AF). We studied whether limited LA surgical ablation concomitant to cardiac surgery is able to maintain LA function., Methods and Results: Thirty-six consecutive patients (age 66 ± 12 years, 53% male, 78% persistent AF) scheduled for valve surgery and/or coronary revascularization and concomitant LA surgical ablation were included. Epicardial pulmonary vein isolation (PVI) and additional endo-epicardial lines were performed using bipolar radiofrequency. An age- and gender-matched control group (n = 36, age 66 ± 9 years, 69% male, 81% paroxysmal AF) was selected from patients undergoing concomitant epicardial PVI only. Left atrial dimensions and function were assessed on two-dimensional echocardiography preoperatively and at 3- and 12-month follow-up. Sinus rhythm (SR) maintenance was 67% for limited LA ablation and 81% for PVI at 1-year follow-up (P = 0.18). Left atrial volume decreased from 72 ± 21 to 50 ± 14 mL (31%, P < 0.01) after limited LA ablation and from 65 ± 23 to 56 ± 20 mL (14%, P < 0.01) after PVI. Atrial transport function was restored in 54% of patients in SR after limited LA ablation compared with 100% of patients in SR after PVI. Atrial strain and contraction parameters (LA ejection fraction, A-wave velocity, reservoir function, and strain rate) significantly decreased after limited LA ablation. After PVI, strain and contraction parameters remained unchanged., Conclusion: Even limited LA ablation decreased LA volume, contraction, transport function, and compliance, indicating both reverse remodelling combined with significant functional deterioration. In contrast, surgical PVI decreased LA volume while function remained unchanged., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objectives: Vasoplegia has been described as a complication after cardiac surgery, particularly in patients with a poor left ventricular ejection fraction. The aim of this study was to assess the incidence, survival and predictors of vasoplegia in patients undergoing heart failure surgery and to propose a risk model., Methods: A retrospective study including heart failure patients who underwent surgical left ventricular restoration, CorCap implantation or left ventricular assist device implantation between 2006 and 2015. Patients were classified by the presence or absence of vasoplegia., Results: Two hundred and twenty-five patients were included. The incidence of vasoplegia was 29%. The 90-day survival rate in vasoplegic patients was lower compared with non-vasoplegic patients (71% vs 91%, P  <   0.001). After adjusting for age, sex and surgical procedure, anaemia (OR 2.195; 95% CI 1.146, 4.204; P  =   0.018) and a higher thyroxine level (OR 1.140; 95% CI 1.033, 1.259; P  =   0.009) increased the risk of vasoplegia; a higher creatinine clearance (OR 0.980; 95% CI 0.965, 0.994; P  =   0.006) and beta-blocker use (OR 0.257; 95% CI 0.112, 0.589; P  =   0.001) decreased the risk. The risk model consisted of the same variables and could adequately identify patients at risk for vasoplegia., Conclusions: Vasoplegia after heart failure surgery is common and results in a lower survival rate. Anaemia and a higher thyroxine level are associated with an increased risk on vasoplegia. In contrast, a higher creatinine clearance and beta-blocker use decrease the risk on vasoplegia. These factors are used in the risk model that may guide treatment strategy., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: Implantable cardioverter-defibrillator (ICD) treatment is beneficial in selected patients. However, it remains difficult to accurately predict which patients benefit most from ICD implantation. For this purpose, different risk models have been developed. The aim was to validate and compare the FADES, MADIT, and SHFM-D models., Methods and Results: All patients receiving a prophylactic ICD at the Leiden University Medical Center were evaluated. Individual model performance was evaluated by C-statistics. Model performances were compared using net reclassification improvement (NRI) and integrated differentiation improvement (IDI). The primary endpoint was non-benefit of ICD treatment, defined as mortality without prior ventricular arrhythmias requiring ICD intervention. A total of 1969 patients were included (age 63 ± 11 years; 79% male). During a median follow-up of 4.5 ± 3.9 years, 318 (16%) patients died without prior ICD intervention. All three risk models were predictive for event-free mortality (all: P < 0.001). The C-statistics were 0.66, 0.69, and 0.75, respectively, for FADES, MADIT, and SHFM-D (all: P < 0.001). Application of the SHFM-D resulted in an improved IDI of 4% and NRI of 26% compared with MADIT; IDI improved 11% with the use of SHFM-D instead of FADES (all: P < 0.001), but NRI remained unchanged (P = 0.71). Patients in the highest-risk category of the MADIT and SHFM-D models had 1.7 times higher risk to experience ICD non-benefit than receive appropriate ICD interventions [MADIT: mean difference (MD) 20% (95% CI: 7-33%), P = 0.001; SHFM-D: MD 16% (95% CI: 5-27%), P = 0.005]. Patients in the highest-risk category of FADES were as likely to experience ICD intervention as ICD non-benefit [MD 3% (95% CI: -8 to 14%), P = 0.60]., Conclusion: The predictive and discriminatory value of SHFM-D to predict non-benefit of ICD treatment is superior to FADES and MADIT in patients receiving prophylactic ICD treatment., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.)

Aims: Multidetector row computed tomography (MDCT) may help to understand the underlying mechanisms of functional tricuspid regurgitation (TR), a highly prevalent valve disease with novel transcatheter therapies under development. The purpose of the present study was to assess the geometrical changes of the tricuspid valve in patients with functional TR using MDCT and to correlate these changes with the TR grade assessed with echocardiography., Methods and Results: In 114 patients undergoing transcatheter aortic valve implantation (47 men, age 81 ± 8 years), including 33 (28.9%) patients with TR ≥ 3+, the tricuspid valve and right ventricle (RV) were geometrically analysed with 320-slice MDCT. The antero-posterior and septal-lateral diameters, perimeter and area of the annulus, degree of tethering of the anterior, septal and posterior tricuspid valve leaflets, and RV volumes and ejection fraction were assessed and subsequently correlated with TR grade in multivariate models. Patients with pacemaker or implantable cardioverter defibrillator leads were excluded.Patients with TR ≥ 3+ had larger tricuspid annulus area (1539.7 ± 260.2 vs.1228.4 ± 243.5 mm(2), P < 0.001), larger septal and anterior leaflet angles, and larger RV end-systolic volumes (93.2 ± 29.8 vs. 64.2 ± 23.6 mL, P < 0.001) compared with patients with TR < 3+.The antero-posterior tricuspid annulus diameter was independently correlated with TR ≥ 3+ (odds ratio 1.35; 95% confidence interval 1.07-1.69, P = 0.010), after adjusting for estimated pulmonary pressure and RV end-systolic volume., Conclusion: In patients with TR ≥ 3+, MDCT demonstrated larger tricuspid annulus and RV dimensions and pronounced tethering of the anterior and septal tricuspid leaflet. The antero-posterior annulus diameter was independently correlated with the grade of functional TR., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Objectives: Selection of tubular graft size during David reimplantation technique for aortic root dilatation is based on perioperative leaflet height measurements. The present study evaluated whether transthoracic echocardiography (TTE)-based algorithms may help in selecting the graft size preoperatively., Methods: Thirty patients (52 ± 11 years old, 73% men) who underwent David reimplantation technique were evaluated. The implanted graft size was based on the David's formula. Leaflet height [diameter = 1.1 × ((2 × 2/3 × leaflet height) + 2)), leaflet length (diameter = ((2 × 2/3 × leaflet length) + 2)] and leaflet area [diameter = 0.8 × ((2 × √(total leaflet area/π)) + 2)] TTE-derived formulas were retrospectively developed. The percentage of under- or oversized implanted grafts was calculated and the association between the adequacy of graft sizing using TTE-derived formulas and the incidence of residual aortic regurgitation (AR) was evaluated retrospectively., Results: The incidence of postoperative mild residual AR was 23%. The true diameter of the inplanted graft was oversized based on leaflet height in 15 (50%) patients, based on leaflet length in 13 (43%) patients and based on leaflet area TTE-derived formula in 11 (37%) patients. The incidence of mild AR was significantly lower in undersized grafts compared with oversized grafts based on leaflet length TTE-derived formula (6 vs 46%, P = 0.032) and leaflet area TTE-derived formula (5 vs 55%, P = 0.009)., Conclusions: In patients undergoing David reimplantation technique, grafts considered undersized according to the leaflet length or leaflet area TTE-derived formula were associated with less incidence of residual AR than patients with oversized grafts., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: Electrical reconnection after pulmonary vein (PV) isolation is associated with atrial fibrillation (AF) recurrence. Reconnection may already develop within a 30 min waiting period and may only occur as dormant conduction (DC) revealed by adenosine infusion. This study determines incidence and predictors of DC after cryoballoon ablation incorporating a 30 min waiting period and the effect of treating this 'late' DC on 1 year AF-recurrence., Methods and Results: Consecutive patients scheduled for a first ablation were prospectively included. Intravenous adenosine was administered 30 min after PV isolation to unmask DC (adenosine+). Additional applications were performed to abolish DC. Atrial fibrillation recurrence was evaluated after 3, 6, and 12 months with ECG and 24 h Holter recordings. Results were compared with a prior group of consecutive patients that underwent cryoablation without DC testing (adenosine-). The adenosine+ group consisted of 36 patients (78% male, 61 ± 10 years, paroxysmal AF 86%). ***Dormant conduction was found in 42% of patients (15/36) and 14% of PVs (20/143). Multivariate analysis showed that PV isolation during the first freeze independently reduced DC risk (OR = 0.064, P < 0.01). After 12 ± 1 months, 11 (83%) of adenosine+ patients had no AF-recurrences, compared with 37 (60%) of adenosine- patients (n = 62, 70% male, 59 ± 11 years, 90% paroxysmal AF, P = 0.02). Ablation with DC treatment independently reduced the risk of AF-recurrence (OR = 0.26, P = 0.02)., Conclusion: Incorporating a 30-min waiting period after cryoballoon ablation increases the incidence of DC compared with previous results. Absence of PV isolation during the first freeze is associated with an increased risk of late DC. Treatment of this DC seems to improve outcome., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: The aim of this study was to characterize left ventricular (LV) mechanics in symptomatic and asymptomatic patients with moderate-to-severe or severe aortic regurgitation (AR) and preserved ejection fraction (left ventricular ejection fraction) using two-dimensional speckle tracking echocardiography (2D-STE). The association between baseline LV strain and development of indications for surgery in asymptomatic patients was also evaluated., Methods and Results: A total of 129 patients with moderate-to-severe or severe AR and LVEF >50% (age 55 ± 17 years, 64% male, 53% asymptomatic at baseline) were included. Standard echocardiography and 2D-STE were performed at baseline. Compared with asymptomatic patients, symptomatic patients had significantly impaired LV longitudinal (-14.9 ± 3.0 vs. -16.8 ± 2.5%, P < 0.001), circumferential (-17.5 ± 2.9 vs. -19.3 ± 2.8%, P = 0.001), and radial (35.7 ± 12.2 vs. 43.1 ± 14.7%, P = 0.004) strains. Among 49 asymptomatic patients who were followed up, 26 developed indications for surgery (symptoms onset or LVEF ≤50%). These patients had comparable LV volumes, LVEF, and colour Doppler assessments of AR jet at baseline, but more impaired LV longitudinal (P = 0.009) and circumferential (P = 0.017) strains compared with patients who remained asymptomatic. Impaired baseline LV longitudinal (per 1% decrease, HR = 1.21, P = 0.04) or circumferential (per 1% decrease, HR = 1.22, P = 0.04) strain was independently associated with the need for surgery., Conclusion: Multidirectional LV strain was more impaired in symptomatic than in asymptomatic patients with moderate-to-severe or severe AR, despite preserved LVEF. In asymptomatic AR patients, longitudinal and circumferential strains identified patients who would require surgery during follow-up., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: Prognostic importance of coronary vessel dominance in patients with ST-elevation myocardial infarction (STEMI) remains uncertain. The aim of this study was to assess influence of coronary vessel dominance on the short- and long-term outcome after STEMI., Methods and Results: Coronary angiographic images of consecutive patients presenting with first STEMI were retrospectively reviewed to assess coronary vessel dominance. Patients were followed after STEMI during a median period of 48 (IQR38-61) months for the occurrence of all-cause mortality and the composite of reinfarction and cardiac death. The population comprised 1131 patients of which 971 (86%) patients had a right dominant, 102 (9%) a left dominant, and 58 (5%) a balanced system. After 5 years of follow-up, the cumulative incidence of all-cause mortality was significantly higher in patients with a left dominant system, compared with a right dominant and balanced system (log-rank P = 0.013). Moreover, a left dominant system was an independent predictor for 30-day mortality (OR 2.51, 95% CI 1.11-5.67, P = 0.027) and the composite of reinfarction and cardiac death within 30-days after STEMI (OR 2.25, 95% CI 1.09-4.61, P = 0.028). In patients surviving first 30-days post-STEMI, coronary vessel dominance had no influence on long-term outcome., Conclusions: A left dominant coronary artery system is associated with a significantly increased risk of 30-day mortality and early reinfarction after STEMI. After surviving the first 30-days post-STEMI, coronary vessel dominance had no influence on long-term outcome., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Currently several extraction tools are available in order to allow safe and successful transvenous lead extraction (TLE) of pacemaker and ICD leads; however, no directives exist to guide physicians in their choice of extraction tools and approaches. To aim of the current review is to provide an overview of the success and complication rates of different extraction methods and tools available. A comprehensive search of all published literature was conducted in the databases of PubMed, Embase, Web of Science, and Central. Included papers were original articles describing a specific method of TLE and the corresponding success rates of at least 50 patients. Fifty-three studies were included; the majority (56%) utilized 2 (1-4) different venous extraction approaches (subclavian and femoral), the median number of extraction tools used was 3 (1-6). A stepwise approach was utilized in the majority of the studies, starting with simple traction which resulted in successful TLE in 7-85% of the leads. When applicable the procedure was continued with non-powered tools resulting in a successful extraction of 34-87% leads. Subsequently, powered tools were applied whereby success rates further increased to 74-100%. The final step in TLE was usually utilized by femoral snare leading to an overall TLE success rate of 96-100%. The median procedure-related mortality and major complication described were, respectively, 0% (0-3%) and 1% (0-7%) per patient. In conclusion, a stepwise extraction approach can result in a clinical successful TLE in up to 100% of the leads with a relatively low risk of procedure-related mortality and complications., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Recently, it has been hypothesized that mitral leaflet remodelling may play a role in the pathophysiology of functional mitral regurgitation (FMR). We investigated the characteristics, determinants, and relation of mitral leaflet remodelling to FMR severity., Methods and Results: Three-dimensional transoesophageal echocardiographic data of the mitral valve (MV) were studied in 30 patients with FMR ≥ grade 3 (≥3), 24 patients with FMR < grade 3 (<3), and 22 controls with normal MV. FMR <3 and ≥3 patients showed leaflet remodelling compared with control subjects with larger overall MV leaflet areas (11.47 ± 3.16 and 9.58 ± 1.99 vs. 7.30 ± 1.57 cm(2)/m(2), respectively; all P < 0.01). Tenting volume (r(2) = 0.55), left ventricular (LV) ejection fraction (r(2) = 0.20), annulus area (r(2) = 0.87), and LV sphericity index (r(2) = 0.25) were correlated with overall MV leaflet area (all P < 0.001). Although these correlates were similar between FMR <3 and ≥3 patients (all P > 0.05), the overall MV leaflet area was smaller in FMR ≥3 compared with FMR <3 patients (P = 0.01), indicating less remodelling despite similar tethering degree. Particularly, coaptation/overall MV leaflet area ratio ≤0.24, reflecting insufficient leaflet remodelling, was associated with FMR ≥3 [area under receiver operating characteristic (ROC) curve = 0.93, sensitivity 90%, and specificity 91%]. This ratio was independently associated with FMR ≥3 (odds ratio 70.0, 95% confidence interval 11.7-419.9, P < 0.001) and showed significant correlation with effective regurgitant orifice area (r(2) = 0.38, P < 0.001)., Conclusion: MV leaflet remodelling in FMR is common and relates to LV function, LV sphericity, MV tenting volume, and annulus dilatation. Insufficient leaflet remodelling relative to the mitral annular and LV changes is independently associated with FMR severity., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

A thorough understanding of the developmental signals that direct pluripotent stem cells (PSCs) toward a cardiac fate is essential for translational applications in disease modeling and therapy. We screened a panel of 44 cytokines/signaling molecules for their ability to enhance Nkx2.5(+) cardiac progenitor cell (CPC) formation during in vitro embryonic stem cell (ESC) differentiation. Treatment of murine ESCs with insulin or insulin-like growth factors (IGF1/2) during early differentiation increased mesodermal cell proliferation and, consequently, CPC formation. Furthermore, we show that downstream mediators of IGF signaling (e.g., phospho-Akt and mTOR) are required for this effect. These data support a novel role for IGF family ligands to expand the developing mesoderm and promote cardiac differentiation. Insulin or IGF treatment could provide an effective strategy to increase the PSC-based generation of CPCs and cardiomyocytes for applications in regenerative medicine., (© 2014 AlphaMed Press.)

Background: The spatial QRS-T angle describes the relation between ventricular depolarization and repolarization. Having a wide (abnormal) angle is considered an important predictor of arrhythmic events. Given the high incidence of sudden cardiac death in dialysis patients, this parameter is of particular interest in this patient group. The objective of this study was to assess the association of (modifiable) echocardiographic parameters and an abnormal spatial QRS-T angle in dialysis patients., Methods: A total of 94 consecutive dialysis patients were included. In all patients a 12-lead electrocardiogram (ECG), a two-dimensional echocardiogram and routine blood samples were obtained. The spatial QRS-T angle was then calculated from the 12-lead ECG. An abnormal spatial QRS-T angle was defined as ≥130° in males and ≥116° in females., Results: An abnormal spatial QRS-T angle was present in 27 (29%) patients. Patients with an abnormal spatial angle had a lower left ventricular ejection fraction (LVEF) of 47 ± 7 versus 55 ± 6% (P < 0.001) and had a higher left ventricular (LV) dyssynchrony, with a septal to lateral (S-L) delay of peak systolic velocity of 70 inter quartile range (iIQR) (40, 100) ms versus 30 IQR (10, 70) ms (P = 0.001), respectively. Multivariate logistic regression analysis controlling for possible confounders demonstrated that LVEF [odds ratio (OR) 0.82; 95% confidence interval (CI) 0.72-0.93, P = 0.001] and LV dyssynchrony (OR 1.19 per 10 ms; 95% CI 1.03-1.38, P = 0.02) were independent determinants of an abnormal spatial QRS-T angle in this patient group., Conclusions: LVEF and dyssynchrony are echocardiographic determinants of an abnormal spatial QRS-T angle in dialysis patients and might therefore represent a potential target for the prevention of sudden cardiac death in these patients.

Background: Clinical or echocardiographic mid-term responses to cardiac resynchronization therapy (CRT) may have a different influence on a long-term prognosis of heart failure patients treated with CRT. The aim of the evaluation was to establish which definition of response to CRT, clinical or echocardiographic, best predicts long-term prognosis., Methods and Results: A total of 679 heart failure patients treated with CRT were included. All the patients underwent a complete history and physical examination and transthoracic echocardiogram prior to CRT implantation and at 6-month follow-up. The clinical and echocardiographic responses to CRT were defined based on clinical improvement (≥1 NYHA class) and LV reverse remodelling (reduction in LV end-systolic volume ≥15%) at 6-month follow-up, respectively. All the patients were prospectively followed up for the occurrence of death. The mean age was 65 ± 11 years and 79% of the patients were male. At 6-month follow-up, 510 (77%) patients showed clinical response to CRT and 412 (62%) patients showed echocardiographic response to CRT. During a mean follow-up of 37 ± 22 months, 140 (21%) patients died. Clinical and echocardiographic responses to CRT were both significantly related to all-cause mortality on univariable analysis. However, on multivariable Cox-regression analysis only echocardiographic response to CRT was independently associated with superior survival (hazard ratio: 0.38; 95% CI: 0.27-0.50; P < 0.001)., Conclusion: In a large population of heart failure patients treated with CRT, the reduction in LV end-systolic volume at the mid-term follow-up demonstrated to be a better predictor of long-term survival than improvement in the clinical status.

Aims: A novel duty-cycled bipolar/unipolar ablation catheter pulmonary vein ablation catheter (PVAC) has been developed to achieve pulmonary vein (PV) isolation in patients with atrial fibrillation (AF). Ablation with PVAC was recently found to induce PV narrowing at 3 months follow-up. The long-term effects of this catheter on PV dimensions are however unknown and were evaluated with this study., Methods and Results: Patients (n = 62, 71% male, age 60 ± 7 years) with drug-refractory AF scheduled for a first ablation procedure were evaluated. A multi-slice computed tomography (MSCT) scan was performed before and 1 year after the initial procedure. Pulmonary vein dimensions and left atrial (LA) volume were measured on MSCT. To correct for reverse remodelling of the LA, the ostial area/LA volume ratio before and after PVAC was calculated. As reverse remodelling may depend on procedural outcome, patients were divided in two groups depending on sinus rhythm (SR) maintenance or AF recurrence 1 year after ablation. Baseline characteristics were comparable between the SR group (n = 41) and the AF recurrence group (n = 21). At one year follow-up, ostial area of the PVs (n = 219) was significantly reduced from 236 ± 7.0 to 173 ± 7.4 mm(2) (27% narrowing, P < 0.01), independent of ablation outcome. Pulmonary vein narrowing was mild in 37% of PVs (25-50%), 9% was moderate (50-70%), and 3% severe (>70%). Left atrial volumes were found to be significantly reduced after ablation (14 and 5% for the SR group and AF recurrence group, respectively, P < 0.01). After adjustment for LA volume reduction, narrowing of PV ostial area remained significant in these patients (P < 0.01)., Conclusion: Ablation with PVAC results in a significant decrease in PV dimensions after long-term follow-up. In line with previous literature, PV narrowing was mild and patients did not develop any clinical symptoms.

Aims: Coronary atherosclerosis has been associated with the development of atrial fibrillation (AF). However, little is known about the impact of coronary atherosclerosis on the outcome treatment of AF. The aim of this study was to investigate the impact of coronary atherosclerosis on the efficacy of radiofrequency catheter ablation (RFCA) for AF using multi-detector row computed tomography (MDCT)., Methods: In 125 consecutive patients undergoing RFCA for AF, a pre-procedural MDCT examination (coronary angiography and/or coronary calcium score) was performed to evaluate the presence and severity of coronary atherosclerosis. Furthermore, all patients underwent a comprehensive echocardiographic evaluation to measure the left atrial size and to rule out structural heart disease. After RFCA all patients were regularly evaluated at the outpatient clinic., Results: After a mean follow-up of 12 ± 3 months, 78 patients (62%) had maintained stable sinus rhythm and 47 patients (38%) had recurrence of AF. Left atrial volume index was a significant predictor of AF recurrence after RFCA. The presence of coronary atherosclerosis on MDCT did not influence the efficacy of RFCA for AF., Conclusions: The presence of coronary atherosclerosis on MDCT is not associated with a higher risk for AF recurrence after RFCA.

Aims: During epicardial electroanatomical mapping (EAM), it is difficult to differentiate between fibrosis and fat, as both exhibit attenuated bipolar voltage (BV). The purpose of this study was to assess whether unipolar voltage (UV), BV, and electrogram characteristics (EC) can distinguish fibrosis from viable myocardium and fat during epicardial EAM for ventricular tachycardia (VT) ablation in non-ischaemic cardiomyopathy (NICM)., Methods and Results: Ten NICM patients (7 males, 56 ± 13 years) with VT underwent epicardial EAM with real-time integration of computed tomography-derived epicardial fat and contrast-enhanced MRI-derived scar. Bipolar voltage (filtered 30-400 Hz), UV (filtered 1-240 Hz), and EC (duration and morphology) were correlated with the presence of fat and scar. At sites devoid of fat, the optimal cutoff values to differentiate between scar and myocardium were 1.81 mV for BV and 7.95 mV for UV. Bipolar voltage, UV, and electrogram duration >50 ms distinguished scar from myocardium in areas covered with <2.8 mm fat (all P < 0.001), but not ≥ 2.8 mm fat. In contrast, electrogram morphology-characteristics could also detect scar covered with ≥ 2.8 mm fat (P = 0.001). A newly developed three-step algorithm combining electrogram morphology, duration, and UV could correctly identify scar with a sensitivity of 75%. Unipolar voltage but not BV could detect intramural scar in the absence of fat., Conclusions: Both BV ≤ 1.81 mV and UV ≤ 7.95 mV are useful for detection of scar during epicardial EAM, in the absence of ≥ 2.8 mm fat. However, EC can be used to detect scar covered with fat. A newly developed algorithm combining UV and EC can differentiate between scar and viable myocardium. Unipolar voltage but not BV could detect intramural scar.

Aims: In order to improve the abysmal outcome of dialysis patients, it is critical to identify patients with a high mortality risk. The spatial QRS-T angle, which can be easily calculated from the 12 lead electrocardiogram (ECG), might be useful in the prognostication in dialysis patients. The objective of this study was to establish the prognostic value of the spatial QRS-T angle., Methods and Results: All patients who initiated dialysis therapy between 2002 and 2009 in the hospitals of Leiden (LUMC) and Amsterdam (AMC) at least 3 months on dialysis were included. The spatial QRS-T angle was calculated, from a routinely acquired ECG, and its relationship with mortality was assessed. An abnormal spatial QRS-T angle was defined as ≥ 130° in men and ≥ 116° in women. In total, 277 consecutive patients (172 male, mean age 56.3 ± 17.0) were included. An abnormal spatial QRS-T angle was associated with a higher risk of death from all causes [hazard ratio (HR) 2.33; 95% confidence interval (CI) 1.46-3.70] and especially a higher risk of sudden cardiac death (HR 2.99; 95% CI 1.04-8.60). Furthermore, an abnormal spatial QRS-T angle was of incremental prognostic value, when added to a risk model consisting of known risk factors., Conclusion: In chronic dialysis patients the spatial QRS-T angle is a significant and independent predictor of all-cause and especially sudden cardiac death. It implies that this parameter can be used to identify high risk patients.

Aims: Despite a successful surgical procedure and adherence to current recommendations, postoperative left ventricular (LV) dysfunction after mitral valve repair (MVr) for organic mitral regurgitation (MR) may still occur. New approaches are therefore needed to detect subclinical preoperative LV dysfunction. LV global longitudinal strain (GLS), assessed with speckle-tracking echocardiographic analysis, has been proposed as a novel measure to better depict latent LV dysfunction. The aim of this study was to investigate the value of GLS to predict long-term LV dysfunction after MVr., Methods and Results: A total of 233 patients (61% men, 61 ± 12 years) with moderate-severe organic MR who underwent successful MVr between 2000 and 2009 were included. Echocardiography was performed at baseline and long-term follow-up (34 ± 20 months) after MVr. LV dysfunction at follow-up was defined as LV ejection fraction (EF) <50% and was present in 29 (12%) patients. A cut-off value of -19.9% of GLS showed a sensitivity and specificity of 90 and 79% to predict long-term LV dysfunction. By univariate logistic regression analysis, baseline LVEF ≤60%, LV end-systolic diameter (ESD) ≥40 mm, atrial fibrillation, presence of symptoms, and GLS >-19.9% were predictors of long-term LV dysfunction. By multivariate analysis, GLS remained an independent predictor of LV dysfunction (odds ratio 23.16, 95% confidence interval: 6.53-82.10, P < 0.001), together with LVESD., Conclusion: In a large series of patients operated within the last decade, MVr resulted in a low incidence of long-term LV dysfunction. A GLS of >-19.9% demonstrated to be a major independent predictor of long-term LV dysfunction after adjustment for parameters currently implemented into guidelines.

Aims: The relationship between temporal changes in left ventricular (LV) dyssynchrony and LV functional recovery after acute myocardial infarction (MI) remains unclear. Accordingly, the aim of the present study was to evaluate the temporal evolution of LV synchronicity after acute MI, and to explore the relationship between changes in LV systolic function and LV synchronicity., Methods and Results: In 193 patients with a first acute MI, LV dyssynchrony (SDI) and global systolic function were evaluated with real-time three-dimensional echocardiography 48 h after percutaneous coronary intervention and at 6 months follow-up. Changes in LV systolic function and synchronicity were evaluated at the follow-up and the relationship between these changes was explored. A total of 59 (40%) patients had an anterior acute MI. Median peak value of troponin T was 2.97 µg/L (1.41-6.06 µg/L). Mean LVEF was 47 ± 8% and mean SDI was 5.01 ± 2.10%, respectively. At 6 months follow-up, a significant improvement in LVEF (50 ± 9 vs. 47 ± 8%; P < 0.001) and SDI (4.52 ± 1.97 vs. 5.01 ± 2.10%; P = 0.003) was noted. A strong correlation was found between LVEF change and SDI change (β = -0.63; P < 0.001). At multivariate analysis, SDI change was an independent factor associated with changes in LVEF. Importantly, an addition of SDI change to the multivariate model significantly increased the R(2) from 0.41 to 0.57 (F change 49.0, P < 0.001)., Conclusion: A temporal evolution of LV synchronicity was observed after a first, mechanically reperfused, acute MI. The reduction in LV dyssynchrony independently influenced LV functional recovery in these patients.

Cardiomyogenic differentiation of stem cells can be accomplished by coculture with cardiomyocytes (CMCs). To facilitate their identification, stem cells are often labeled through viral transduction with a fluorescent protein. A second marker to distinguish stem cell-derived CMCs from native CMCs is rarely used. This study aimed to investigate the occurrence of secondary transduction of unlabeled neonatal rat (nr) CMCs after coculture with human cells that had been transduced 0, 7, or 14 days earlier with a vesicular stomatitis virus (VSV) G protein-pseudotyped lentiviral vector (LV) encoding enhanced green fluorescent protein (GFP). To reduce secondary LV transfer, GFP-labeled cells were incubated with non-heat-inactivated human serum (NHI) or with VSV-neutralizing rabbit serum (αVSV). Heat-inactivated human serum and normal rabbit serum were used as controls. Immunostaining showed substantial GFP gene transfer to nrCMCs in cocultures started at the day of transduction indicated by the presence of GFP-positive/human lamin A/C-negative nrCMCs. The extent of secondary transduction was significantly reduced in cocultures initiated 7 days after GFP transduction, while it was completely abolished when human cells were added to nrCMCs 14 days post-transduction. Both NHI and αVSV significantly reduced the occurrence of secondary transduction compared to their controls. However, under all circumstances, GFP-labeled human cells had to be passaged for 14 days prior to coculture initiation to prevent any horizontal GFP gene transfer to the nrCMCs. This study emphasizes that differentiation experiments involving the use of viral vector-marked donor cells should be interpreted with caution and describes measures to reduce/prevent secondary transduction., (Copyright © 2012 AlphaMed Press.)

Aims: The aims of this study were: (i) to characterize consecutive cardiac resynchronization therapy (CRT) recipients with right bundle branch block (RBBB) in comparison with left bundle branch block (LBBB) and (ii) to identify independent predictors of long-term outcome among CRT recipients with RBBB. The presence of RBBB has been associated with poorer prognosis after CRT compared with LBBB; however, little is known about the differences in cardiac mechanics between RBBB and LBBB patients. Furthermore, predictors of favourable outcome after CRT in patients with RBBB have not been identified., Methods and Results: Five hundred and sixty-one consecutive CRT recipients (89 with RBBB and 472 with LBBB) underwent echocardiography before and 6 months after CRT to determine left ventricular (LV) size and function, and interventricular and LV dyssynchrony (as measured by tissue Doppler imaging). Long-term follow-up to identify a composite endpoint of all-cause mortality or heart failure hospitalization was available. Right bundle branch block patients exhibited a higher prevalence of male gender, ischaemic heart disease, atrial fibrillation, and lower exercise capacity when compared with LBBB patients, despite smaller LV volumes. In addition, the extent of both interventricular and LV dyssynchrony was less in RBBB patients. Six months after CRT, RBBB patients also showed limited LV reverse remodelling. At long-term follow-up, LV dyssynchrony and mitral regurgitation were identified as independent predictors of all-cause mortality or heart failure hospitalization among RBBB patients., Conclusion: Left ventricular dyssynchrony may be an important determinant of outcome following CRT in patients with RBBB and may help in the selection of CRT candidates.

Aims: Limited information is available regarding the relationship between coronary vessel dominance and prognosis. Therefore, the purpose of this study was to determine the prognostic value of coronary vessel dominance in relation to significant coronary artery disease (CAD) in patients referred for computed tomography coronary angiography (CTA)., Methods and Results: The study population consisted of 1425 patients (869 men, 57 ± 12 years) referred for CTA. To evaluate the impact of vessel dominance and significant CAD on CTA on outcome, patients were followed during a median period of 24 months for the occurrence of non-fatal myocardial infarction and all-cause mortality. The presence of a left dominant system was identified as a significant predictor for non-fatal myocardial infarction and all-cause mortality (HR: 3.20; 95% CI: 1.67-6.13, P < 0.001) and had incremental value over baseline risk factors and severity of CAD on CTA. In addition, in the subgroup of patients with significant CAD on CTA, patients with a left dominant system had a worse outcome compared with patients with a right dominant system (cumulative event rates: 9.5% and 35% at 3-year follow-up for a right and left dominant coronary artery system, respectively, log-rank P < 0.001)., Conclusions: The presence of a left dominant system was identified as an independent predictor of non-fatal myocardial infarction and all-cause mortality, especially in patients with significant CAD on CTA. Therefore, the assessment of coronary vessel dominance on CTA may further enhance risk stratification beyond the assessment of significant CAD on CTA.

Gap junctional coupling is important for functional integration of transplanted cells with host myocardium. However, the role of gap junctions in cardiomyogenic differentiation of transplanted cells has not been directly investigated. The objective of this work is to study the role of connexin43 (Cx43) in cardiomyogenic differentiation of human mesenchymal stem cells (hMSCs). Knockdown of Cx43 gene expression (Cx43↓) was established in naturally Cx43-rich fetal amniotic membrane (AM) hMSCs, while Cx43 was overexpressed (Cx43↑) in inherently Cx43-poor adult adipose tissue (AT) hMSCs. The hMSCs were exposed to cardiomyogenic stimuli by coincubation with neonatal rat ventricular cardiomyocytes (nrCMCs) for 10 days. Differentiation was assessed by immunostaining and whole-cell current clamping. To establish whether the effects of Cx43 knockdown could be rescued, Cx45 was overexpressed in Cx43↓ fetal AM hMSCs. Ten days after coincubation, not a single Cx43↓ fetal AM hMSC, control adult AT MSC, or Cx43↑ adult AT mesenchymal stem cell (MSC) expressed α-actinin, while control fetal AM hMSCs did (2.2% ± 0.4%, n = 5,000). Moreover, functional cardiomyogenic differentiation, based on action potential recordings, occurred only in control fetal AM hMSCs. Of interest, Cx45 overexpression in Cx43↓ fetal AM hMSCs restored their ability to undergo cardiomyogenesis (1.6% ± 0.4%, n = 2,500) in coculture with nrCMCs. Gap junctional coupling is required for differentiation of fetal AM hMSCs into functional CMCs after coincubation with nrCMCs. Heterocellular gap junctional coupling thus plays an important role in the transfer of cardiomyogenic signals from nrCMCs to fetal hMSCs but is not sufficient to induce cardiomyogenic differentiation in adult AT hMSCs., (Copyright © 2012 AlphaMed Press.)