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Left ventricular assist devices (LVADs) are gaining increasing importance as therapeutic strategy in advanced heart failure (HF), not only as bridge to recovery or to transplant, but also as destination therapy. Even though long-term LVADs are considered a precious resource to expand the treatment options and improve clinical outcome these patients, these are limited by peri-operative and post-operative complications, such as device-related infections, haemocompatibility-related events, device mispositioning and right ventricular failure. For this reason, a precise pre-operative, peri-operative and post-operative evaluation of these patients is crucial for the selection of LVADs candidates and the management LVADs recipients. The use of different imaging modalities offers important information to complete the study of patients with LVADs in each phase of their assessment, with peculiar advantages/disadvantages, ideal application and reference parameters for each modality. This clinical consensus statement sought to guide the use of multimodality imaging for the evaluation of patients with advanced HF undergoing LVADs implantation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) inhibitor pathway with immune checkpoint blockade have shown promising outcomes in managing metastatic renal cancer. However, they increase the risk of a person developing high blood pressure and cardiovascular complications., Case Summary: In this study, we report the case of a 73-year-old woman on axitinib and pembrolizumab for her Stage 4 renal cell carcinoma. She presented with intractable chest pain and high systolic blood pressure, not responding to opiates. Her computed tomography angiography results showed an acute intra-mural haematoma with a rupture in the descending thoracic aorta. She underwent emergency thoracic endovascular aortic repair. Post-operatively, she recovered fully without any neurological or cardiovascular issues., Discussion: The severity of cardiovascular haemodynamic complications arising from the consumption of VEGF inhibitors and from immunotherapy and the lack of anti-hypertensive strategies to adequately manage such events require an unequivocal and urgent assessment of their cardiovascular safety. This case highlights the crucial role of cardiovascular oncology in managing such acute aortic catastrophes., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The role of cardiac implantable electronic device (CIED)-related tricuspid regurgitation (TR) is increasingly recognized as an independent clinical entity. Hence, interventional TR treatment options continuously evolve, surgical risk assessment and peri-operative care improve the management of CIED-related TR, and the role of lead extraction is of high interest. Furthermore, novel surgical and interventional tricuspid valve treatment options are increasingly applied to patients suffering from TR associated with or related to CIEDs. This multidisciplinary review article developed with electrophysiologists, interventional cardiologists, imaging specialists, and cardiac surgeons aims to give an overview of the mechanisms of disease, diagnostics, and proposes treatment algorithms of patients suffering from TR associated with CIED lead(s) or leadless pacemakers., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Early right-sided heart failure (RHF) was seen in 22% of recipients of a left ventricular assist device (LVAD) in the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). However, the optimal treatment of post-LVAD RHF is not well known. Levosimendan has proven to be effective in patients with cardiogenic shock and in those with end-stage heart failure. We sought to evaluate the efficacy of levosimendan on post-LVAD RHF and 30-day and 1-year mortality., Methods: The EUROMACS Registry was used to identify adults with mainstream continuous-flow LVAD implants who were treated with preoperative levosimendan compared to a propensity matched control cohort., Results: In total, 3661 patients received mainstream LVAD, of which 399 (11%) were treated with levosimendan pre-LVAD. Patients given levosimendan had a higher EUROMACS RHF score [4 (2- 5.5) vs 2 (2- 4); P < 0.001], received more right ventricular assist devices (RVAD) [32 (8%) vs 178 (5.5%); P = 0.038] and stayed longer in the intensive care unit post-LVAD implant [19 (8-35) vs 11(5-25); P < 0.001]. Yet, there was no significant difference in the rate of RHF, 30-day, or 1-year mortality. Also, in the matched cohort (357 patients taking levosimendan compared to an average of 622 controls across 20 imputations), we found no evidence for a difference in postoperative severe RHF, RVAD implant rate, length of stay in the intensive care unit or 30-day and 1-year mortality., Conclusions: In this analysis of the EUROMACS registry, we found no evidence for an association between levosimendan and early RHF or death, albeit patients taking levosimendan had much higher risk profiles. For a definitive conclusion, a multicentre, randomized study is warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Data on the impact and course of uncorrected tricuspid regurgitation (TR) during left ventricular assist device (LVAD) implantation are scarce and inconsistent. This study explores the clinical impact and natural course of uncorrected TR in patients after LVAD implantation., Methods: The European Registry for Patients with Mechanical Circulatory Support was used to identify adult patients with LVAD implants without concomitant tricuspid valve surgery. A mediation model was developed to assess the association of TR with 30-day mortality via other risk factors. Generalized mixed models were used to model the course of post-LVAD TR. Joint models were used to perform sensitivity analyses., Results: A total of 2496 procedures were included (median age: 56 years; men: 83%). TR was not directly associated with higher 30-day mortality, but mediation analyses suggested an indirect association via preoperative elevated right atrial pressure and creatinine (P = 0.035) and bilirubin (P = 0.027) levels. Post-LVAD TR was also associated with increased late mortality [hazard ratio 1.16 (1.06-1.3); P = 0.001]. On average, uncorrected TR diminished after LVAD implantation. The probability of having moderate-to-severe TR immediately after an implant in patients with none-to-mild TR pre-LVAD was 10%; in patients with moderate-to-severe TR pre-LVAD, it was 35% and continued to decrease in patients with moderate-to-severe TR pre-LVAD, regardless of pre-LVAD right ventricular failure or pulmonary hypertension., Conclusions: Uncorrected TR pre-LVAD and post-LVAD is associated with increased early and late mortality. Nevertheless, on average, TR diminishes progressively without intervention after an LVAD implant. Therefore, these data suggest that patient selection for concomitant tricuspid valve surgery should not be based solely on TR grade., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Aims: To evaluate long-term safety and efficacy of ticagrelor monotherapy in patients undergoing percutaneous coronary interventions (PCIs) in relation to chronic obstructive pulmonary disease (COPD) at baseline and the occurrence of dyspnoea reported as adverse event (AE) that may lead to treatment non-adherence., Methods and Results: This is a non-prespecified, post hoc analysis of the randomized GLOBAL LEADERS trial (n = 15 991), comparing the experimental strategy of 23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy (DAPT) after PCI with the reference strategy of 12-month DAPT followed by 12-month aspirin monotherapy. Impact of COPD and dyspnoea AE (as a time-dependent covariate) on clinical outcomes was evaluated up to 2 years. The primary endpoint was a 2-year all-cause mortality or non-fatal, centrally adjudicated, new Q-wave myocardial infarction. The presence of COPD (n = 832) was the strongest clinical predictor of 2-year all-cause mortality after PCI [hazard ratio (HR) 2.84; 95% confidence interval (CI) 2.21-3.66; P adjusted = 0.001] in this cohort (n = 15 991). No differential treatment effects on 2-year clinical outcomes were found in patients with and without COPD (primary endpoint: HR 0.88; 95% CI 0.58-1.35; P = 0.562; P int = 0.952). Overall, at 2 years dyspnoea was reported as an AE in 2101 patients, more frequently among COPD patients, irrespective of treatment allocation (27.2% in experimental arm vs. 14.5% in reference arm, P = 0.001). Its occurrence was not associated with a higher rate of the primary endpoint (P adjusted = 0.640) in the experimental vs. the reference arm., Conclusion: In this exploratory analysis, COPD negatively impacted long-term prognosis after PCI. Despite higher incidence of dyspnoea in the experimental arm, in particular among COPD patients, the safety of the experimental treatment strategy appeared not to be affected., Clinical Trial Registration Unique Identifier: NCT01813435., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: It remains unknown whether the treatment of hypertension influences the mortality of patients diagnosed with coronavirus disease 2019 (COVID-19)., Methods and Results: This is a retrospective observational study of all patients admitted with COVID-19 to Huo Shen Shan Hospital. The hospital was dedicated solely to the treatment of COVID-19 in Wuhan, China. Hypertension and the treatments were stratified according to the medical history or medications administrated prior to the infection. Among 2877 hospitalized patients, 29.5% (850/2877) had a history of hypertension. After adjustment for confounders, patients with hypertension had a two-fold increase in the relative risk of mortality as compared with patients without hypertension [4.0% vs. 1.1%, adjusted hazard ratio (HR) 2.12, 95% confidence interval (CI) 1.17-3.82, P = 0.013]. Patients with a history of hypertension but without antihypertensive treatment (n = 140) were associated with a significantly higher risk of mortality compared with those with antihypertensive treatments (n = 730) (7.9% vs. 3.2%, adjusted HR 2.17, 95% CI 1.03-4.57, P = 0.041). The mortality rates were similar between the renin-angiotensin-aldosterone system (RAAS) inhibitor (4/183) and non-RAAS inhibitor (19/527) cohorts (2.2% vs. 3.6%, adjusted HR 0.85, 95% CI 0.28-2.58, P = 0.774). However, in a study-level meta-analysis of four studies, the result showed that patients with RAAS inhibitor use tend to have a lower risk of mortality (relative risk 0.65, 95% CI 0.45-0.94, P = 0.20)., Conclusion: While hypertension and the discontinuation of antihypertensive treatment are suspected to be related to increased risk of mortality, in this retrospective observational analysis, we did not detect any harm of RAAS inhibitors in patients infected with COVID-19. However, the results should be considered as exploratory and interpreted cautiously., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Tricuspid regurgitation (TR) is a frequent and complex problem, commonly combined with left-sided heart disease, such as mitral regurgitation. Significant TR is associated with increased mortality if left untreated or recurrent after therapy. Tricuspid regurgitation was historically often disregarded and remained undertreated. Surgery is currently the only Class I Guideline recommended therapy for TR, in the form of annuloplasty, leaflet repair, or valve replacement. As growing experience of transcatheter therapy in structural heart disease, many dedicated transcatheter tricuspid repair or replacement devices, which mimic well-established surgical techniques, are currently under development. Nevertheless, many aspects of TR are little understood, including the disease process, surgical or interventional risk stratification, and predictors of successful therapy. The optimal treatment timing and the choice of proper surgical or interventional technique for significant TR remain to be elucidated. In this context, we aim to highlight the current evidence, underline major controversial issues in this field and present a future roadmap for TR therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: We evaluated the impact of preoperative liver function on early and 1-year postoperative outcomes in patients supported with a left ventricular assist device (LVAD) and subsequent evolution of liver function markers., Methods: A retrospective multicentre cohort study was conducted, including all patients undergoing continuous-flow LVAD implantation. The Model for End-stage Liver Disease (MELD) score was used to define liver dysfunction., Results: Overall, 290 patients with an LVAD [78% HeartMate II, 15% HVAD and 7% HeartMate 3, mean age 55 (18), 76% men] were included. Over 40 000 measurements of liver function markers were collected over a 1-year period. A receiver operating characteristic curve analysis for the 1-year mortality rate identified the optimal cut-off value of 12.6 for the MELD score. Therefore, the cohort was dichotomized into patients with an MELD score of less than or greater than 12.6. The early (90-day) survival rates in patients with and without liver dysfunction were 76% and 91% (P = 0.002) and 65% and 90% at 1 year, respectively (P < 0.001). Furthermore, patients with preoperative liver dysfunction had more embolic events and more re-explorations. At the 1-year follow-up, liver function markers showed an overall improvement in the majority of patients, with or without pre-LVAD liver dysfunction., Conclusions: Preoperative liver dysfunction is associated with higher early 90-day and 1-year mortality rates after LVAD implantation. Furthermore, liver function improved in both patient groups. It has become imperative to optimize the selection criteria for possible LVAD candidates, since those who survive the first year show excellent recovery of their liver markers., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Tricuspid regurgitation (TR) is common in patients receiving a left ventricular assist device (LVAD). Controversy exists as to whether concomitant tricuspid valve surgery (TVS) is beneficial in currently treated patients. Therefore, our goal was to investigate the effect of TVS concomitant with a LVAD implant., Methods: The European Registry for Patients with Mechanical Circulatory Support was used to identify adult patients. Matched patients with and without concomitant TVS were compared using a propensity score matching strategy., Results: In total, 3323 patients underwent LVAD implantation of which 299 (9%) had TVS. After matching, 258 patients without TVS were matched to 258 patients with TVS. In the matched population, hospital deaths, days on inotropic support, temporary right ventricular assist device implants and hospital stay were comparable, whereas stay in the intensive care unit was higher in the TVS cohort (11 vs 15 days; P = 0.026). Late deaths (P = 0.17), cumulative incidence of unexpected hospital readmission (P = 0.15) and right heart failure (P = 0.55) were comparable between patients with and without concomitant TVS. In the matched population, probability of moderate-to-severe TR immediately after surgery was lower in patients with concomitant TVS compared to patients without TVS (33% vs 70%; P = 0.001). Nevertheless, the probability of moderate-to-severe TR decreased more quickly in patients without TVS (P = 0.030), resulting in comparable probabilities of moderate-to-severe TR within 1.5 years of follow-up., Conclusions: In matched patients, TVS concomitant with LVAD implant does not seem to be associated with better clinical outcomes. Concomitant TVS reduced TR significantly early after LVAD implant; however, differences in probability of TR disappeared during the follow-up period., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Aims: To evaluate the impact of an experimental strategy [23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy (DAPT)] vs. a reference regimen (12-month aspirin monotherapy following 12-month DAPT) after complex percutaneous coronary intervention (PCI)., Methods and Results: In the present post hoc analysis of the Global Leaders trial, the primary endpoint [composite of all-cause death or new Q-wave myocardial infarction (MI)] at 2 years was assessed in patients with complex PCI, which includes at least one of the following characteristics: multivessel PCI, ≥3 stents implanted, ≥3 lesions treated, bifurcation PCI with ≥2 stents, or total stent length >60 mm. In addition, patient-oriented composite endpoint (POCE) (composite of all-cause death, any stroke, any MI, or any revascularization) and net adverse clinical events (NACE) [composite of POCE or Bleeding Academic Research Consortium (BARC) Type 3 or 5 bleeding] were explored. Among 15 450 patients included in this analysis, 4570 who underwent complex PCI had a higher risk of ischaemic and bleeding events. In patients with complex PCI, the experimental strategy significantly reduced risks of the primary endpoint [hazard ratio (HR): 0.64, 95% confidence interval (CI): 0.48-0.85] and POCE (HR: 0.80, 95% CI: 0.69-0.93), but not in those with non-complex PCI (Pinteraction = 0.015 and 0.017, respectively). The risk of BARC Type 3 or 5 bleeding was comparable (HR: 0.97, 95% CI: 0.67-1.40), resulting in a significant risk reduction in NACE (HR: 0.80, 95% CI: 0.69-0.92; Pinteraction = 0.011)., Conclusion: Ticagrelor monotherapy following 1-month DAPT could provide a net clinical benefit for patients with complex PCI. However, in view of the overall neutral results of the trial, these findings of a post hoc analysis should be considered as hypothesis generating., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: Moderate-to-severe tricuspid regurgitation is common in end-stage heart disease and is associated with an impaired survival after left ventricular assist device (LVAD) surgery. Controversy remains whether concomitant tricuspid valve surgery (TVS) during LVAD implantation is beneficial. We aimed to provide a contemporary overview of outcomes in patients who underwent LVAD surgery with or without concomitant TVS., Methods: A systematic literature search was performed for articles published between January 2005 and March 2017. Studies comparing patients undergoing isolated LVAD implantation and LVAD + TVS were included. Early outcomes were pooled in risk ratios using random effects models, and late survival was visualized by a pooled Kaplan-Meier curve., Results: Eight publications were included in the meta-analysis, including 562 undergoing isolated LVAD implantation and 303 patients with LVAD + TVS. Patients undergoing LVAD + TVS had a higher tricuspid regurgitation grade, central venous pressure and bilirubin levels at baseline and were more often female. We found no significant differences in early mortality and late mortality, early right ventricular failure and late right ventricular failure, acute kidney failure, early right ventricular assist device implantation or length of hospital stay. Cardiopulmonary bypass time was longer in patients undergoing additional TVS [mean difference +35 min 95% confidence interval (16-55), P = 0.001]., Conclusions: Adding TVS during LVAD implantation is not associated with worse outcome. Adding TVS, nevertheless, may be beneficial, as baseline characteristics of patients undergoing LVAD + TVS were suggestive of a more progressive underlying disease, but with comparable short-term outcome and long-term outcome with patients undergoing isolated LVAD.

Aims: Patients with a left ventricular assist device (LVAD) are challenging to evaluate using conventional imaging techniques, such as standard echocardiography (SE). The aim of this pilot study was to evaluate the potential of contrast echocardiography (CE) for the evaluation of the left ventricle (LV)., Methods and Results: This prospective study included 14 ambulatory patients (mean age 58 ± 9 years, 79% male) with a LVAD (all HeartMate 3, Abbott Laboratories, Chicago, IL, USA). Nine (64%) patients had an ischaemic cardiomyopathy, and 5 (36%) had a non-ischaemic cardiomyopathy. All patients underwent SE and CE using intravenous administration of Sonovue contrast agent (Bracco, Milan, Italy). The echocardiograms were assessed by three observers, using a standard 17-segment model of the LV. Left ventricular end-diastolic volume (LVEDV) was assessed using the biplane Simpson method. The contrast agent was well tolerated by all patients, without any side effects. Overall, SE allowed visualization of 57% of LV segments (135/238) and CE allowed visualization of 79% of LV segments (187/238), P < 0.001. Per patient, SE resulted in visualization of 9.6 ± 5.2 segments and CE was able to visualize 13.4 ± 5.8 segments (P < 0.001). Administration of contrast agent significantly improved the assessment of LVEDV (feasibility SE: 36% vs. CE: 79%, P < 0.05)., Conclusion: Routine use of a contrast agent appears safe when used in patients having a new third generation LVAD and may enhance the diagnostic accuracy of transthoracic echocardiography in these patients. LV size determination can be obtained more often due to improved LV visualization using contrast agent.

Aims: The Lotus and SAPIEN3 are second-generation transcatheter heart valves, which are designed to minimize paravalvular aortic regurgitation (PAR) after transcatheter aortic valve replacement (TAVR). We sought to compare both devices for valve performance and with emphasis on PAR by independent core laboratory analysis., Methods and Results: A total of 162 (79 Lotus and 83 SAPIEN3) consecutive patients (51% female, 80 ± 8 years, Logistic EuroSCORE 14.8 ± 9.4%) who underwent TAVR because of aortic stenosis were included. Patients with aortic valve-in-valve treatment were excluded. Pre-discharge echocardiograms were analysed by an independent core laboratory using the Valve Academic Research Consortium 2 criteria. There were no differences in baseline and procedural characteristics, except for a larger aortic annulus and sizing indices in SAPIEN3-treated patients and frequency of post-dilatation (0% in Lotus and 13.1% in SAPIEN3). Both valves have similar mean residual gradient, indexed effective orifice area and Doppler velocity index when adjusted to valve size. The frequency of mild (13.9% vs. 31.3%) and at least moderate (1.3% vs. 3.6%) PAR was less after Lotus than after SAPIEN3 implantation (P = 0.02). Multi-slice computed tomography-based annulus and left ventricular outflow tract diameters, calcification and percentage of oversizing were not different between those with or without mild or more PAR. On multivariate analysis, the use of Lotus valve was associated with less (odds ratio OR, 0.41, P = 0.03) occurrence of PAR., Conclusion: Overall, haemodynamic performance was comparable between the Lotus and SAPIEN3 valves. Lotus valve required less oversizing and was associated with less PAR than SAPIEN3., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.)

Aims: The aim of this prospective study was to evaluate the feasibility and establish normal values of functional right ventricle (RV) parameters as assessed in our four, long-axis view RV model using iRotate echocardiography. Furthermore, we evaluated the potential use of this model in patients with abnormally loaded RVs., Method and Results: One hundred and fifty-five healthy subjects aged 20-72 years (≥28 subjects per decile) were prospectively recruited. We used non-dedicated RV speckle-tracking software to test the feasibility and to establish normal range values of peak systolic global longitudinal RV strain (RV-GLS) from the RV free-walls (septum was excluded). Also normal range values for: dimensions, tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (TDI-S') were established. The feasibility of RV-GLS was 88, 84, and 62%, respectively, in the lateral, inferior, and anterior free wall. Mean RV-GLS normal values were -24.5 ± 4.9% for lateral wall and -25.4 ± 5.0% for anterior wall. Mean RV-GLS in the inferior wall was -23.2 ± 4.4% in the aortic (Ao) view and -20.7 ± 5.0% in the coronal (CV) view. The feasibility of mean RV-GLS was 100% in the anterior, lateral, and inferior walls in abnormally dilated RVs., Conclusion: The feasibility of all RV parameters assessed in the four-view iRotate model is good to excellent. Normal values for RV dimension and function of the anterior, inferior, and lateral RV walls have been established. Further studies and dedicated RV speckle-tracking software are warranted to discover the full potential of this new technique., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)

Aims: Paravalvular aortic leakage (PVL) after transcatheter aortic valve implantation (TAVI) is a complication with potentially severe consequences. The relation between native aortic root calcium burden, stent frame eccentricity and PVL was not studied before., Methods and Results: Two-hundred-and-twenty-three consecutive patients with severe aortic stenosis who underwent TAVI with a Medtronic CoreValve System© and who had available pre-discharge transthoracic echocardiography were studied. Echocardiographic stent inflow frame eccentricity was defined as major-minor diameter in a short-axis view >2 mm. PVL was scored according to the updated Valve Academic Research Consortium (VARC-2) recommendations. In a subgroup of 162 (73%) patients, the calcium Agatston score was available. Stent frame eccentricity was seen in 77 (35%) of patients. The correlation between the Agatston score and stent frame eccentricity was significant (ρ = 0.241, P = 0.003). Paravalvular leakage was absent in 91 cases (41%), mild in 67 (30%), moderate in 51 (23%), and severe in 14 (6%) cases. The correlation between stent frame eccentricity and PVL severity was significant (ρ = 0.525, P < 0.0001). There was a relation between particular eccentric stent frame shapes and the site of PVL., Conclusion: Calcification of the aortic annulus is associated with a subsequent eccentric shape of the CoreValve prosthesis. This eccentric shape results in more PVL, with the localization of PVL related to the shape of stent frame eccentricity., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aims: Transcatheter mitral valve replacement (TMVR) provides definitive valve replacement through a minimally invasive procedure. In the setting of TMVR, it remains unclear how relevant the differences between different mitral annular (MA) diameters are. We sought to define a simplified and reproducible method to describe the MA size., Methods and Results: Using cardiac computed tomography angiography (CTA) studies of 47 patients, 3D MA perimeter (P3D) was annotated. The aorto-mitral continuity was excluded from MA contour either by manual annotation (yielding a saddle-shape model) or by simple truncation at the medial and lateral trigones (yielding a D-shape model). The method of the least squares was used to generate the projected MA area (Aproj) and perimeter (Pproj). Intercommissural (IC) and septolateral (SL) diameters, Dmean = (IC diameter + SL diameter)/2, area-derived diameter (DArea = 2 x √(A/π)) and perimeter-derived diameter (DPerimeter = P/π) were measured. MA eccentricity, height, and calcification (MAC) were assessed. Thirty studies were re-read by the same and by another observer to test intra- and inter-observer reproducibility. Patients (age, 75 ± 12 years, 66% males) had a wide range of mitral regurgitation severity (none-trace in 8%, mild in 55%, moderate-severe in 37%), MA size (area: 5-16 cm2), eccentricity (-8-52%), and height (3-11 mm). MAC was seen in 11 cases, in whom MAC arc occupied 26 ± 20% of the MA circumference. DArea (36.0 ± 4.0 mm) and DPerimeter (37.1 ± 3.8 mm) correlated strongly (R2 = 0.97) and were not significantly different (P = 0.15). The IC (39.3 ± 4.6 mm) and the SL (31.4 ± 4.5 mm) diameters were significantly different from DArea (P < 0.001) while Dmean (35.4 ± 4.0 mm) was not (P = 0.5). The correlation of DArea was stronger with Dmean (R2 = 0.96) than with IC and SL diameters (R2 = 0.69 and 0.76, respectively). The average difference between DArea and Dmean was +0.6 mm and the 95% limits of agreement were 2.1 and -0.9 mm. Similar results were found when the D-shape model was applied. All MA diameters showed good reproducibility with high intraclass correlation coefficient (0.93-0.98), small average bias (0.37-1.1 mm), and low coefficient of variation (3-7%) for intra- and inter-observer comparisons. Reproducibility of DArea was lower in patients with MAC., Conclusion: MA sizing by CTA is readily feasible and reproducible. Dmean is a simple index that can be used to infer the effective MA size., (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 echocardiographic focus to detect abnormalities in genetically hypertrophic cardiomyopathy (HCM) affected subjects without left ventricular (LV) hypertrophy (G+/LVH-) has been on diastolic abnormalities in transmitral flow and longitudinal myocardial function with tissue Doppler imaging. The aim of this study was to assess diastolic LV unstrain and untwist., Methods and Results: Forty-one consecutive genotyped family members of HCM patients (mean age 37 ± 11 years, 16 men) and 41 age- and gender-matched healthy volunteers underwent speckle-tracking echocardiography to measure untwist and unstrain. No significant differences between G+/LVH- and control subjects were seen in maximal systolic twist and global longitudinal strain. In diastole, the early peak untwist rate was significantly lower in G+/LVH- subjects compared with control subjects (62 ± 19°s - 1 vs. 76 ± 30°s - 1, P <0.05), whereas the late peak untwist rate tended to be higher. Untwist from maximal twist until the first 20% of diastole was delayed in G+/LVH- subjects (39.3 ± 12.9% vs. 51.3 ± 15.6%, P <0.005). Late diastolic unstrain rate was significantly higher in G+/LVH- subjects in the inferoseptal wall (111 ± 33 s - 1 vs. 94 ± 32 s - 1, P = 0.024), the inferolateral wall (105 ± 42 vs. 75 ± 35 s - 1, P = 0.007) and the anteroseptal wall (97 ± 26 vs. 80 ± 23 s - 1, P = 0.010). Unstrain from maximal twist until the first 20% of diastole was delayed in G+/LVH- subjects in the inferoseptal (18.9 ± 14.0% vs. 30.1 ± 17.7%, P = 0.005), inferolateral (27.1 ± 16.3% vs. 39.2 ± 18.0%, P = 0.015) and anteroseptal (19.1 ± 14.7% vs. 35.8 ± 18.5%, P = 0.0003) segments., Conclusions: In mutation carriers, for HCM LV, untwist and unstrain are delayed and untwist rate and unstrain rate are decreased., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)

The increasing interest in left atrial appendage occlusion (LAAO) for ischaemic stroke prevention in atrial fibrillation (AF) fuels the need for more clinical data on the safety and effectiveness of this therapy. Besides an assessment of the effectiveness of the therapy in specific patients groups, comparisons with pharmacological stroke prophylaxis, surgical approaches, and other device-based therapies are warranted. This paper documents the consensus reached among clinical experts in relevant disciplines from Europe and North America, European cardiology professional societies, and representatives from the medical device industry regarding definitions for parameters and endpoints to be assessed in clinical studies. Adherence to these definitions is proposed in order to achieve a consistent approach across clinical studies on LAAO among the involved stakeholders and various clinical disciplines and thereby facilitate continued evaluation of therapeutic strategies available., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Paravalvular leakage (PVL) is an important complication of transcatheter aortic valve implantation (TAVI). It contributed to the erosion of the clinical benefits of TAVI and confidence of its adoption as a default therapy in low surgical-risk patients. Newer TAVI technologies are provided with effective paravalvular sealing as well as retrieval/reposition mechanisms that are believed to considerably lower the risk of PVL. Meanwhile, developments in timely detection and accurate quantitation of PVL remain lagging behind those technological advances. The Valve Academic Research Consortium-standardized criteria of PVL assessment are based on echocardiography and are, according to experts' opinion, not adequately validated. Peri-procedural diagnosis, based on angiographic, haemodynamic, and/or echocardiographic methods, is so far without standardization of acquisition or interpretation. The aim of this report is to review the strengths and limitations of the current technologies used for PVL adjudication. Understanding this strengths/limitations ratio is important to define an appropriate scheme for detection and quantitation of PVLs both in clinical trials and in routine clinical practice., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: Aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) is often first diagnosed by angiography and then confirmed and followed-up by transthoracic echocardiography (TTE). Consistency between both methods is important for follow-up. We sought to determine inter-technique reproducibility of the assessment of paravalvular AR after TAVI., Methods and Results: The study included 165 patients treated with a self-expanding bioprosthesis and had angiography and TTE performed at a median interval of 4 days. TTE parameters of AR severity included VARC score (the average AR grade determined by the echocardiographic VARC-II criteria), pressure half time (PHT), regurgitation jet features in long-axis views (LAX score) and colour Doppler (CD) score (=paravalvular AR jet circumferential extent (%) + LAX score). Using receiver-operating characteristics curves, the cut-points that best defined an angiographic >mild AR were identified.On TTE, AR was paravalvular in all cases, multi-jet in 28%, and predominantly (64%) detected in the commissural region between the right and left coronary sinuses. Using VARC-II criteria (combining at least two), TTE agreed with angiographic classification in 53% of cases (k = 0.14). Greater than mild AR could better be defined by one of the following combinations of criteria: (i) LAX score >4.25 and VARC-II score >1.33; (ii) CD score >11.5 and PHT <400 ms. The combination of the CD score with PHT gave the best sum of sensitivity, specificity, positive, and negative predictive values., Conclusions: Agreement between angiography and TTE (using the VARC-II criteria) in the grading of post-TAVI AR is modest, and this might have contributed to the inconsistency of data on the rate and fate of paravalvular AR. Inter-technique reproducibility can be improved using a combination of CD and hemodynamic parameters., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Aims: This study sought to investigate regional left ventricular (LV) rotation in patients with hypertrophic cardiomyopathy (HCM)., Methods and Results: The study comprised 44 patients with HCM with a typical reverse septal curvature (age 40 ± 14 years, 33 men) and 44 healthy volunteers (age 39 ± 14 years, 32 men) in whom LV rotation could be assessed at the basal and apical LV level with speckle-tracking echocardiography, using the QLAB Advanced Quantification Software version 6.0 (Philips, Best, The Netherlands). In HCM patients, lower values of initial counter-clockwise rotation at the basal LV level (1.5 ± 1.2 vs. 0.6 ± 0.9°, P < 0.001) were seen, in particular in the septal segment (1.7 ± 1.6 vs. 0.4 ± 0.7°, P < 0.001). After this period, the direction of rotation changed to clockwise with a peak basal rotation of -4.8 ± 2.0° in controls vs. -6.1 ± 2.5° in HCM patients (P < 0.05). Peak basal rotation in HCM patients was in particular higher in the anterior (-6.6 ± 3.0 vs. -4.4 ± 2.4°, P < 0.01) and septal (-5.4 ± 2.6 vs. -3.9 ± 1.9°, P < 0.05) segments. The normalized (corrected for peak basal rotation) global back-rotation rate was lower in HCM patients (4.1 ± 3.1 vs. 6.3 ± 4.9 s(-1), P < 0.05), in particular driven by a lower rate in the septal segment (3.8 ± 2.6 vs. 6.4 ± 4.8 s(-1), P < 0.01). At the apical level, changes in rotation and back-rotation were more homogeneous., Conclusion: Changes in rotation and back-rotation at the LV basal level in HCM patients are mainly caused by regional changes in the basal septal and anterior segments, the segments mostly involved in the hypertrophic process.

Aims: Comorbidity, such as myocardial infarction, diabetes, and renal failure, plays a pivotal role in the prognosis of a patient with arrhythmias. However, data on the prognostic impact of comorbiditiy in heart failure patients with cardiac resynchronization therapy and defibrillation (CRT-D) are scarce. The purpose of this study was to determine the impact of comorbidity on survival in CRT-D patients., Methods and Results: The study population consisted of 463 heart failure patients who received a CRT-D between 1999 and 2008 in Rotterdam and Basel. The Charlson comorbidity index (CCI) is often used as an adjusting variable in prognostic models. The Cox proportional hazards analysis was performed to determine the independent effect of comorbidity on survival. During a median follow-up of 30.5 months, 85 patients died. Mortality rates at 1 and 7 years were 6.3 and 32.3%. Cumulative incidence of implantable cardioverter defibrillator (ICD) therapy at 7 years was 50%, and death without ICD therapy was observed in 9% of patients. At least three comorbid conditions were observed in 81% of patients. Patients who died had a higher CCI score compared with those who survived (3.9 ± 1.5 vs. 2.9 ± 1.5; P < 0.001). An age-adjusted CCI score ≥ 5 was a predictor of mortality (hazard ratio 3.69, 95% CI 2.06-6.60; P < 0.001) independent from indication for ICD therapy, and from ICD interventions during the clinical course., Conclusion: Comorbidity is often present in heart failure patients, and a high comorbidity burden was a significant predictor of mortality in CRT-D recipients. Comorbidity cannot predict appropriate ICD therapy. Death without prior ICD therapy occurs in a minor proportion of patients.

Aims: To investigate the outcome of cardiac evaluation and the risk stratification for sudden cardiac death (SCD) in asymptomatic hypertrophic cardiomyopathy (HCM) mutation carriers., Methods and Results: Seventy-six HCM mutation carriers from 32 families identified by predictive DNA testing underwent cardiac evaluation including history, examination, electrocardiography, Doppler echocardiography, exercise testing, and 24 h Holter monitoring. The published diagnostic criteria for HCM in adult members of affected families were used to diagnose HCM. Thirty-three (43%) men and 43 (57%) women with a mean age of 42 years (range 16-79) were examined; in 31 (41%) HCM was diagnosed. Disease penetrance was age related and men were more often affected than women (P = 0.04). Myosin Binding Protein C (MYBPC3) mutation carriers were affected at higher age than Myosin Heavy Chain (MYH7) mutation carriers (P = 0.01). Risk factors for SCD were present in affected and unaffected carriers., Conclusion: Hypertrophic cardiomyopathy was diagnosed in 41% of carriers. Disease penetrance was age dependent, warranting repeated cardiologic evaluation. The MYBPC3 mutation carriers were affected at higher age than MYH7 mutation carriers. Risk factors for SCD were present in carriers with and without HCM. Follow-up studies are necessary to evaluate the effectiveness of risk stratification for SCD in this population.

Aims: This study sought to find the most robust method for left ventricular (LV) rotation measurement by speckle tracking echocardiography (STE) with the new QLAB Advanced Quantification Software (version 6.0, Philips, Best, The Netherlands)., Methods and Results: The study population consisted of 40 non-selected patients (mean age 48 +/- 18 year, 20 men) and 50 non-selected healthy volunteers (mean age 34 +/- 12 year, 21 men). Feasibility and intra-observer reproducibility of the measurement of LV rotation parameters by STE were assessed for two different methods (Method A: six tracking points placed mid-myocardial and Method B: six tracking points placed endocardial and epicardial forming six myocardial segments). Subsequently, inter-observer and temporal reproducibility of the most robust method were assessed. Complete LV rotation assessment was more feasible with Method A (60 out of 90 subjects, 67% vs. 50 out of 90 subjects, 56%). In the 49 subjects in whom both Methods A and B were feasible, intra-observer reproducibility of LV rotation parameters was better with Method A (variabilities 2 +/- 3 to 10 +/- 9% vs. 2 +/- 4 to 21 +/- 18%). With this method, inter-observer variability varied from 4 +/- 4 to 13 +/- 9% and temporal variability from 4 +/- 6 to 19 +/- 15%., Conclusion: The most robust method to assess LV rotation with QLAB software is from the mid-myocardium. This method is feasible in approximately two-thirds of subjects and has good intra-observer, inter-observer, and temporal reproducibility, allowing to study changes over time in LV rotation in an individual patient.

Non-compaction of the ventricular myocardium is a recently recognized rare disorder of the endomyocardial morphogenesis. The disease can be characterized by systolic and diastolic heart failure, ventricular arrhythmias and systemic embolization. The present case suggests the clinical role of real-time three-dimensional echocardiography in the spatial evaluation of both ventricles in suspected biventricular non-compaction cardiomyopathy.

Aims: Real-time three-dimensional echocardiography (RT3DE) allows quick volumetric scanning of the left ventricle (LV). We evaluated the diagnostic accuracy of contrast-enhanced stress RT3DE for the detection of coronary artery disease (CAD) in comparison with coronary arteriography as the reference technique., Methods and Results: Forty-five consecutive patients (age 59 +/- 10, 31 males) referred for coronary angiography were examined by contrast-enhanced RT3DE. Wall motion analysis was performed off-line by dedicated software. New or worsening wall motion abnormalities were detected in 17 of 28 patients with significant CAD (sensitivity 61%), and in two of 17 patients without significant CAD (specificity 88%). The sensitivity for detection of single-vessel CAD was 8/15 patients (53%), for two-vessel CAD 4/6 (67%), and for three-vessel CAD 5/7 (71%). In 35 patients, comparison with conventional RT3DE was available. The image quality index at rest improved from 2.5 +/- 1.2 to 3.2 +/- 1.0 (P < 0.001) with contrast and at peak stress from 2.3 +/- 1.2 to 3.1 +/- 1.0 (P < 0.001). Interobserver agreement on the diagnosis of myocardial ischaemia improved from 26 of 35 studies (74%, kappa = 0.44) with conventional stress RT3DE to 30 of 35 studies (86%, kappa = 0.69) with contrast-enhanced stress RT3DE. Sensitivity increased from 50 to 55% and specificity from 69 to 85% with contrast-enhanced stress RT3DE in this subset of patients., Conclusion: Despite some important practical and theoretical benefits, contrast-enhanced stress RT3DE currently has only moderate diagnostic sensitivity due to several technical limitations as temporal and spatial resolution.

Aims: Studies reporting improved left ventricular (LV) function of percutaneous skeletal myoblast (SkM) injection in patients with ischaemic cardiomyopathy had follow-up not exceeding 12 months, and did not include a control group. Our group has reported evidence for myoblast efficacy in the first five out of the 14 treated patients. The objective of the present evaluation was to assess if these effects were sustained at long-term follow-up. We compared function of patients treated with SkM 4 years earlier with a matched control group. Secondary endpoints included mortality, NYHA class, N-terminal pro-B-natriuretic peptide levels, incidence of arrhythmias, and quality of life., Methods and Results: Fourteen patients with ischaemic cardiomyopathy who underwent SkM injection were compared with 28 non-randomized control patients matched for age, sex, location, and extent of myocardial infarction. Contrast echocardiography and tissue Doppler imaging (TDI) was performed to compare global and regional LV function. At 4-year follow-up, three patients (21%) had died in the treated group and 11 patients (39%) in the control group (P = 0.8). In the survivors, LV ejection fraction (EF) was 35 +/- 10% and 37 +/- 9% in the SkM group and 36 +/- 8% and 36 +/- 6% in the controls at baseline and 4 years follow-up, respectively (P = 0.96 between groups at follow-up). TDI-derived systolic velocity in the injected sites was 5.4 +/- 1.8 cm/s in the SkM group when compared with 5.1 +/- 1.6 cm/s in corresponding sites in the control group (P = 0.47). None of the secondary endpoints showed a difference between the groups. However, in the patients fitted with an internal cardioverter defibrillator, more arrhythmias leading to interventions occurred in the treated group than in the control group, 87% and 13%, respectively (P = 0.015)., Conclusion: Percutaneous intramyocardial SkM injection in ischaemic cardiomyopathy has no sustained positive effect on resting global or regional LV function, respectively, at 4-year follow-up. Moreover, the procedure may induce a higher risk of developing serious arrhythmias, but larger patient series are required before more precise characterization of the safety and efficacy profile of the procedure is possible.

Recently, debate has erupted about the clinical significance of cardiovascular shunts. Several major health problems such as stroke and migraine have been associated with patent foramen ovale (PFO) with right-to-left shunt (RLS). The nature of the relationship between these syndromes and PFO is not clearly understood. Technical advances have led to more therapeutic options including device closure of PFO, hence prevention of such a PFO-related stroke has become feasible. Therefore, optimal diagnosis of PFO has become of greater clinical importance. Contrast echocardiography with non-transpulmonary contrast agents has been the cornerstone in diagnosis of PFO with RLS for over four decades. Despite being a relatively invasive procedure, transesophageal echocardiography (TEE) is considered the gold standard for detection of RLS. Several other echocardiographic techniques such as transthoracic echocardiography (TTE) with second harmonic imaging and transcranial Doppler ultrasonography (TCD) have shown increased sensitivity and specificity compared to TEE for the detection of PFO with RLS. Moreover, improvement of skills and techniques used for detection of these shunts has led to greater detection of small and large sized RLS in the echocardiographic laboratory. This review gives and overview of the echocardiographic techniques, contrast agents and manoeuvres used for detection of the major cardiovascular shunts and their clinical relevance to major health problems.

Aortic stiffness is an important predictor of cardiovascular morbidity and mortality. Non-invasive measurement of aortic stiffness is a promising challenge for echocardiography. The most important limitation of previous studies was that regional differences for aortic stiffness were not taken into consideration. In our patient, we demonstrated the usefulness of real-time three-dimensional echocardiography in assessment of regional aortic stiffness.

Aims: The current study sought to assess if pre-implantation lateral-to-septal delay (LSD) > or =60 ms assessed by spectral pulsed-wave myocardial tissue Doppler imaging (PW-TDI) could predict successful long-term outcome after cardiac resynchronization therapy (CRT)., Methods and Results: Sixty patients (72% males, mean age 59 +/- 10 years) who were referred for CRT according to the ACC/ESC guidelines were enrolled in the study. All patients underwent spectral PW-TDI before and 1 year after CRT. Two left ventricular (LV) dyssynchrony time intervals, T(O) and T(P) (time to onset and peak of LV myocardial velocity, respectively), LSD were recorded. Left ventricular dyssynchrony was defined as LSD > or =60 ms. Clinical response was defined as an improvement in >1 NYHA class plus improvement in 6-min walk distance (6MWD) > or =25%, echocardiographic response was defined as a > or =15% reduction in LV end-systolic volume (LV-ESV). One year after CRT, 50 patients (83%) were clinical responders and 47 patients (78%) were echocardiographic responders. Both T(O) and T(P) LV dyssynchrony indices failed to predict echocardiographic CRT outcome. In addition, there were no significant differences between 'synchronous' and 'dyssynchronous' patient populations at baseline or follow-up in either clinical (NYHA class and 6MWD) or echocardiographic (LV ejection fraction, LV end-diastolic, and end-systolic) variables., Conclusion: The great majority of patients referred for CRT benefit clinically from it. However, spectral PW-TDI failed to predict CRT outcome. When PW-TDI dyssynchrony was applied for selection of proper CRT patients, up to 80-86% of the patients with synchronous LSD that had proven clinical and echocardiographic benefit from CRT would have been denied CRT.